Review ArticleCoevolution of Mucosal Immunoglobulins andthe Polymeric Immunoglobulin Receptor Evidence Thatthe Commensal Microbiota Provided the Driving Force

Charlotte S Kaetzel

Department of Microbiology Immunology and Molecular Genetics University of Kentucky College of Medicine203 Combs Cancer Research Building 800 Rose Street Lexington KY 40536 USA

Correspondence should be addressed to Charlotte S Kaetzel cskaetukyedu

Received 25 November 2013 Accepted 29 December 2013 Published 4 March 2014

Academic Editors M C Bene and J L Stafford

Copyright copy 2014 Charlotte S KaetzelThis is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Immunoglobulins (Igs) inmucosal secretions contribute to immune homeostasis by limiting access ofmicrobial and environmentalantigens to the body proper maintaining the integrity of the epithelial barrier and shaping the composition of the commensalmicrobiota The emergence of IgM in cartilaginous fish represented the primordial mucosal Ig which is expressed in all highervertebrates Expansion and diversification of themucosal Ig repertoire led to the emergence of IgT in bony fishes IgX in amphibiansand IgA in reptiles birds and mammals Parallel evolution of cellular receptors for the constant (Fc) regions of Igs providedmechanisms for their transport and immune effector functionsThe most ancient of these Fc receptors is the polymeric Ig receptor(pIgR)which first appeared in an ancestor of bonyfishesThepIgR transports polymeric IgM IgT IgX and IgA across epithelial cellsinto external secretions Diversification and refinement of the structure of mucosal Igs during tetrapod evolution were paralleledby structural changes in pIgR culminating in the multifunctional secretory IgA complex in mammals In this paper evidence ispresented that the mutualistic relationship between the commensal microbiota and the vertebrate host provided the driving forcefor coevolution of mucosal Igs and pIgR

1 Introduction

Themucosal surfaces of the body form the primary interfacewith the outside world providing a conduit for intake ofnutrients and air and a home for beneficial microbes thatact as ldquoextended self rdquo [1] Host cells that populate mucosalsurfaces must carry out the challenging task of maintaininga mutualistic relationship with the resident microbiota whileprotecting the body proper against potential pathogens toxicenvironmental substances and soluble dietary antigens thatcould act as systemic allergens Adaptive immune systemscharacterized by clonally expressed somatically diversifiedantigen receptors in lymphocytes first emerged in a commonancestor of modern vertebrates [2 3] (Figure 1) Jawless fishof the superclass Agnatha (hagfishes and lampreys) generatevariable-like receptors (VLRs) for antigen (Ag) by a mecha-nism involving gene conversionThe evolution of the RAG12dependent mechanism of V(D)J somatic recombination in

an ancestor of modern jawed vertebrates led to the firstappearance of Ag-specific immunoglobulins (Igs) and T-cell antigen receptors [4 5] The basic structural unit of Igscomprises 2 identical light chains encoded by IGL genes and2 identical heavy chains encoded by IGH genes (Figure 2)The polypeptide chains of Ig light and heavy chains consistof repeating units of approximately 110 amino acids so-called ldquoIg-likerdquo domains with a characteristic 3-dimensionalstructure [6 7] Each domain is encoded by a single exonsuggesting that the IGL and IGH genes evolved by duplicationand diversification of a primordial Ig-like gene Ig light chainscomprise an N-terminal variable (VL) domain followed by aconstant (CL) domain of either the 120581or120582 type Ig heavy chainscomprise an N-terminal variable domain (VH) followed by3-4 constant domains (CH1ndashCH3 or 4) The sequence of Igheavy chain constant regions (designated by Greek letterssuch as 120572 120574 or 120583) defines the Ig class or isotype Pairing ofVH and VL domains on adjacent Ig heavy and light chains

Hindawi Publishing CorporationISRN ImmunologyVolume 2014 Article ID 541537 20 pageshttpdxdoiorg1011552014541537

2 ISRN Immunology

Vertebrata

Gnathostomata

Osteichthyes

Sarcopterygii

Tetrapoda

Amniota

Placentals

Marsupials

Monotremes

Birds

Crocodilians

Lizards and snakes

Turtles

Frogs

Salamanders

Lungfishes

Coelacanths

Cartilaginous fishes

Lampreys

HagfishesAgnathans

Amphibians

Reptiles

Mammals

IgM

IgT

IgX

IgD

IgD

IgD

IgD

IgY

IgY

IgY

VLR

IgE

IgM

IgGIgA

IgA

IgA

Ray-finned bony fishes

and birds

Lobe-finnedbony fishes IgM

IgM

IgM

IgM

IgM

IgM

IgWD

IgWD

IgWD

IgWD IgNAR

Figure 1 A model for evolution of immunoglobulin isotypes in vertebrates The antigen-binding variable lymphocyte receptors (VLRs)expressed in extant Agnathans are thought to represent the precursors of modern immunoglobulins (Igs) Genes encoding Ig heavy andlight chains apparently emerged prior to the split between cartilaginous and bony fishes resulting in expression of Ig molecules that arecharacteristic of higher vertebrates Cartilaginous fishes express an IgD-like molecule (IgWD) and IgM which is found evenly distributedbetween blood and mucosal secretionsThe first evidence of a dedicated mucosal Ig isotype came with the emergence of IgT in an ancestor ofmodern bony fishes Subsequent duplication of Ig constant region genes and evolution of Ig class switchingmechanisms in a common ancestorof tetrapods allowed the production ofmultiple Ig isotypes during immune responses Color coding indicates the presumed evolution of avianand mammalian IgA from a precursor of amphibian IgX and evolution of mammalian IgG and IgE from a precursor of amphibian IgY

forms the antigen-binding site while the Fc regions of the Igheavy chains (comprising the two most C-terminal constantdomains) confer isotype-specific immune effector functionsSome Ig isotypes can form higher-order polymers of thebasic 4-chain unit thus increasing the number of Ag-bindingsites and enhancing Fc-mediated functions The emergenceof new Ig isotypes during vertebrate evolution allowed fordiversification of Ig-mediated immune functions includingthose specialized for mucosal surfaces (reviewed in [8])Many Ig-mediated immune functions involve interactionswith isotype-specific cellular receptors for the Fc region ofIg heavy chains (Figure 3) The most evolutionarily ancientFc receptor is the polymeric Ig receptor (pIgR) a proteinexpressed selectively bymucosal and glandular epithelial cellsthat transports polymeric Igs into external secretions It hasbeen hypothesized that the complex relationship betweenthe vertebrate host and its resident microbiota provided thedriving force for evolution of the adaptive immune system[1 5] In this review the concept will be explored that animportant consequence of this selective pressure was thecoevolution of mucosal Igs and pIgR

2 Evolution of Mucosal Immunoglobulins

21 Cartilaginous Fishes Primordial Ig-like genes arebelieved to have arisen in a common ancestor of the Gna-thostomata (jawed vertebrates) [2 3] (Figure 1) The most

primitive extant jawed vertebrates comprise the class Chon-drichthyes (cartilaginous fishes) including sharks raysand skates Multiple Ig isotypes have been identified inthe horned shark (Heterodontus francisci) [18] nurse shark(Ginglymostoma cirratum) [19 20] and several species ofskates [21] The primordial IgM of cartilaginous fishes isorthologous to the IgM of higher vertebrates while a secondIg isotype initially called IgW is orthologous to IgD [22] Athird Ig isotype identified in the nurse shark called the Igldquonew antigen receptorrdquo (IgNAR) is homologous to IgM andIgWD but does not have an ortholog in higher vertebrates[19] The IGH and IGL genes are dispersed throughout thegenome of cartilaginous fish in hundreds of clusters eachrepresenting an individual isotype [18 21]

22 Bony Fishes Major changes in the organization of Iggenes occurred during the emergence of the Teleostomithe clade of jawed vertebrates that includes the superclassesOsteichthyes (bony fishes) and Tetrapoda (four-limbed ver-tebrates) (Figure 1) The dispersed IGH loci characteristic ofcartilaginous fishes were replaced with a translocon orga-nization comprising a 51015840 region of VH DH and JH genesegments encoding the Ig heavy chain variable region fol-lowed by tandem CH gene segments encoding Ig heavy chainconstant regions for different isotypes (reviewed in [23])Thistranslocation organization allows a B lymphocyte to ldquoswitchrdquoproduction from one Ig heavy chain isotype to another

ISRN Immunology 3

domain

domain

domain

Hinge region

Fc region

Antigen-binding site

CL

VL

VH

CH1 domain

CH2 domain

CH3 domain

Figure 2 The basic structure of immunoglobulins The basic structural unit of Igs comprises 2 identical light chains (shown in red andblue) and 2 identical heavy chains (shown in red and blue) The polypeptide chains of Ig light and heavy chains consist of repeating unitsof approximately 110 amino acids so-called ldquoIg-likerdquo domains with a characteristic 3-dimensional structure Ig light chains comprise an N-terminal variable (VL) domain followed by a constant (CL) domain of either the 120581 or 120582 type Ig heavy chains comprise an N-terminal variabledomain (VH) followed by 3-4 constant domains (CH1ndashCH3 or 4)The sequence of Ig heavy chain constant regions (designated byGreek letterssuch as 120572 120574 or 120583) defines the Ig class or isotype The structure shown here is characteristic of mammalian IgA IgD and IgG in which theCH1 and CH2 domains of the heavy chains are connected by a short cysteine- and proline-rich hinge region The structure of all Igs in lowervertebrates (as well as IgM and IgE in mammals) differs in that the CH2 domain replaces the hinge region and the Fc region comprises theCH3 and CH4 domains Pairing of VH and VL domains on adjacent Ig heavy and light chains forms the antigen-binding site while the Fcregions of the Ig heavy chains (comprising the two most C-terminal constant domains) confer isotype-specific immune effector functions

during immune responses by a process of DNA rearrange-ment called class switch recombination (CSR) [24ndash26] Mostof the studies of Ig structure and function in bony fisheshave focused on the Actinopterygii (ray-finned bony fishes)which comprise 99 of the over 30000 living species offish mainly within the infraclass Teleostei Early studies inseveral teleost species including plaice (Pleuronectes platessa)[27] common carp (Cyprinus carpio) [28] rainbow trout(Oncorhynchus mykiss) [29] and channel catfish (Ictaluruspunctatus) [30] demonstrated that immunization bymucosalroutes (oral anal and skin) elicited antibody responses in theskin intestinal mucus and bile In 2005 a novel Ig isotypewas described in rainbow trout [31] zebrafish (Danio rerio)[32] and fugu (Fugu rubripes) [33] designated IgT (for teleost)or IgZ (for zebrafish) In the same year an unusual Igisotype described in the common carp which appeared tobe a chimera of IgM and IgZ [34] was identified (Cyprinuscarpio) Subsequent studies in a number of teleost speciesrevealed a common translocon structure in the IGH locuswith tandem gene segments encoding the constant regionsof IgM IgD and IgT(Z) [35ndash37] Functional studies revealed

that the molar ratio of IgT to IgM was 60-fold higher in gutmucus than in serum of rainbow trout and that specific IgTantibodies were induced in the gut following oral infectionwith the parasite Ceratomyxa shasta [38] In this study IgT-expressing lymphocytes were found to represent 543 of allB cells in the intestinal lamina propria Interestingly IgT wasfound as amonomer in serum but as a tetramer in gutmucussuggestive of a selectivemechanism for polymerization of IgTin mucosal B cells similar to that observed for IgA in highervertebrates Thus IgT appears to be the most primitive Igisotype with specialized functions at mucosal surfaces

Although IgT has been identified in most Actinopterygiithus far studied some exceptions have been noted Theabsence of a gene encoding IgT was recently reported in theSiberian sturgeon (Acipenser baerii) a species of the orderAcipenseriformes which occupies a unique phylogeneticniche between the cartilaginous fishes and the Teleostei Theabsence of IgT was also reported in the medaka (Oryziaslatipes) a teleost of the order Beloniformes [39] SurprisinglyIgT is absent in channel catfish a teleost of the order Siluri-formes which is closely related to the order Cypriniformes

4 ISRN Immunology

Ig-like domain

Cysteine-rich domain

Fibronectin type II repeat

C-type lectin-like domain

pIgR

PolymericIgM IgTIgX IgA

Epithelialcells

(CD351)

IgM IgA

B cells

(CD89)

IgA

NeutrophilsMonocytes

Eosinophils

(CD64)

IgG

Monocytes

NeutrophilsEosinophils

(CD32)

IgG

Monocytes

NeutrophilsPlatelets

LangerhansB cells

(CD16)

IgG

NK cells

MonocytesNeutrophilsEosinophils

IgE

Mast cellsBasophils

LangerhansMonocytes

(CD23)

IgE

B cellsT cells

MonocytesEosinophils

FcRn

IgG

Endothelial

Epithelialcells

cells

FcRY

IgY

Endothelialcells

Fc120572120583R

MΦs

Fc120572RI

MΦsMΦs MΦs

MΦs

Fc120574RI Fc120574RII Fc120574RIII

120574120575 T cells

Fc120576RIIFc120576RI

MΦs

1205732m

MHC I-like domain

Figure 3 Fc receptors are Ig isotype- and cell type-specific These schematic diagrams illustrate basic structural features of selectedFc receptors all of which are Type I transmembrane proteins The structures are not to scale and do not imply specific 3-dimensionalconformations All of the structures represent the human homolog of the indicated protein except for FcRY which is from chicken Binding ofthe constant (Fc) region of Igs to cellular receptors initiates transport across epithelial cells or intracellular signaling in cells of hematopoieticorigin The membrane-proximal Ig-like domain of FcRn pairs with the Ig-like domain of soluble 1205732-microglobulin (1205732m) The Ig-bindingsubunits of Fc120572RI Fc120574RI Fc120574RII Fc120574RIII and Fc120576RI (shownhere) pair with other protein subunits (not shown) to initiate signaling pathwaysThis figure was compiled using information from [9ndash15]

that includes the IgT-expressing carp and zebrafish The IGHloci of the few extant species of the class Sarcopterygii (lobe-finned bony fishes including coelacanths and lungfishes)differ from those ofmost of the Actinopterygii (Figure 1)TheAfrican coelacanth (Latimeria chalumnae) one of only twospecies of an ancient class of lobe-finned fishes lacks IgM andhas a single Ig heavy chain gene that resembles the IgWDgene of cartilaginous fishes [40] By contrast the Africanlungfish (Protopterus aethiopicus) expresses both IgM and anisotype resembling IgWD [41] No ortholog of IgT has beenidentified in lobe-finned bony fishes Given the diversity of Iggenes in bony fishes the evolutionary origin of IgT remainsobscure Furthermore while IgT shares many functionalsimilarities with IgA in higher vertebrates the structuralgenes for IgT and IgA are not orthologous [23] Thus thegene encoding IgT appears to be an evolutionary dead-endthat emerged in some lineages of bony fishes in response topressures for immunological protection of mucosal surfaceslikely driven by the resident microbiota as well as mucosalpathogens

23 Amphibians Duplication and diversification of genesegments within the IGH locus in a common ancestor of theTetrapoda (four-limbed vertebrates) led to the appearanceof additional heavy chain Ig isotypes (reviewed in [42])(Figure 1) Most extant species of tetrapods have a single IGHlocus the location of which is syntenic with the human IGHlocus Ectothermic vertebrates of the class Amphibia are themost primitive tetrapods having diverged about 370 millionyears ago from a common ancestor with reptiles birds andmammals Early studies of the structural and immunologicalproperties of Igs from several species of clawed frogs (Xeno-pus) suggested the emergence of two novel Ig isotypes IgXand IgY [43ndash47] (Figure 1) B cells expressing IgX but not IgYwere found abundantly in the intestinal epithelium whereasIgX-positive cells were rarely detected in the spleen and IgXlevels were very low in serum [47] Interestingly thymectomyabolished expression of IgY but not IgM or IgX consistentwith a T-independent role for IgX in the mucosal immunesystem of amphibians Genes encoding IgX and IgY weresubsequently identified in 2 species of salamanders [48 49]

ISRN Immunology 5

suggesting that these Ig isotypes may have emerged in acommon ancestor of amphibians To date no studies havebeen reported on IGH loci in caecilians A recent study inXenopus laevis established the position of amphibian IgX asthe evolutionary precursor of IgA in birds and mammals[50] These investigators found that larval thymectomy didnot affect levels of IgX and did not alter the compositionof the gut microbiota confirming the T-independence ofthe IgX response in Xenopus Phylogenetic comparisons ofIgT in bony fishes and IgX in amphibians suggest that theseIg isotypes evolved independently [23] likely responding tosimilar pressures from the resident microbiota and mucosalpathogens

24 Reptiles and Birds The clade Amniota within the super-class Tetrapoda can be subdivided into the sauropsids (rep-tiles and birds) and synapsids (mammals and their closerelatives) (Figure 1) The distinction between reptiles andbirds is based largely on physical characteristics rather thanphylogeny distinguishing the cold-blooded reptiles withscales from the warm-blooded birds with feathers Earlystudies of Igs in turtles lizards and snakes were basedlargely on their physicochemical and antigenic propertiesrevealing a predominance of IgM and lesser amounts of IgYin bile and gut secretions [51ndash53] Subsequent analyses usingantibodies to chicken IgA failed to detect a cross-reactive Igisotype in reptiles [54 55] The recent availability of wholegenome sequences for 2 species of turtles (Chrysemys pictaand Pelodiscus sinensis) [36 56] and the green anole lizard(Anolis carolinensis) [57] demonstrated the presence of genesegments encoding IgM IgD and multiple subclasses ofIgY but no ortholog of IgX in amphibians or IgA in birdsand mammals The leopard gecko (Eublepharis macularius)expresses IgM IgD and a third Ig isotype that is intermediatein homology between IgA and IgY [50 58] (designatedIgldquoArdquo for the purposes of this review) The recent availabilityof whole genome sequences for 4 crocodilians (Alligatorsinensis Alligator mississippiensis Crocodylus siamensis andCrocodylus porosus) revealed significant differences in theIGH loci compared to other reptiles including multiple sub-classes of IgM IgD and IgA (orthologous to the IgA genes ofbirds and mammals) but no IgY [59 60] Early studies of theimmune systems of birds (class Aves) revealed the presenceof an ortholog of mammalian IgA in mucosal secretionsand an ortholog of IgG (designated IgY) in serum [61ndash69]Mapping of the IGH locus in chickens and ducks revealed aninverted gene segment encoding IgA downstream of the IgMgene segment and upstream of the IgY gene segment andloss of the gene segment encoding IgD [70 71] Availabilityof whole genome sequences for a variety of bird species inthe National Center for Biotechnology Information (NCBI)database demonstrates the consistent presence of IgM IgAand IgY and the absence of IgD A recent analysis of Iggene transcripts in the ostrich (Struthio camelus) revealedsimilarities with chickens ducks and other birds includingthe expression of IgM IgA and IgY and the absence of IgD[72] Because the ostrich is one of the most primitive extantspecies of birds it appears that the distinctive organization

of the IGH locus evolved very early during the divergence ofthe avian lineage Furthermore a phylogenetic comparisonof Ig heavy chain sequences from amphibians with those ofhigher vertebrates demonstrated with high statistical supportthat IgX from amphibians and IgA from birds share arecent common ancestor [50] Taken together the evidenceis consistent with an IGH locus in a common ancestor ofreptiles and birds that included gene segments encoding IgMIgD IgA and IgY Instability in the IGH locus in individuallineages apparently resulted in the selective loss of IgA inmostturtles lizards and snakes IgY in crocodilians and IgD inbirds

25 Mammals The structure of Ig genes and their encodedproteins has been studied extensively in extant species of theclass Mammalia including the egg-laying monotremes thepouch-bearing marsupials and the placentals (eutherians)(reviewed in [8]) The IGH locus in all known mammalsis organized as a translocon with gene segments encodingIgM IgD 2 or more subclasses of IgG 1 or more subclassesof IgA and IgE an isotype unique to mammals (Figure 1)A recent phylogenetic analysis of Ig heavy chain classes intetrapods indicated with high statistical probability that theIgA gene(s) in mammals evolved from an IgX gene in acommon ancestor of all tetrapods while the IgG and IgEgenes evolved more recently from IgY in a common ancestorof amniotes [50] Continuing diversification in the IGH locusinmammals is evidenced by differences in the number of IgGand IgA subclasses and in the structure of Ig heavy chainsUnlike all Ig heavy chains in lower vertebrates comprising 1variable Ig-like domain (VH) and 4 constant Ig-like domains(CH1ndashCH4) the CH2 domain in mammalian IgA IgD andIgG was replaced with a short flexible hinge region richin cysteine and proline residues [73] The heavy chain ofmammalian IgE has retained the prototypic 4 constant Ig-likedomains (as has IgM) suggesting that the evolution of thehinge region in mammalian IgG occurred after the evolutionof IgG and IgE from an ancestral IgY gene (Figure 1)

Determination of the structure of the IGH locus in themonotreme duck-billed platypus (Ornithorhynchus anatinus)revealed the presence of 8 CH genes (including 2 subclassesof IgG and 2 subclasses of IgG) arranged in the order C

120583-

C120575-Co-C1205742-C1205741-C1205721-C120576-C1205722 [74 75] Interestingly the gene

encoding platypus IgD lacks a hinge region and is moresimilar in structure to IgD in lower vertebrates than the IgDof eutherian mammals Downstream of the C

120575gene in the

platypus is a novel Co gene (omicron for Ornithorhynchus)which appears to have evolved from an ancestral IgY geneIn contrast to the platypus only one IgA gene was identifiedin another monotreme the echidna (Tachyglossus aculeatus)and in several species of marsupials [76ndash80] Similarly asingle structural gene for IgA has been identified in 3 speciesof the eutherian order Rodentia mouse (Mus musculus)[81] rat (Rattus norvegicus) (unpublishedGenbank accessionnumber AJ510151) and gerbil (Meriones unguiculatus) [82]By contrast the IGH locus in the European rabbit (Orycto-lagus cuniculus order Lagomorpha) is unique among mam-mals apparently having evolved from a common ancestor

6 ISRN Immunology

prior to the divergence of marsupials and monotremes fromeutherians Distinctive features include a single IgG subclass13 functional IgA subclasses and absence of IgD [83ndash85] Amore typical organization of the IGH locus including singlesubclasses of IgM IgD IgA and IgE and 2 subclasses ofIgG has been reported in mammals of the orders Carnivora[86 87] Cetartiodactyla (even-toed ungulates whales anddolphins) [88ndash91] and Perissodactyla (odd-toed ungulates)[92]

Mammals of the order Primates including humanshave the greatest number and diversity of Ig classes andsubclasses among all of the tetrapods Mapping of IGH locihas now been completed for a number of primate speciesincluding human (Homo sapiens) gorilla (Gorilla gorilla)chimpanzee (Pan troglodytes) orangutan (Pongo pygmaeus)gibbon (Hylobates lar) baboon (Papio anubis) mangabey(Cercocebus torquatus atys) and three species of macaquesthe crab-eating monkey (Macaca fascicularis) pig-tailedmonkey (Macaca nemestrina) and rhesus monkey (Macacamulatta) [93ndash97] A distinguishing feature of primates in thefamily Hominidae (great apes including humans gorillaschimpanzees and orangutans) and the family Hylobatidae(gibbons) is the presence of two IgA subclasses Althoughthe orangutan is a member of the family Hominidae its IGHlocus contains only one IgA subclass gene homologous to theIgA1 gene of other hominoids [95] By contrast primates inthe family Cercopithecidae (Old World monkeys includingbaboons mangabeys and macaques) have a single IgA geneGenetic analysis of the IGH locus of primates suggested thatduplication and diversification of the primordial C

1205741-C1205742-

C120576-C120572region occurred in a common ancestor of the great

apes after the divergence from Old World monkeys [98 99]These events resulted in the current organization of the IGHlocus in extant species of great apes with four IgG subclassesand two IgA subclasses (the duplicated C

120576gene became a

nonfunctional pseudogene hence only one class of IgE isexpressed) The close phylogenetic relationship among theC120572genes in the hominoids and Hylobatidae suggests that

the C1205721

and C1205722

genes evolved from a single C120572gene in a

common ancestor of the great apes and that the C1205722gene was

subsequently lost in the orangutan Evidence of continuingevolution in the IGH locus of humans was demonstrated bythe finding of triplication of the C

1205741-C1205742-C120576-C120572region in

several families [100] Subsequent genetic analyses inmultipleethnic groups revealed that gene duplications and deletionsin the human IGH locus are surprisingly common withfrequencies up to 22 in Japanese and Chinese populations[101]

3 Emergence of the IGJ Gene andEvolution of Polymeric Igs

The ability to produce Igs as both monomers (ie one unitcomprising 2 identical heavy chains and 2 identical lightchains) and polymers (covalently linked aggregates of 2 ormore Ig units) dates to the emergence of primitive Igs incartilaginous fish [23 42 50] Whereas pentameric IgM istypically found in serum as well as secretions the polymeric

forms of IgT IgX and IgA are generally restricted to mucosalsecretions The discovery of a low molecular weight ldquoJrdquo orldquojoiningrdquo chain as a component of polymeric Igs suggesteda potential mechanism for polymerization of individual Igmolecules into highermolecular weight complexes [102ndash104]The most primitive extant vertebrates in which the IGJ genehas been identified are the cartilaginous fish concurrent withthe presence of polymeric IgM Although the IGJ gene hasbeen identified in almost all lineages of jawed vertebratesit is surprisingly absent in some lineages of Osteichthyes(bony fishes) No ortholog of the IGJ gene has been identifiedin any species of the class Actinopterygii (ray-finned bonyfishes) for which the genome has been sequenced and anno-tated including Atlantic cod (Gadus morhua) common carp(Cyprinus carpio) tilapia (Oreochromis niloticus) zebrafish(Danio rerio) medaka (Oryzias latipes) and three-spinedstickleback (Gasterosteus aculeatus) In contrast to the ray-finned bony fishes IGJ genes and functional J chain proteinswere recently identified in two species of the class Sar-copterygii (lobe-finned bony fishes the West Indian Oceancoelacanth (Latimeria chalumnae) and the African lungfish(Protopterus dolloi) [105]) These findings suggest that theIGJ gene was lost during the evolution of the Actinopterygiiafter their divergence from a common ancestor with theSarcopterygii Despite the absence of J chain ray-finned bonyfishes are capable of forming polymeric IgM and IgT that canbe transported into mucosal secretions [38]

4 Evolution of Cellular Receptors for Igs

Theunique structure of vertebrate Igs allows for simultaneousbinding of antigen via the N-terminal variable regions ofthe Ig heavy and light chains and execution of effectorfunctions via the C-terminal constant (Fc) region of the Igheavy chains Evolution of multiple Ig heavy chain isotypesin higher vertebrates expanded the repertoire of Ig-mediatedeffector functions including specialized functions atmucosalsurfaces The simplest effector functions involve neutral-ization of microbes and their toxic byproducts whereaskilling of microbes can be affected by interaction of Igs withsoluble factors found in serumand secretionsThe concurrentemergence of Igs and proteins of the classical complementpathway in cartilaginous fishes is the earliest example of aspecific immune effector function mediated by the Fc regionof Ig heavy chains [106] As the immune system diversifiedduring vertebrate evolution cellular receptors for Ig heavychains (Fc receptors) allowed host cells to bind Igs forthe purpose of internalization transport andor activationof intracellular signaling pathways The most evolutionarilyancient of the vertebrate Fc receptors is the polymeric Igreceptor (pIgR) which first emerged in bony fishes (reviewedin [8]) (Figure 3)Theprimary function of pIgR is to transportpolymeric Igs (IgM IgT IgX and IgA) across glandular andmucosal epithelial cells into external secretions (see below)The fact that the extracellular Ig-binding region of pIgR iscomposed of multiple Ig-like domains suggests that the PIGR

ISRN Immunology 7

gene evolved by duplication of a primordial Ig gene is drivenby the need for an efficient mechanism for transport ofmucosal Igs into external secretions Similar forces may havedriven the evolution of FcRY a receptor first described forits function of transporting IgY from maternal blood tothe embryo yolk sac in chicken [9 107ndash109] FcRY is notstructurally homologous to pIgR or mammalian Fc receptorsbut is instead homologous to mammalian receptors formannose and phospholipase A2 with lectin-like extracellulardomains (Figure 3) A BLAST search of the National Centerfor Biotechnology Information (NCBI) nucleotide databasefor homologs of the gene encoding chicken FcRY (designatedPLA2R1 based on its homology to phospholipase A2 receptor1) revealed homologous genes in many bird species as wellas turtles lizards alligators and mammals However thefunctional significance of FcRYPLA2R1 in the transport ofIgY in reptiles (and possibly IgG in mammals) has not beenexplored A functional equivalent of FcRY in mammals isFcRn which mediates transport of IgG across endothelialand epithelial cells in such tissues as placenta and mucosalepithelia (reviewed in [110 111]) FcRn is homologous in struc-ture to major histocompatibility class (MHC) I moleculescomprising a ligand-binding alpha chain associated withsoluble 1205732-microglobulin (Figure 3)

A unique feature of the mammalian immune system isthe expression of Fc receptors for various Ig isotypes bycells of hematopoietic origin (Figure 3) (reviewed in [10])Engagement of these Fc receptors by Ig (in the presenceor absence of bound antigen depending on the particularFc receptor) initiates intracellular signaling pathways thatcan either augment or inhibit immune responses Withthe exception of Fc120576RII which has a single C-type lectin-like domain the extracellular Ig-binding regions of thesehematopoietic Fc receptors comprise 1 2 or 3 Ig-like domains[10] Genes encoding Fc120572120583R Fc120574RI Fc120574RIII Fc120576RI andFc120576RII are widely distributed among mammalian specieswhereas genes encoding Fc120572RI and Fc120574RII are restricted tothe primate lineage suggesting recent evolutionary originsThe genes encoding the120572120573 andor 120574 chains of Fc120576RI Fc120574RIIand Fc120574RIII are linked in a cluster on the long arm of humanchromosome 1 (1q23) not far removed from the gene for the120572 chain of Fc120574RI at 1q21 This tight linkage is consistent withduplication and diversification of a primordial FcR gene ina common ancestor of mammals The primate-specific genesencoding the 120572 and 120573 chains of Fc120574RII appear to have evolvedmore recently Another cluster of immune-related genes onthe long arm of chromosome 1 includes the genes for pIgR(1q31) and Fc120572120583R (1q32) Although the overall homologybetween pIgR and Fc120572120583R is relatively low they share aconserved binding site for IgA and IgM in the N-terminalIg-like domain Interestingly the genes encoding FcRn andFc120572RI are closely linked on the long arm of chromosome19 (19q133 and 19q1342 resp) although they bear littlehomology beyond the presence of a single Ig-like domain inthe extracellular region Finally the gene for the lectin-likereceptor Fc120576RII is located in an unrelated locus on the shortarm of chromosome 19 (19p133)

PIGR

dIgA

pIgR

Ag

SIgA

Free SC

Figure 4 Transcytosis of pIgR through a polarized epithelial celland formation of secretory Igs A polarized columnar epithelial cellis illustrated with the apical surface at the top and the basolateralsurface at the bottom Newly synthesized pIgR is targeted to thebasolateral surface where it binds polymeric Ig (pIg illustrated hereas dimeric (d)IgA) with or without bound antigen (Ag) Followingreceptor-mediated endocytosis pIg-bound and unoccupied pIgRmolecules are transported through a series of intracellular vesiclesto the apical surface Proteolytic cleavage of pIgR at the extracellularface of the plasma membrane releases free secretory component(SC) and secretory SIg (illustrated here as SIgA) Modified from [13]with permission from John Wiley and sons

5 Unique Biological Functions of pIgR

ThepIgR is expressed on the surface of glandular andmucosalepithelial binds where it binds selectively to polymericIg (pIg) and mediates its transport across epithelial cellsinto external secretions (reviewed in [17 111 112]) Most of

8 ISRN Immunology

02

100

Human IgA1Gorilla IgA1

Gorilla IgA281

6164

Human IgA2

Chimpanzee IgA2Chimpanzee IgA1

Gibbon IgA1Gibbon IgA2

Orangutan IgABaboon IgA

Rhesus macaque IgA53 100

98 69Dog IgA

Pig IgA100 Cattle IgA

52

Horse IgARabbit IgA (13 subclasses)

Mouse IgA57

99

Possum IgA

93

Chicken IgAPlatypus IgA1100

5095

Platypus IgA2

Trout IgTFrog IgX

Gecko IgldquoArdquo

(a)

02

Human pIgR

100Chimpanzee pIgRGorilla pIgR

55Gibbon pIgROrangutan pIgR100

100

100 Baboon pIgRRhesus macaque pIgR

Mouse pIgR

66

96

100 Pig pIgRCattle pIgR

85Horse pIgR

Dog pIgR

74

Rabbit pIgRPossum pIgR

Platypus pIgR

Chicken pIgR

10075

5979

Trout pIgRFrog pIgR

Anole pIgR

71

(b)

Figure 5 Coevolution of mucosal Igs and pIgR Simplified neighbor-joining phylogenetic trees of vertebrate (a) Ig and (b) pIgR proteinsequences with human IgA1 and pIgR denoted as outgroups Horizontal distances are proportional to the degree of divergence followinga multiple alignment of amino acid sequences Numbers at nodes denote bootstrap support for each bifurcation after 100 replicationsAccession numbers for mucosal Ig sequences human (Homo sapiens) IgA1 J00220 IgA2 (allotype m1) J00221 gorilla (Gorilla gorilla) IgA1X53703 IgA2 X53707 chimpanzee (Pan troglodytes) IgA1 X53702 IgA2 X53706 gibbon (Hylobates lar) IgA1 X53708 IgA2 X53709 Borneanorangutan (Pongo pygmaeus) IgA X53704 baboon (Papio anubis) IgA DQ868435 rhesus macaque (Macaca mulatta) AY039245 pig (Susscrofa) IgA U12594 cattle (Bos taurus) IgA AF109167 dog (Canis lupus familiaris) IgA L36871 horse (Equus caballus) IgA AY247966mouse (Mus musculus) IgA D11468 rabbit (Oryctolagus cuniculus) IgA1 X51647 brushtail possum (Trichosurus vulpecula) IgA AF027382duck-billed platypus (Ornithorhynchus anatinus) IgA1 AY055778 IgA2 AY055779 chicken (Gallus gallus) IgA AAB226142 leopard gecko(Eublepharis macularius) IgldquoArdquo (so designated because of its uncertain phylogeny with homology to both IgA and IgY) ABG726841African clawed frog (Xenopus laevis) IgX S03186 rainbow trout (Oncorhynchus mykiss) IgT AAW669811 Accession numbers for pIgRsequences with species that vary from those used for the mucosal Ig alignment in panel A noted in parentheses human NM 002644chimpanzee XM 003308710 gorilla XM 004028295 gibbon XM 003272974 Sumatran orangutan (Pongo abelii) NM 001131626 baboonXM 003893189 rhesus macaque XM 001083307 pig NM 214159 cattle NM 174143 dog XM 537133 horse XM 001492298 mouseNM 011082 rabbit NM 001171045 brushtail possum AF091137 duck-billed platypus XM 001508602 chicken NM 001044644 green anole(Anolis carolinensis) XM 003224013 African clawed frog EF079076 rainbow trout FJ940682

ISRN Immunology 9

our knowledge of pIgR-mediated transcytosis of mucosalIgs is derived from studies of mammalian secretory IgA(SIgA) as illustrated in Figure 4 Transcription of the PIGRgene and translation of pIgR mRNA is accompanied byinsertion of the nascent protein into the endoplasmic retic-ulum The pIgR undergoes substantial glycosylation duringtransport through the ER and Golgi apparatus and is thentargeted to the basolateral surface of polarized epithelialcells Membrane-bound pIgR binds pIg and pIg-containingimmune complexes which are internalized along with unoc-cupied pIgR via receptor-mediated endocytosis and thentranscytosed through a series of intracellular vesicles to theapical surface During transcytosis intracellular pIg antibod-ies can neutralize bacteria viruses and other antigens thathave gained access to the interior of the epithelial cell Atthe apical surface proteolytic cleavage of the membrane-spanning region of pIgR leads to the release of its extracellulardomain known as secretory component (SC) either in freeform or covalently bound to pIg Secretory Igs can neutralizepathogens and antigens within the mucosal lumen andfacilitate excretion of antigens that were transported throughthe epithelial cell as IgA immune complexes The SC moietyof SIgA has been shown to protect IgA from degradationby host and bacterial proteases and along with free SCconfers additional innate immune functions that protectthe epithelial surface from microbial invasion and limitpotentially damaging host inflammatory responses (reviewedin [113]) The finding of an SC-like polypeptide associatedwith polymeric IgT in rainbow trout [38] polymeric IgXin Xenopus [50] and polymeric IgA in birds [114] suggeststhat all vertebrate pIgRs share the function of transportingpolymeric Igs into external secretions In many mammalianspecies pIgR mediates epithelial transcytosis of both poly-meric IgM and IgA (reviewed in [111]) Although directevidence is not yet available it is reasonable to assume thatpIgR transports IgM in lower vertebrates It will be interestingto investigate whether the SCmoiety of secretory Igs in lowervertebrates mediates additional innate immune functions ashas been demonstrated for mammalian SC

6 Coevolution of pIgR and Mucosal Igs

Molecular cloning of the PIGR gene was first reportedfor mammalian species including eutherians marsupialsand monotremes [115ndash127] Subsequent elucidation of PIGRsequences from diverse species of jawed vertebrates hasallowed a comprehensive analysis of the evolutionary originsof the PIGR gene [38 128 128ndash132] and additional sequencesavailable in the Genbank database Whereas no ortholog ofthe PIGR gene has been found in any species of cartilaginousfish the PIGR gene has been annotated in all species of teleostfish for which the genome has been sequenced No orthologof the PIGR gene has been reported in lobe-finned bonyfishes but further analyses of whole genome sequences willbe required to determine whether the PIGR gene was lostfollowing the split of the Sarcopterygii It thus appears thatthe PIGR gene emerged in a common ancestor of highervertebrates after the split of cartilaginous fish and prior

to the evolution of modern teleosts likely driven by theselective pressure to provide a mechanism for transport ofpolymeric Igs such as IgM and IgT into mucosal secretionsThis hypothesis is supported by a comparison of phylogenetictrees based on amino acid sequences for IgT IgX and IgAheavy chains and pIgR (Figure 5)The predicted evolutionarydistance between trout IgT and frog IgX is similar to thedistance between trout and frog pIgR suggesting that thetransition from IgT to IgX as the dominantmucosal Ig isotypewas accompanied by adaptations in pIgR structure Similarparallels can be seen in the transition from IgX to IgA inreptiles birds and mammals and the concurrent evolutionof pIgR

Alignments of the amino acid sequences of mucosal Igheavy chains and pIgR from 10 representative vertebratespecies provide further support for the theory of coevolutionof mucosal IGH and PIGR genes (Figure 6) A commonfeature of Ig and pIgR proteins is the presence of repeatingIg-like domains (see Figure 2 for the basic structure of thesedomains) The structure of IgT IgX and IgA heavy chainsfrom fish amphibians reptiles and birds is similar to thatof IgM with 4 constant Ig-like domains In mammalianIgA (and IgG) the exon for the 2nd constant region wastruncated to encode a short ldquohingerdquo region which confersgreater mobility to the antigen-binding region at the N-terminusThus the CH3 domain of IgT IgX and IgA in lowervertebrates is structurally and functionally homologous tothe CH2 domain of mammalian IgA The heavy chains ofIgT IgX and IgA have retained a characteristic feature ofthe IgM heavy chain that is the presence of a conservedcysteine residue in the tailpiece that allows disulfide bondingbetween heavy chains of individual Ig proteins to formhigher molecular weight polymers These large Ig structurescontaining multiple antigen-binding sites are particularlywell suited for immune clearance of large antigens found atmucosal surfaces such as intact microbes and food particlesIn mucosal Igs from most vertebrate orders the J chainprotein initiates this polymerization process by disulfidebonding with 2 Ig heavy chains remaining associated withthe polymeric Ig at a stoichiometric ratio of 1 J chain subunitper 2 3 4 or 5 Ig units Despite the absence of J chainthe predominant form of IgM and IgT in mucus secretionsin rainbow trout was found to be polymeric in contrastto monomeric forms of IgM and IgT in the blood [38] Inmammals IgM is mainly found as a pentamer whereas theshorter heavy chain ofmammalian IgA restricts its polymericforms to dimers trimers and tetramers Further studies willbe required to characterize the polymeric structures of IgMIgT IgX and IgA in lower vertebrates

Alignment of pIgR amino acid sequences from 10 rep-resentative vertebrate species reveals structural changes thatwere evolved in parallel with structural changes in mucosalIgs (Figure 6(b)) All pIgR proteins have an N-terminalhydrophobic leader peptide required for targeting of thenascent protein into the ER The extracellular region ofpIgR protein is characterized by repeating ldquoIg-likerdquo domainssimilar to Ig heavy chains [115 133] Interestingly the num-ber of extracellular Ig-like domains has increased duringvertebrate evolution culminating with a total of 5 domains

10 ISRN Immunology

TailpieceHinge

Tailpiece

Mammalian IgA

VVVVVVVVVV

200121 300 400 4721

Human IgA1Rhesus IgA

Cattle IgAMouse IgA

Possum IgAPlatypus IgAChicken IgA

Frog IgXTrout IgT

Premammalian IgTXA

Gecko IgldquoArdquo

CH1

CH1

CH2

CH2

CH3

CH3

CH4

(a)

Leader 1 2 3 4 5

Ig homology extracellular domains

Linker CytoplasmicTM

1001 200 300 400 500 600 700 764

HumanRhesus

CattleMouse

PossumPlatypusChicken

AnoleFrog

Trout

(b)

Figure 6 Interspecies similarity in mucosal Ig and pIgR protein sequences from 10 representative vertebrate species Alignments in aminoacid sequences correspond to the phylogenetic trees shown in Figure 5 (a) Numbering ofmucosal Ig amino acids corresponds to the sequenceof human IgA1 beginning with the first residue of the variable domain CH heavy chain constant region domain (b) Numbering of pIgRamino acids corresponds to the sequence of human pIgR beginning with the first residue of the leader peptide TM transmembrane Forboth alignments the intensity of shading at each position signifies the degree of similarity amongmucosal Ig or pIgR sequences from differentspecies Gaps in sequence alignments signify regions of limited interspecies homology Approximate boundaries are noted of key structuralelements in mucosal Ig and pIgR proteins

in mammalian pIgR By contrast pIgR from amphibiansreptiles and birds contains 4 extracellular domains lackinga homolog of domain 2 of mammalian pIgR The mostprimitive form of pIgR found in teleost fish contains only2 extracellular domains homologous to domains 1 and 5of mammalian pIgR Interspecies homology is greatest indomain 1 which has been shown to be critical for binding ofmammalian pIgR to polymeric Igs (reviewed in [111]) Highlyconserved internal disulfide bonds are found in all the Ig-like domains of pIgR characteristic of the immunoglobulinfold An additional disulfide bond is found in domain 5 ofpIgR frommammals birds reptiles and amphibians but notfish In human SIgA this ldquoextrardquo disulfide bond in domain 5has been shown to rearrange to form a disulfide bond with

cysteine residues in one of the heavy chains of polymericIgA [134] Although the structure of SIgA has not beenfully characterized for lower vertebrates it is reasonable toassume that similar disulfide bonds form between domain 5of pIgR and polymeric IgA or IgX from birds reptiles andamphibians The linker region connecting domain 5 of pIgRto the transmembrane domain has a random structure that ispoorly conserved across species Proteolytic cleavage of pIgRwithin this domain leads to the release of SC from the apicalsurface of epithelial cells either free or bound to polymericIg The cytoplasmic domain of mammalian pIgR containsa number of intracellular sorting motifs that interact withcytoplasmic proteins to direct pIgR through the transcytoticpathway (reviewed in [111]) These motifs are reasonably

ISRN Immunology 11

Linker

TMCytoplasmic

J chain

Hinge 1

2

34

5

CL

VLVH

C1205721C1205722 C1205723

(a)

Linker

TMCytoplasmic

J chain

1

3 4

5

CL

VL

VH

C1205941205721

C1205941205722C1205941205723 C1205941205724

(b)

11

5

LinkerTM

Cytoplasmic

5

CL

VL

VH

C1205911C1205912

C1205913 C1205914

pIgR Ig-like domain

H chain Ig-like domain

L chain Ig-like domain

J chain

Disulfide bond

(c)

Figure 7 Theoretical model for changes in the structure of secretory Igs during evolution (a) The structure for mammalian SIgA is adaptedfrom the model of Woof and Russell [16] for human SIgA1 with permission from Nature Publishing Group (b) and (c) Theoretical modelsfor the structure of IgXA from amphibians and birds and SIgT from teleost fish respectively are predicted from alignment of Ig heavy chainand pIgR sequences with mammalian homologs

well conserved in pIgR from birds and reptiles but not inpIgR from amphibians and fish suggesting that complexmechanisms of intracellular trafficking of pIgR coevolvedwith the increasing complexity of the mucosal immunesystem

7 Hypothetical Models for Changes inSecretory Ig Structure during Coevolutionof Mucosal Igs and pIgR

A large number of structural and functional analyses overthe past 30 years allowed the development of detailed modelsfor the structure of mammalian SIgA (reviewed in [111 135])(Figure 7(a)) Domains 1 and 5 of pIgR the most highlyconserved Ig-like domains associate with theC1205722 subunits oftwo adjacent IgA heavy chains in a near-planar structure [136137] During transcytosis a disulfide bond forms betweenhighly conserved cysteine residues in domain 5 of pIgRand the C1205722 domain of one of the IgA heavy chains [134]Domains 2 3 and 4 allow mammalian pIgR to assume aflexible extended structure which is thought to wrap aroundthe IgA heavy chains and protect against degradation fromhost and microbial proteases Binding of mammalian pIgRto polymeric IgA or IgM requires the presence of J chain

connecting the Ig subunits (reviewed in [138]) and J chain-deficient mice fail to transport IgA and IgM into externalsecretions [139ndash141] Structure-function studies usingmutantforms of human J chain suggested that J chain binds directlyto pIgR and also maintains polymeric Ig in an optimalconformation for pIgR binding and transcytosis [142] Theunstructured linker region connecting domain 5 of pIgRto the transmembrane (TM) region gives membrane-boundpIgR the flexibility to bind large polymeric Igs (with orwithout associated antigens) and provides an exposed site forproteolytic cleavage of pIgR to SC The C-terminal region ofpIgR extends past the cytoplasmic face of the plasma mem-brane allowing association with cytoplasmic factors thatregulate trafficking of pIgR with or without bound polymericIg

Although detailed structural studies have not yet beenperformed on secretory Igs from lower vertebrates hypo-thetical models can be constructed based on alignmentswith their mammalian homologs A model for secretoryIgXA in birds reptiles and amphibians is illustrated inFigure 7(b) showing the C

1205941205722 domain in place of the hinge

region ofmammalian IgAThenumbering of the extracellulardomains of pIgR corresponds to the homologous domainsin mammalian pIgR noting the absence of domain 2 In

12 ISRN Immunology

this model the C120594120572

3 domains of two adjacent IgXA heavychains (homologous to the C

1205722 domain of mammalian IgA)

bind to the highly conserved domains 1 and 5 of pIgRGiven the conservation of the analogous cysteine residuesin domain 5 of pIgR and the C

1205941205723 domain of IgXA it

is assumed that a disulfide bond forms between pIgR andpolymeric Ig during epithelial transcytosis in birds reptilesand amphibiansThe absence of domain 2 in pIgR from thesevertebrate orders necessitates a more rigid structure thanthat of mammalian pIgR with a corresponding decrease inits ability to wrap around the IgXA heavy chains and pro-vide protection against proteoltyic degradation Despite theshorter length of pIgR in birds reptiles and amphibians theassociation with the J chain subunit of polymeric IgXA stillappears to be required Recombinant pIgR from the Africanfrog (Xenopus laevis) was shown to bind with moderatelyhigh affinity to human polymeric IgA containing J chain butnot to monomeric IgA [125] The affinity of Xenopus pIgRfor human pIgA was improved when Xenopus J chain wassubstituted for human J chain in a chimeric polymeric IgAmolecule The lack of sequence conservation across speciesin the linker region connecting domain 5 of pIgR to the TMregion suggests that it acts as a nonspecific ldquospacerrdquo As statedabove the cytoplasmic region of pIgR appears to have evolvedover time to provide enhanced regulation of pIgR trafficking

The hypothetical structure of secretory IgT from teleostfish in Figure 7(c) illustrates how the most primitive form ofpIgR comprising only extracellular domains 1 and 5 couldassociate with polymeric Ig and mediate epithelial transcy-tosis Association of pIgR domain 1 with the C

1205913 domain of

IgT would preserve the functional homology with secretoryIgs in higher vertebrates The short length of teleost pIgRwould necessitate the association of domain 5 with a C

1205913

domain on one of the heavy chains of the same IgT ratherthan spanning across to the adjaent IgT subunit While thismodel preserves the highly conserved association of pIgRdomain 1 with the orthologous domain of the IgT heavychain it does not explain the selectivity of teleost pIgR forpolymeric rather than monomeric IgT Although there is noexperimental evidence to support this model it could behypothesized that dimerization of two pIgR molecules in theplasmamembrane is required for high affinity binding of IgTas illustrated in the model in Figure 7(c) This hypotheticalmodel would also explain the lack of a necessity for J chainin polymeric IgT since each subunit in the pIgR dimer wouldonly be in contact with one IgT subunit The unstructuredlinker region connecting domain 5 of pIgR to the TM regionwould provide flexibility for association of 2 membrane-bound pIgR molecules with a large polymeric IgT molecule

Taken together the structural models for secretory Igsshown in Figure 7 are consistent with the selection of a morefunctional pIgR molecule over evolutionary time Duplica-tion and diversification of the extracellular Ig-like domainsof pIgR would provide a longer more flexible surface forbinding to polymeric Igs with higher affinity and protectingthe Ig heavy chains against proteolytic attack Expansion ofthe cytoplasmic domain of pIgR and incorporation of motifsfor binding cytoplasmic proteins would allow regulated

trafficking of pIgR and polymeric Igs across mucosal andglandular epithelial cells Importantly these models illustratea potential path for coevolution of IGH and PIGR genesdriven by the common selective pressure to provide antigen-specific humoral immune responses at mucosal surfaces

8 Evidence that the CommensalMicrobiota Provided the Driving Force forCoevolution of Mucosal Igs and pIgR

From the earliest evolution of vertebrate animals mucosal Igshave been an integral part of the emerging adaptive immunesystem Clearly many environmental factors served as driv-ing forces for the evolution of the adaptive immune systemin vertebrates including a longer lifespan thanmany (but notall) invertebrates and amore diverse diet that could introducea broader range of potential gut pathogens However it hasbeen proposed that the most significant force may havebeen the dramatic increase in the numbers and complexityof the resident microbiota in the evolution of vertebratesfrom their invertebrate ancestors [1 143 144] Antibodiesin mucosal secretions contribute to immune homeostasis bylimiting access of microbes and their products to the bodyproper maintaining the integrity of the epithelial barrier andshaping the composition of the commensal microbiota infavor of metabolically beneficial microorganisms [145] Thepredominance of polymeric Igs in these secretions promotesthese functions by providing multiple antigen-binding sitesper Ig complex thus increasing the overall avidity of antigen-antibody interactions Structural and functional refinementsin mucosal Igs culminating with the multifunctional secre-tory IgA molecule in mammals have further enhanced theirability to enhance immune homeostasis

The early emergence of pIgR in vertebrate evolutionprovided a mechanism for efficient transport of mucosal Igsinto external secretions It is well documented that crosstalkbetween mucosal epithelial cells and the resident microbiotamodulates expression of pIgR (reviewed in [17 111 112]) andit is reasonable to assume that these host-microbe interac-tions provided a driving force for evolution of the PIGR genein vertebrates The first demonstration that gut bacteria maymodulate pIgR expression in epithelial cells was the findingthat butyrate a bacterial fermentation product and importantenergy source in the colon upregulated expression of pIgRin the human colonic epithelial cell line HT-29 [146] A rolefor commensal bacteria in pIgR regulation was subsequentlydemonstrated by the observation that pIgR expression wasincreased when germ-free mice were colonized with Bacteri-oides thetaiotaomicron a prominent organism of the normalmouse and human intestinal microbiota [147] Amore recentstudy using a model of reversible colonization of germ-free mice with a nondividing mutant of Escherichia colidemonstrated that a long-lived SIgA response could besustained that specifically recognized the inducing bacteria[148] However exposure of E coli-colonized mice to otherbacteria limited the duration of the SIgA response against theoriginal colonizer suggesting a dynamic equilibriumbetweenmembers of the gut microbial community and host SIgA A

ISRN Immunology 13

study from the laboratory of Finn-Eirik Johansen demon-strated that diversity of the bacterial community in the cecallumen was reduced in pIgR-knockoutmice supporting a rolefor SIgA in limiting overgrowth of selected species [149] Incontrast the community of bacteria adherent to the epithelialsurface was more diverse in pIgR-knockout mice than inwild-typemice and these adherent bacteria caused enhancedexpression of several epithelial antimicrobial peptides Thesefindings suggest that bacteria-specific SIgA anchored in themucus layer restricts adhesion of bacteria to the epithelialsurface and limits bacterial stimulation of host epithelial cellsA recent study from the authorrsquos laboratory employing abreeding scheme in which119875119894119892119903minusminus damswere bred to119875119894119892119903+minusmales and vice versa demonstrated that SIgA antibodiesin breast milk promote long-term intestinal homeostasis byregulating the gut microbiota and gene expression in colonicepithelial cells [150]

A direct role for commensal andor pathogenic bacteriain the regulation of pIgR expression suggests that the innateimmune system may ldquoprimerdquo epithelial cells for transportof polymeric Ig produced during the adaptive immuneresponse Host cells mediate innate immune responses tomicrobial components through toll-like receptor (TLR) sig-naling (reviewed in [151 152]) Intestinal epithelial cells havebeen shown to express a wide variety of TLRs the expressionof which is upregulated during intestinal inflammation [153ndash155] Significantly expression of pIgR was shown to beupregulated in the HT-29 human intestinal epithelial cellline by bacterial LPS a ligand for TLR4 [156 157] Similarinduction of PIGR gene transcription was seen followingdirect binding of bacteria of the family Enterobacteriaceaewhich express a form of LPS that stimulates TLR4 [158]A recent study from the authorrsquos laboratory demonstratedthat shRNA-mediated knockdown of myeloid differentiationprimary response protein 88 (MyD88) a cytoplasmic adapterprotein that transduces signals from cell surface TLR4blocked the induction of PIGR gene transcription by LPS inHT-29 cells [159] The in vivo significance was confirmed bythe finding that mice with a targeted deletion of the Myd88gene only in intestinal epithelial cells had reduced expressionof pIgR compared to wild-type littermates [159] Mice withtargeted depletion of MyD88 in intestinal epithelial cells alsoexhibited reduced expression of mucin-2 the major compo-nent of the intestinal mucus layer and several antimicrobialpeptides and decreased transmucosal electrical resistanceThese alterations in epithelial barrier function were accom-panied by significant changes in the composition of the fecalmicrobiota increased numbers of bacteria adherent to theintestinal mucus layer and a dramatic increase in transloca-tion of gut bacteria into the drainingmesenteric lymphnodesincluding the opportunistic pathogen Klebsiella pneumoniaeThese findings demonstrate that MyD88-mediated crosstalkbetween the gut microbiota and intestinal epithelial cells iscrucial for optimal expression of pIgR production of SIgAdevelopment of a healthy gut microbiota and maintenanceof intestinal homeostasis

A model can be proposed in which continuous stimu-lation of intestinal epithelial cells by gut bacteria regulates

Lumen

Mucus

Epithelium

Lamina

PIGR

TLRs

MyD88

Bacteria

Plasma cells

propria

Polymeric Ig

Polymeric Ig receptor

Secretory component

Figure 8 Crosstalk between the polymeric immunoglobulin recep-tor secretory immunoglobulins and the gut microbiotaThe single-layered epithelium that lines the gastrointestinal tract is coveredwith a thick mucus layer which physically excludes members ofthe resident microbiota but allows diffusion of shed components ofmicrobial cells Stimulation of epithelial toll-like receptors (TLRs)with microbial products engages the cytoplasmic adaptor proteinMyD88 and initiates NF120581B-dependent signaling pathways Translo-cation of activated NF120581B and other transcription factors to thenucleus enhances transcription of thePIGR gene Activation of TLRsmay also stimulate pIgR transcytosis Polymeric Igs secreted bylamina propria plasma cells bind to pIgRon the basolateral surface ofepithelial cells and are transcytosed to the apical surface along withunoccupied pIgR Proteolytic cleavage of pIgR at the apical surfacereleases secretory SIg and free secretory component (SC) Binding ofSIg and SC to luminal bacteria promotes association with themucuslayer and prevents direct access of bacteria to the epithelial surfaceOver time the continuous crosstalk with SIg shapes the compositionof the gut microbiota Modified from [17] under terms of authorrsquoscopyright with Nature Publishing Group

pIgR expression and transport of SIgA and promotes immuneexclusion of resident and pathogenic bacteria (Figure 8) Adense layer of mucus which increases in thickness fromthe proximal to the distal colon serves to separate bacteriafrom direct contact with the epithelial surface Secretionof microbial-associated molecular patterns (MAMPs) bycommensal bacteria stimulates MyD88-dependent TLR sig-naling leading to enhanced expression of pIgR and antimi-crobial peptides and increased mucus production Bindingof pIgA to pIgR and possibly also signaling via MAMPs

14 ISRN Immunology

enhances transcytosis of pIgA pIgA-containing immunecomplexes and unoccupied pIgR which promotes clearanceof antigens and pathogens from the lamina propria intra-cellular neutralization and release of SIgA and SC at theluminal surface SIgA and SC serve to trap bacteria in themucus layer limiting their access to the epithelial surface Inmice with a targeted deletion of the Muc2 gene which havea severely depleted mucus layer in the colon SIgA and SCfail to associate with the surface of colonic epithelial cells[160] The presence of SIgA in the intestinal lumen whetherderived passively frommaternalmilk or actively via epithelialtranscytosis shapes the composition of the gut microbiotaand modulates intestinal epithelial gene expression

9 Concluding Remarks

The first microbes that emerged on Earth almost 4 billionyears ago encountered a hostile world where nutrients werescarce hazards were everywhere and life was short Withthe evolution of multicellular organisms about 3 billion yearslater a select group ofmicrobes chose to sacrifice an indepen-dent existence for the benefits of a mutualistic relationshipwith eukaryotic hosts Prokaryotic-eukaryotic mutualismreached its apex some 500 million years ago with theemergence of primitive vertebrates whose gastrointestinaltracts were populated by an abundant and diverse commensalmicrobiota In humans the large intestine is home to some100 trillion microorganisms 10 times more than the totalnumber of eukaryotic cells in the entire body The microbesthat inhabit the vertebrate GI tract provide many benefitsto the eukaryotic host including digestion of complex foodmolecules synthesis of vitamins and production of solublefactors that enhance the development of the host immunesystem In return the eukaryotic host provides the microbeswith a warm moist place to live abundant food low oxygentension and a soft bed of mucus on which to form biofilmsWhen this mutually beneficial arrangement is challenged bypathogenicmicrobes the eukaryotic host and the commensalmicrobiota join forces to battle the pathogens and protectthe body from invasion The vertebrate immune system isequipped with a well-trained army of immune cells and asophisticated arsenal of weapons (cell surface molecules andsecreted factors) that protect the host from all but the mostvirulent pathogens This immune ldquoarmyrdquo also serves as aconstant reminder to the commensal microbes that whilethey are free to enjoy the amenities of the mucosal surfacesthey are not welcome in the body proper The emergence ofantigen-specific Igs and T-cell receptors in jawed vertebratesbegan a process of immunological diversification that led tothe development of a specialized mucosal immune systemin higher vertebrates in which secretory Igs play a centralrole The relationship between host and microbiota is clearlyreciprocal the mucosal Igs that evolved in response toselective pressure from the commensal microbiota play acentral role throughout life in shaping the compositiongenetics andmetabolic activity of themicrobiota [1 161 162]

The epithelial layer lining mucosal surfaces provides aphysical and innate immune barrier against penetration of

the body proper by microbes undigested food antigens andpotentially noxious environmental substances The evolu-tionary challenge of transporting mucosal Igs into externalsecretions without compromising the epithelial barrier wasmet by the emergence of the PIGR gene in an ancestor ofbony fishes encoding an epithelial-specific transmembraneprotein that actively transports polymeric Igs across mucosaland glandular epithelia (Figure 4) Structural similaritiesbetween Igs and the extracellular Ig-binding domains of pIgR(Figure 6) suggest that duplication and diversification of agene encoding primordial Ig-like domain may have givenrise to the PIGR gene in a primitive vertebrate ancestorParallel refinement of the structures of mucosal Igs andpIgR during tetrapod evolution (Figures 6 and 7) culminatedin the evolution of the multifunctional SIgA molecule inmammals in which the pIgR-derived SC subunit providesinnate immune functions and protects the antigen-bindingIgA polymer from proteolytic degradation In addition toacting as a powerful force during vertebrate evolution thereciprocal relationship between pIgR mucosal Igs and thecommensal microbiota provides benefits throughout thelife of the individual Microbial colonization of newbornvertebrates stimulates development of mucosal B cells andclass switching to mucosal Ig isotypes [1 163] Microbialfactors upregulate expression of pIgR enhancing transportof mucosal Igs into external secretions where they in turnregulate the microbiotaThis beautifully orchestrated processallows us to maintain a healthy relationship with our resi-dent microbiota while providing mutual protection againstpathogens

Conflict of Interests

The author declares that there is no conflict of interestsregarding the publication of this paper

Acknowledgments

This work was supported by Grant no AI069027 from theNational Institutes of Health of the United States of America(and an associatedAmerican Recovery andReinvestmentActsupplement) and a Senior Research Award from the Crohnrsquosand Colitis Foundation of America

References

[1] C L Maynard C O Elson R D Hatton and C T WeaverldquoReciprocal interactions of the intestinal microbiota andimmune systemrdquo Nature vol 489 no 7415 pp 231ndash241 2012

[2] M F Flajnik and M Kasahara ldquoOrigin and evolution of theadaptive immune system genetic events and selective pres-suresrdquo Nature Reviews Genetics vol 11 no 1 pp 47ndash59 2010

[3] M F Flajnik and L du Pasquier ldquoEvolution of the immunesystemrdquo in Fundamental Immunology W E Paul Ed chapter4 pp 67ndash128 Lippincott Williams ampWilkins Philadelphia PaUSA 2012

[4] M Hirano S Das P Guo and M D Cooper ldquoThe evolutionof adaptive immunity in vertebratesrdquo Advances in Immunologyvol 109 pp 125ndash157 2011

ISRN Immunology 15

[5] T BoehmNMcCurley Y SutohM SchorppMKasahara andM D Cooper ldquoVLR-based adaptive immunityrdquo Annual Reviewof Immunology vol 30 pp 203ndash220 2012

[6] T Hunkapiller and L Hood ldquoImmunology the growing immu-noglobulin gene superfamilyrdquoNature vol 323 no 6083 pp 15ndash16 1986

[7] P Bork L Holm and C Sander ldquoThe immunoglobulin foldstructural classification sequence patterns and common corerdquoJournal of Molecular Biology vol 242 no 4 pp 309ndash320 1994

[8] C S Kaetzel and M W Russell ldquoPhylogeny and comparativephysiology of IgArdquo in Mucosal Immunology J Mestecky WStrober H Cheroutre B Kelsall B N Lambrecht and M WRussell Eds chapter 19 Academic PressElsevier WalthamMass USA 2014

[9] Y He and P J Bjorkman ldquoStructure of FcRY an avian immu-noglobulin receptor related to mammalian mannose receptorsand its complex with IgYrdquo Proceedings of the National Academyof Sciences of the United States of America vol 108 no 30 pp12431ndash12436 2011

[10] J M Woof and D R Burton ldquoHuman antibody-Fc receptorinteractions illuminated by crystal structuresrdquo Nature ReviewsImmunology vol 4 no 2 pp 89ndash99 2004

[11] W L Martin A P West Jr L Gan and P J Bjorkman ldquoCrystalstructure at 28 A of an FcRnheterodimeric Fc complexmechanism of pH-dependent bindingrdquo Molecular Cell vol 7no 4 pp 867ndash877 2001

[12] E S Ward ldquoAcquiring maternal immunoglobulin differentreceptors similar functionsrdquo Immunity vol 20 no 5 pp 507ndash508 2004

[13] C S Kaetzel ldquoThe polymeric immunoglobulin receptor bridg-ing innate and adaptive immune responses atmucosal surfacesrdquoImmunological Reviews vol 206 no 1 pp 83ndash99 2005

[14] M Acharya G Borland A L Edkins et al ldquoCD23Fc120576RIImolecular multi-taskingrdquo Clinical and Experimental Immunol-ogy vol 162 no 1 pp 12ndash23 2010

[15] V B Klimovich ldquoIgM and its receptors structural and func-tional aspectsrdquo Biochemistry vol 76 no 5 pp 534ndash549 2011

[16] J MWoof andMW Russell ldquoStructure and function relation-ships in IgArdquo Mucosal Immunology vol 4 no 6 pp 590ndash5972011

[17] F-E Johansen and C S Kaetzel ldquoRegulation of the polymericimmunoglobulin receptor and IgA transport new advances inenvironmental factors that stimulate pIgR expression and itsrole in mucosal immunityrdquo Mucosal Immunology vol 4 no 6pp 598ndash602 2011

[18] F Kokubu K Hinds R Litman M J Shamblott and G WLitman ldquoExtensive families of constant region genes in a phy-logenetically primitive vertebrate indicate an additional levelof immunoglobulin complexityrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 84 no16 pp 5868ndash5872 1987

[19] A S Greenberg A L Hughes J Guo D Avila E CMcKinneyand M F Flajnik ldquoA novel ldquochimericrdquo antibody class in carti-laginous fish IgMmay not be the primordial immunoglobulinrdquoEuropean Journal of Immunology vol 26 no 5 pp 1123ndash11291996

[20] H Dooley and M F Flajnik ldquoShark immunity bites back affin-ity maturation and memory response in the nurse shark Ging-lymostoma cirratumrdquo European Journal of Immunology vol 35no 3 pp 936ndash945 2005

[21] S F Schluter R M Bernstein and J J Marchalonis ldquoMolecularorigins and evolution of immunoglobulin heavy-chain genes ofjawed vertebratesrdquo Immunology Today vol 18 no 11 pp 543ndash549 1997

[22] Y Ohta and M Flajnik ldquoIgD like IgM is a primordial immu-noglobulin class perpetuated in most jawed vertebratesrdquo Pro-ceedings of the National Academy of Sciences of the United Statesof America vol 103 no 28 pp 10723ndash10728 2006

[23] S Fillatreau A Six S Magadan R Castro J O Sunyer andP Boudinot ldquoThe astonishing diversity of Ig classes and B cellrepertoires in teleost fishrdquo Frontiers in Immunology vol 4 no28 2013

[24] W Harriman H Volk N Defranoux and M Wabl ldquoImmu-noglobulin class switch recombinationrdquo Annual Review ofImmunology vol 11 pp 361ndash384 1993

[25] J Stavnezer and C T Amemiya ldquoEvolution of isotype switch-ingrdquo Seminars in Immunology vol 16 no 4 pp 257ndash275 2004

[26] V M Barreto Q Pan-Hammarstrom Y Zhao L Ham-marstrom Z Misulovin and M C Nussenzweig ldquoAID frombony fish catalyzes class switch recombinationrdquo Journal ofExperimental Medicine vol 202 no 6 pp 733ndash738 2005

[27] T C Fletcher and AWhite ldquoAntibody production in the plaice(Pleuronectes platessa L) after oral and parenteral immuniza-tion with Vibrio anguillarum antigensrdquo Aquaculture vol 1 pp417ndash428 1972

[28] J W H M Rombout L J Blok C H J Lamers and E EgbertsldquoImmunization of carp (Cyprinus carpio) with a Vibrio anguil-larum bacterin indications for a common mucosal immunesystemrdquo Developmental and Comparative Immunology vol 10no 3 pp 341ndash351 1986

[29] U Georgopoulou and J-M Vernier ldquoLocal immunologicalresponse in the posterior intestinal segment of the rainbowtrout after oral administration of macromoleculesrdquo Develop-mental andComparative Immunology vol 10 no 4 pp 529ndash5371986

[30] C J Lobb ldquoSecretory immunity induced in catfish Ictaluruspunctatus following bath immunizationrdquo Developmental andComparative Immunology vol 11 no 4 pp 727ndash738 1987

[31] J D Hansen E D Landis and R B Phillips ldquoDiscovery ofa unique Ig heavy-chain (IgT) in rainbow trout implicationsfor a distinctive B cell developmental pathway in teleost fishrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 102 no 19 pp 6919ndash6924 2005

[32] N Danilova J Bussmann K Jekosch and L A Steiner ldquoTheimmunoglobulin heavy-chain locus in zebrafish identificationand expression of a previously unknown isotype immunoglob-ulin Zrdquo Nature Immunology vol 6 no 3 pp 295ndash302 2005

[33] R Savan A Aman K Sato R Yamaguchi and M Sakai ldquoDis-covery of a new class of immunoglobulin heavy chain fromfugurdquo European Journal of Immunology vol 35 no 11 pp 3320ndash3331 2005

[34] R Savan A AmanMNakao HWatanuki andM Sakai ldquoDis-covery of a novel immunoglobulin heavy chain gene chimerafrom common carp (Cyprinus carpio L)rdquo Immunogenetics vol57 no 6 pp 458ndash463 2005

[35] F Gambon-Deza C Sanchez-Espinel and S Magadan-Mompo ldquoPresence of an unique IgT on the IGH locus in three-spined stickleback fish (Gasterosteus aculeatus) and the veryrecent generation of a repertoire of VH genesrdquo Developmentaland Comparative Immunology vol 34 no 2 pp 114ndash122 2010

[36] T M Tadiso K K Lie and I Hordvik ldquoMolecular cloning ofIgT fromAtlantic salmon and analysis of the relative expression

16 ISRN Immunology

of 120591 120583 and 120575 in different tissuesrdquo Veterinary Immunology andImmunopathology vol 139 no 1 pp 17ndash26 2011

[37] S Mashoof C Pohlenz P L Chen et al ldquoExpressed IgH 120583and 120591 transcripts share diversity segment in ranched Thunnusorientalisrdquo Developmental and Comparative Immunology vol43 no 1 pp 76ndash86 2014

[38] Y-A Zhang I Salinas J Li et al ldquoIgT a primitive immunoglob-ulin class specialized in mucosal immunityrdquo Nature Immunol-ogy vol 11 no 9 pp 827ndash835 2010

[39] S Magadan-Mompo C Sanchez-Espinel and F Gambon-Deza ldquoImmunoglobulin heavy chains in medaka (Oryziaslatipes)rdquo BMC Evolutionary Biology vol 11 no 1 article 1652011

[40] C T Amemiya J Alfoldi A P Lee et al ldquoThe African coela-canth genome provides insights into tetrapod evolutionrdquoNature vol 496 no 7445 pp 311ndash316 2013

[41] T Ota J P Rast G W Litman and C T Amemiya ldquoLineage-restricted retention of a primitive immunoglobulin heavy chainisotype within the Dipnoi reveals an evolutionary paradoxrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 100 no 5 pp 2501ndash2506 2003

[42] Y Sun Z Wei N Li and Y Zhao ldquoA comparative overview ofimmunoglobulin genes and the generation of their diversity intetrapodsrdquo Developmental and Comparative Immunology vol39 no 1-2 pp 103ndash109 2013

[43] I Hadji-Azimi ldquoAnuran immunoglobulins a reviewrdquo Develop-mental and Comparative Immunology vol 3 no 2 pp 223ndash2431979

[44] E Hsu M F Flajnik and L du Pasquier ldquoA third immunoglob-ulin class in amphibiansrdquo The Journal of Immunology vol 135no 3 pp 1998ndash2004 1985

[45] C T Amemiya R N Haire and G W Litman ldquoNucleotidesequence of a cDNA encoding a third distinct Xenopusimmunoglobulin heavy chain isotyperdquo Nucleic Acids Researchvol 17 no 13 p 5388 1989

[46] R Muszligmann M Wilson A Marcuz M Courtet and L duPasquier ldquoMembrane exon sequences of the three Xenopus Igclasses explain the evolutionary origin of mammalian isotypesrdquoEuropean Journal of Immunology vol 26 no 2 pp 409ndash4141996

[47] R Muszligmann L du Pasquier and E Hsu ldquoIs Xenopus IgX ananalog of IgArdquo European Journal of Immunology vol 26 no12 pp 2823ndash2830 1996

[48] B Schaerlinger and J-P Frippiat ldquoIgX antibodies in the urodeleamphibian Ambystoma mexicanumrdquo Developmental and Com-parative Immunology vol 32 no 8 pp 908ndash915 2008

[49] B Schaerlinger M Bascove and J-P Frippiat ldquoA new isotypeof immunoglobulin heavy chain in the urodele amphibianPleurodeles waltl predominantly expressed in larvaerdquoMolecularImmunology vol 45 no 3 pp 776ndash786 2008

[50] S Mashoof A Goodroe C C Du et al ldquoAncient T-independence of mucosal IgXA gut microbiota unaffected bylarval thymectomy in Xenopus laevisrdquo Mucosal Immunologyvol 6 no 2 pp 358ndash368 2013

[51] J P Vaerman J Picard and J F Heremans ldquoStructural dataon chicken IgA and failure to identify the IgA of the tortoiserdquoin Immunologic Phylogeny vol 64 of Advances in ExperimentalMedicine and Biology pp 185ndash195 Springer New York NYUSA 1975

[52] J L Portis and J E Coe ldquoIgM the secretory immunoglobulinof reptiles and amphibiansrdquo Nature vol 258 no 5535 pp 547ndash548 1975

[53] J E Coe D Leong J L Portis and L A Thomas ldquoImmuneresponse in the garter snake (Thamnophis ordinoides)rdquo Immu-nology vol 31 no 3 pp 417ndash424 1976

[54] D Hadge and H Ambrosius ldquoEvolution of low molecularweight immunoglobulinsmdashIV IgY-like immunoglobulins ofbirds reptiles and amphibians precursors of mammalian IgArdquoMolecular Immunology vol 21 no 8 pp 699ndash707 1984

[55] D Hadge and H Ambrosius ldquoEvolution of low molecularweight immunoglobulins V Degree of antigenic relationshipbetween the 7S immunoglobulins ofmammals birds and lowervertebrates to the turkey IgYrdquo Developmental and ComparativeImmunology vol 10 no 3 pp 377ndash385 1986

[56] S Magadan-Mompo C Sanchez-Espinel and F Gambon-Deza ldquoImmunoglobulin genes of the turtlesrdquo Immunogeneticsvol 65 no 3 pp 227ndash237 2013

[57] Z Wei Q Wu L Ren et al ldquoExpression of IgM IgD and IgYin a reptile Anolis carolinensisrdquoThe Journal of Immunology vol183 no 6 pp 3858ndash3864 2009

[58] F Gambon-Deza C Sanchez-Espinel and J V Beneitez ldquoAnovel IgA-like immunoglobulin in the reptile Eublepharis mac-ulariusrdquo Developmental and Comparative Immunology vol 31no 6 pp 596ndash605 2007

[59] G Cheng Y Gao T Wang et al ldquoExtensive diversification ofIgH subclass-encoding genes and IgM subclass switching incrocodiliansrdquo Nature Communications vol 4 article 1337 2013

[60] S Magadan-Mompo C Sanchez-Espinel and F Gambon-Deza ldquoIgH loci of American alligator and saltwater crocodileshed light on IgA evolutionrdquo Immunogenetics vol 65 no 7 pp531ndash541 2013

[61] E Orlans and M E Rose ldquoAn IgA-like immunoglobulin in thefowlrdquo Immunochemistry vol 9 no 8 pp 833ndash838 1972

[62] G A Leslie and L N Martin ldquoStudies on the secretory immu-nologic system of fowl 3 Serum and secretory IgA of thechickenrdquoThe Journal of Immunology vol 110 no 1 pp 1ndash9 1973

[63] J Bienenstock D Y Perey J Gauldie and B J UnderdownldquoChicken 120574A physicochemical and immunochemical charac-teristicsrdquoThe Journal of Immunology vol 110 no 2 pp 524ndash5331973

[64] A M Lebacq-Verheyden J P Vaerman and J F HeremansldquoQuantification and distribution of chicken immunoglobulinsIgA IgM and IgG in serum and secretionsrdquo Immunology vol27 no 4 pp 683ndash692 1974

[65] J Goudswaard A Noordzij R H van Dam J A vanderDonk and J P Vaerman ldquoThe immunoglobulins of the turkey(Meleagris gallopavo) Isolation and characterization of IgGIgM and IgA in body fluids eggs and intraocular tissuesrdquoPoultry science vol 56 no 6 pp 1847ndash1851 1977

[66] D Hadge and H Ambrosius ldquoComparative studies on thestructure of biliary immunoglobulins of some avian speciesII Antigenic properties of the biliary immunoglobulins ofchicken turkey duck and gooserdquo Developmental and Compar-ative Immunology vol 12 no 2 pp 319ndash329 1988

[67] J Goudswaard J P Vaerman and J F Heremans ldquoThreeimmunoglobulin classes in the pigeon (Columbia livia)rdquo Inter-national Archives of Allergy andApplied Immunology vol 53 no5 pp 409ndash419 1977

[68] P L K Ng and D A Higgins ldquoBile immunoglobulin of theduck (Anas platyrhynchos) I Preliminary characterization andontogenyrdquo Immunology vol 58 no 2 pp 323ndash327 1986

[69] K E Magor G W Warr Y Bando D L Middleton and DA Higgins ldquoSecretory immune system of the duck (Anas

ISRN Immunology 17

platyrhynchos) Identification and expression of the genesencoding IgA and IgM heavy chainsrdquo European Journal ofImmunology vol 28 no 3 pp 1063ndash1068 1998

[70] Y Zhao H Rabbani A Shimizu and L Hammarstrom ldquoMap-ping of the chicken immunoglobulin heavy-chain constantregion gene locus reveals an inverted 120572 gene upstream of acondensed 120592 generdquo Immunology vol 101 no 3 pp 348ndash3532000

[71] M L Lundqvist D L Middleton S Hazard and G W WarrldquoThe immunoglobulin heavy chain locus of the duck genomicorganization and expression of D J and C region genesrdquo TheJournal of Biological Chemistry vol 276 no 50 pp 46729ndash46736 2001

[72] T HuangM Zhang ZWei et al ldquoAnalysis of immunoglobulintranscripts in the ostrich Struthio camelus a primitive avianspeciesrdquo PLoS ONE vol 7 no 3 Article ID e34346 2012

[73] K H Roux ldquoImmunoglobulin structure and function asrevealed by electron microscopyrdquo International Archives ofAllergy and Immunology vol 120 no 2 pp 85ndash99 1999

[74] F Gambon-Deza C Sanchez-Espinel and S Magadan-Mompo ldquoThe immunoglobulin heavy chain locus in the platy-pus (Ornithorhynchus anatinus)rdquo Molecular Immunology vol46 no 13 pp 2515ndash2523 2009

[75] Y Zhao H Cui C M Whittington et al ldquoOrnithorhynchusanatinus (platypus) links the evolution of immunoglobulingenes in eutherian mammals and nonmammalian tetrapodsrdquoThe Journal of Immunology vol 183 no 5 pp 3285ndash3293 2009

[76] M Aveskogh and L Hellman ldquoEvidence for an early appear-ance of modern post-switch isotypes in mammalian evolutioncloning of IgE IgG and IgA from the marsupial Monodelphisdomesticardquo European Journal of Immunology vol 28 no 9 pp2738ndash2750 1998

[77] K Belov G A Harrison and DW Cooper ldquoMolecular cloningof the cDNA encoding the constant region of the immunoglob-ulin a heavy chain (C120572) from amarsupialTrichosurus vulpecula(common brushtail possum)rdquo Immunology Letters vol 60 no2-3 pp 165ndash170 1998

[78] K Belov K R Zenger L Hellman and DW Cooper ldquoEchidnaIgA supports mammalian unity and traditional Therian rela-tionshiprdquo Mammalian Genome vol 13 no 11 pp 656ndash6632002

[79] K Belov and L Hellman ldquoImmunoglobulin genetics of Orni-thorhynchus anatinus (platypus) and Tachyglossus aculeatus(short-beaked echidna)rdquo Comparative Biochemistry and Phys-iology vol 136 no 4 pp 811ndash819 2003

[80] M VernerssonM Aveskogh BMunday and L Hellman ldquoEvi-dence for an early appearance of modern post-switch immu-noglobulin isotypes in mammalian evolution (II) cloning ofIgE IgG1 and IgG2 fromamonotreme the duck-billed platypusOrnithorhynchus anatinusrdquo European Journal of Immunologyvol 32 no 8 pp 2145ndash2155 2002

[81] C Auffray R Nageotte and J L Sikorav ldquoMouse immunoglob-ulin A nucleotide sequence of the structural gene for the 120572heavy chain derived from cloned cDNAsrdquo Gene vol 13 no 4pp 365ndash374 1981

[82] T Ukaji D Sumiyama and O Kai ldquoSequence determinationof the heavy-chain constant region in four immunoglobulinclasses of Mongolian gerbils (Meriones unguiculatus)rdquo Experi-mental Animals vol 61 no 2 pp 99ndash107 2012

[83] R C Burnett W C Hanly S K Zhai and K L Knight ldquoTheIgA heavy chain gene family in rabbit cloning and sequence

analysis of 13 C120572 genesrdquo The EMBO Journal vol 8 no 13 pp4041ndash4047 1989

[84] D K Lanning S-K Zhai and K L Knight ldquoAnalysis of the 31015840C120583 region of the rabbit Ig heavy chain locusrdquoGene vol 309 no2 pp 135ndash144 2003

[85] F Ros J Puels N Reichenberger W van Schooten R Buelowand J Platzer ldquoSequence analysis of 05Mb of the rabbitgermline immunoglobulin heavy chain locusrdquo Gene vol 330no 1-2 pp 49ndash59 2004

[86] M Patel D Selinger G E Mark G J Hickey and G FHollis ldquoSequence of the dog immunoglobulin alpha and epsilonconstant region genesrdquo Immunogenetics vol 41 no 5 pp 282ndash286 1995

[87] Z Zhao Y Zhao Q Pan-Hammarstrom et al ldquoPhysical map-ping of the giant panda immunoglobulin heavy chain constantregion genesrdquo Developmental and Comparative Immunologyvol 31 no 10 pp 1034ndash1049 2007

[88] W R Brown and J E Butler ldquoCharacterization of a C120572 gene ofswinerdquoMolecular Immunology vol 31 no 8 pp 633ndash642 1994

[89] W R Brown H Rabbani J E Butler and L HammarstromldquoCharacterization of the bovine C120572 generdquo Immunology vol 91no 1 pp 1ndash6 1997

[90] G PWhite P Roche M R Brandon S E Newton and E N TMeeusen ldquoCloning and characterization of sheep (Ovis aries)immunoglobulin 120572 chainrdquo Immunogenetics vol 48 no 5 pp359ndash362 1998

[91] AMancia T A Romano H A Gefroh et al ldquoCharacterizationof the immunoglobulin A heavy chain gene of the Atlantic bot-tlenose dolphin (Tursiops truncatus)rdquo Veterinary Immunologyand Immunopathology vol 118 no 3-4 pp 304ndash309 2007

[92] B Wagner I Greiser-Wilke and D F Antczak ldquoCharacteriza-tion of the horse [Equus caballus] IGHA generdquo Immunogeneticsvol 55 no 8 pp 552ndash560 2003

[93] N Takahashi S Ueda and M Obata ldquoStructure of humanimmunoglobulin gamma genes implications for evolution of agene familyrdquo Cell vol 29 no 2 pp 671ndash679 1982

[94] J G Flanagan M-P Lefranc and T H Rabbitts ldquoMechanismsof divergence and convergence of the human immunoglobulin1205721 and 1205722 constant region gene sequencesrdquo Cell vol 36 no 3pp 681ndash688 1984

[95] S Kawamura K Omoto and S Ueda ldquoEvolutionary hypervari-ability in the hinge region of the immunoglobulin alpha generdquoJournal of Molecular Biology vol 215 no 2 pp 201ndash206 1990

[96] F Scinicariello F Masseoud L Jayashankar and R AttanasioldquoSooty mangabey (Cercocebus torquatus atys) IGHG and IGHAgenesrdquo Immunogenetics vol 58 no 12 pp 955ndash965 2006

[97] K A Rogers L Jayashankar F Scinicariello and R AttanasioldquoNonhuman primate IgA genetic heterogeneity and interac-tions with CD89rdquoThe Journal of Immunology vol 180 no 7 pp4816ndash4824 2008

[98] S Kawamura N Saitou and S Ueda ldquoConcerted evolution ofthe primate immunoglobulin 120572-gene through gene conversionrdquoThe Journal of Biological Chemistry vol 267 no 11 pp 7359ndash7367 1992

[99] S Kawamura and S Ueda ldquoImmunoglobulin C119867gene family in

hominoids and its evolutionary historyrdquo Genomics vol 13 no1 pp 194ndash200 1992

[100] A Brusco U Cariota A Bottaro et al ldquoStructural andimmunologic analysis of gene triplications in the Ig heavy chainconstant region locusrdquoThe Journal of Immunology vol 152 no1 pp 129ndash135 1994

18 ISRN Immunology

[101] H Rabbani Q Pan N Kondo C I E Smith and L Ham-marstrom ldquoDuplications and deletions of the human IGHClocus evolutionary implicationsrdquo Immunogenetics vol 45 no2 pp 136ndash141 1996

[102] P F Weinheimer J Mestecky and R T Acton ldquoSpecies distri-bution of J chainrdquoThe Journal of Immunology vol 107 no 4 pp1211ndash1212 1971

[103] F P Inman and J Mestecky ldquoThe J chain of polymeric immu-noglobulinsrdquo inContemporary Topics inMolecular Immunologyvol 3 pp 111ndash141 Springer New York NY USA 1974

[104] P Brandtzaeg ldquoPresence of J chain in human immunocytescontaining various immunoglobulin classesrdquo Nature vol 252no 5482 pp 418ndash420 1974

[105] L Tacchi E Larragoite and I Salinas ldquoDiscovery of J chain inAfrican lungfish (Protopterus dolloi Sarcopterygii) using highthroughput transcriptome sequencing implications in mucosalimmunityrdquo PLoS ONE vol 8 no 8 Article ID e70650 2013

[106] I K Zarkadis D Mastellos and J D Lambris ldquoPhylogeneticaspects of the complement systemrdquo Developmental and Com-parative Immunology vol 25 no 8-9 pp 745ndash762 2001

[107] A P West Jr A B Herr and P J Bjorkman ldquoThe chickenyolk sac IgY receptor a functional equivalent of themammalianMHC-related Fc receptor is a phospholipase A

2receptor

homologrdquo Immunity vol 20 no 5 pp 601ndash610 2004[108] D B Tesar E J Cheung and P J Bjorkman ldquoThe chicken

yolk sac IgY receptor a mammalian mannose receptor familymember transcytoses IgY across polarized epithelial cellsrdquoMolecular Biology of the Cell vol 19 no 4 pp 1587ndash1593 2008

[109] A I Taylor R L Beavil B J Sutton and R A Calvert ldquoAmonomeric chicken IgY receptor binds IgY with 21 stoichiom-etryrdquo The Journal of Biological Chemistry vol 284 no 36 pp24168ndash24175 2009

[110] K Baker S-W Qiao T Kuo et al ldquoImmune and non-immunefunctions of the (not so) neonatal Fc receptor FcRnrdquo Seminarsin Immunopathology vol 31 no 2 pp 223ndash236 2009

[111] K Baker R S Blumberg and C S Kaetzel ldquoImmunoglob-ulin transport and immunoglobulin receptorsrdquo in MucosalImmunology J Mestecky W Strober H Cheroutre B KelsallB N Lambrecht andMW Russell Eds chapter 20 AcademicPressElsevier Waltham Mass USA 2014

[112] C S Kaetzel ldquoThepolymeric immunoglobulin receptorrdquo in eLSJohn Wiley amp Sons Chichester UK 2013

[113] N J Mantis N Rol and B Corthesy ldquoSecretory IgArsquos complexroles in immunity andmucosal homeostasis in the gutrdquoMucosalImmunology vol 4 no 6 pp 603ndash611 2011

[114] J V Peppard M E Rose and P Hesketh ldquoA functional homo-logue of mammalian secretory component exists in chickensrdquoEuropean Journal of Immunology vol 13 no 7 pp 566ndash5701983

[115] K E Mostov M Friedlander and G Blobel ldquoThe receptorfor transepithelial transport of IgA and IgM contains multipleimmunoglobulin-like domainsrdquo Nature vol 308 no 5954 pp37ndash43 1984

[116] P Krajci R Solberg M Sandberg O Oyen T Jahnsen and PBrandtzaeg ldquoMolecular cloning of the human transmembranesecretory component (poly-Ig receptor) and its mRNA expres-sion in human tissuesrdquo Biochemical and Biophysical ResearchCommunications vol 158 no 3 pp 783ndash789 1989

[117] P Krajci D Kvale K Tasken and P Brandtzaeg ldquoMolecularcloning and exon-intron mapping of the gene encoding humantransmembrane secretory component (the poly-Ig receptor)rdquo

European Journal of Immunology vol 22 no 9 pp 2309ndash23151992

[118] J F Piskurich J A France C M Tamer C A Willmer CS Kaetzel and D M Kaetzel ldquoInterferon-120574 induces polymericimmunoglobulin receptormRNA in human intestinal epithelialcells by a protein synthesis dependent mechanismrdquo MolecularImmunology vol 30 no 4 pp 413ndash421 1993

[119] J F Piskurich M H Blanchard K R Youngman J A Franceand C S Kaetzel ldquoMolecular cloning of the mouse polymericIg receptor functional regions of the molecule are conservedamong five mammalian speciesrdquo The Journal of Immunologyvol 154 no 4 pp 1735ndash1747 1995

[120] M A Kulseth P Krajci O Myklebost and S RogneldquoCloning and characterization of two forms of bovine polymericimmunoglobulin receptor cDNArdquo DNA and Cell Biology vol14 no 3 pp 251ndash256 1995

[121] K S Koch A S Gleiberman T Aoki et al ldquoDiscordant expres-sion and variable numbers of neighboring GGA- and GAA-richtriplet repeats in the 31015840 untranslated regions of two groups ofmessenger RNAs encoded by the rat polymeric immunoglob-ulin receptor generdquo Nucleic Acids Research vol 23 no 7 pp1098ndash1112 1995

[122] F M Adamski and J Demmer ldquoTwo stages of increased IgAtransfer during lactation in themarsupialTrichosurus vulpecula(brushtail possum)rdquoThe Journal of Immunology vol 162 no 10pp 6009ndash6015 1999

[123] H Kumura T Sone K-I Shimazaki and E KobayashildquoSequence analysis of porcine polymeric immunoglobulinreceptor from mammary epithelial cells present in colostrumrdquoThe Journal of Dairy Research vol 67 no 4 pp 631ndash636 2000

[124] C L Taylor G A Harrison C M Watson and E M DeaneldquocDNA cloning of the polymeric immunoglobulin receptor ofthe marsupial Macropus eugenii (tammar wallaby)rdquo EuropeanJournal of Immunogenetics vol 29 no 2 pp 87ndash93 2002

[125] R Braathen V S Hohman P Brandtzaeg and F-E JohansenldquoSecretory antibody formation conserved binding interactionsbetween J chain and polymeric Ig receptor from humans andamphibiansrdquo The Journal of Immunology vol 178 no 3 pp1589ndash1597 2007

[126] M J Lewis BWagner R M Irvine and J MWoof ldquoIgA in thehorse cloning of equine polymeric Ig receptor and J chain andcharacterization of recombinant forms of equine IgArdquoMucosalImmunology vol 3 no 6 pp 610ndash621 2010

[127] A J Leon D Banner L Xu et al ldquoSequencing annotation andcharacterization of the influenza ferret infectomerdquo Journal ofVirology vol 87 no 4 pp 1957ndash1966 2013

[128] W H Wieland D Orzaez A Lammers H K ParmentierM W A Verstegen and A Schots ldquoA functional polymericimmunoglobulin receptor in chicken (Gallus gallus) indicatesancient role of secretory IgA inmucosal immunityrdquoBiochemicalJournal vol 380 no 3 pp 669ndash676 2004

[129] K Hamuro H Suetake N R Saha K Kikuchi and YSuzuki ldquoA teleost polymeric Ig receptor exhibiting two Ig-likedomains transports tetrameric IgM into the skinrdquo The Journalof Immunology vol 178 no 9 pp 5682ndash5689 2007

[130] J H W M Rombout S J L van der Tuin G Yang et alldquoExpression of the polymeric immunoglobulin receptor (pIgR)in mucosal tissues of common carp (Cyprinus carpio L)rdquo Fishand Shellfish Immunology vol 24 no 5 pp 620ndash628 2008

[131] L-N Feng D-Q Lu J-X Bei et al ldquoMolecular cloning andfunctional analysis of polymeric immunoglobulin receptor gene

ISRN Immunology 19

in orange-spotted grouper (Epinephelus coioides)rdquo ComparativeBiochemistry and Physiology B vol 154 no 3 pp 282ndash289 2009

[132] A E Oslashstergaard S A M Martin T Wang R J M Stet andC J Secombes ldquoRainbow trout (Oncorhynchus mykiss) pos-sessmultiple novel immunoglobulin-like transcripts containingeither an ITAM or ITIMsrdquo Developmental and ComparativeImmunology vol 33 no 4 pp 525ndash532 2009

[133] H Eiffert E Quentin and J Decker ldquoThe primary structureof the human free secretory component and the arrangementof disulfide bondsrdquo Hoppe-Seylerrsquos Zeitschrift fur PhysiologischeChemie vol 365 no 12 pp 1489ndash1495 1984

[134] E Fallgreen-Gebauer W Gebauer A Bastian et al ldquoThe cova-lent linkage of secretory component to IgA Structure of sIgArdquoBiological Chemistry Hoppe-Seyler vol 374 no 11 pp 1023ndash1028 1993

[135] J MWoof ldquoThe structure of IgArdquo inMucosal Immune DefenseImmunoglobulin A C S Kaetzel Ed chapter 1 pp 1ndash24Springer New York NY USA 2007

[136] A Bonner A Almogren P B Furtado M A Kerr and S JPerkins ldquoLocation of secretory component on the Fc edge ofdimeric IgA1 reveals insight into the role of secretory IgA1 inmucosal immunityrdquoMucosal Immunology vol 2 no 1 pp 74ndash84 2009

[137] A Bonner A Almogren P B Furtado M A Kerr and S JPerkins ldquoThe nonplanar secretory IgA2 and near planar secre-tory IgA1 solution structures rationalize their different mucosalimmune responsesrdquo The Journal of Biological Chemistry vol284 no 8 pp 5077ndash5087 2009

[138] J Johansen B Braathen and P Brandtzaeg ldquoRole of J chain insecretory immunoglobulin formationrdquo Scandinavian Journal ofImmunology vol 52 no 3 pp 240ndash248 2000

[139] B A Hendrickson D A Conner D J Ladd et al ldquoAlteredhepatic transport of immunoglobulin A in mice lacking the Jchainrdquo Journal of Experimental Medicine vol 182 no 6 pp1905ndash1911 1995

[140] B A Hendrickson L Rindisbacher B Corthesy et al ldquoLackof association of secretory component with IgA in J chain-deficient micerdquo The Journal of Immunology vol 157 no 2 pp750ndash754 1996

[141] N Lycke L Erlandsson L Ekman K Schon and T Lean-derson ldquoLack of J chain inhibits the transport of gut IgA andabrogates the development of intestinal antitoxic protectionrdquoThe Journal of Immunology vol 163 no 2 pp 913ndash919 1999

[142] F-E Johansen R Braathen and P Brandtzaeg ldquoThe J chainis essential for polymeric Ig receptor-mediated epithelial trans-port of IgArdquoThe Journal of Immunology vol 167 no 9 pp 5185ndash5192 2001

[143] R E Ley D A Peterson and J I Gordon ldquoEcological andevolutionary forces shaping microbial diversity in the humanintestinerdquo Cell vol 124 no 4 pp 837ndash848 2006

[144] M McFall-Ngai ldquoAdaptive immunity care for the communityrdquoNature vol 445 no 7124 p 153 2007

[145] A J Macpherson K D McCoy F-E Johansen and PBrandtzaeg ldquoThe immune geography of IgA induction andfunctionrdquoMucosal Immunology vol 1 no 1 pp 11ndash22 2008

[146] D Kvale and P Brandtzaeg ldquoConstitutive and cytokine inducedexpression of HLA molecules secretory component and inter-cellular adhesion molecule-1 is modulated by butyrate in thecolonic epithelial cell line HT-29rdquo Gut vol 36 no 5 pp 737ndash742 1995

[147] L VHooperMHWong AThelin L Hansson P G Falk andJ I Gordon ldquoMolecular analysis of commensal host-microbialrelationships in the intestinerdquo Science vol 291 no 5505 pp 881ndash884 2001

[148] S Hapfelmeier M A E Lawson E Slack et al ldquoReversiblemicrobial colonization of germ-free mice reveals the dynamicsof IgA immune responsesrdquo Science vol 328 no 5986 pp 1705ndash1709 2010

[149] DH ReikvamMDerrien R Islam et al ldquoEpithelial-microbialcross-talk in polymeric Ig receptor deficient micerdquo EuropeanJournal of Immunology vol 42 no 11 pp 2959ndash2970 2012

[150] EW Rogier A L Frantz M E C Bruno et al ldquoSecretory anti-bodies in breast milk promote long-term intestinal homeostasisby regulating the gut microbiota and host gene expressionrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 111 no 8 pp 3074ndash3079 2014

[151] G M Barton and R Medzhitov ldquoToll-like receptor signalingpathwaysrdquo Science vol 300 no 5625 pp 1524ndash1525 2003

[152] K Takeda and S Akira ldquoToll receptors and pathogen resis-tancerdquo Cellular Microbiology vol 5 no 3 pp 143ndash153 2003

[153] E Cario andD K Podolsky ldquoDifferential alteration in intestinalepithelial cell expression of Toll-like receptor 3 (TLR3) andTLR4 in inflammatory bowel diseaserdquo Infection and Immunityvol 68 no 12 pp 7010ndash7017 2000

[154] M Hausmann S Kiessling S Mestermann et al ldquoToll-likereceptors 2 and 4 are up-regulated during intestinal inflamma-tionrdquo Gastroenterology vol 122 no 7 pp 1987ndash2000 2002

[155] M T Abreu L S Thomas S Y Tesfay et al ldquoRegulation ofTLR4 and MD-2 in the intestinal epithelium evidence for dys-regulated LPS signaling in human inflammatory bowel diseaserdquoin Proceedings of the 90th Annual Meeting of the AmericanAssociation for Immunologists Abstract 3634 Denver ColoUSA 2003

[156] T A Schneeman M E C Bruno H Schjerven F-E JohansenL Chady and C S Kaetzel ldquoRegulation of the polymeric Igreceptor by signaling through TLRs 3 and 4 linking innate andadaptive immune responsesrdquo The Journal of Immunology vol175 no 1 pp 376ndash384 2005

[157] M E C Bruno A L Frantz E W Rogier F-E Johansen andC S Kaetzel ldquoRegulation of the polymeric immunoglobulinreceptor by the classical and alternative NF-120581B pathways inintestinal epithelial cellsrdquoMucosal Immunology vol 4 no 4 pp468ndash478 2011

[158] M E C Bruno E W Rogier A L Frantz A T Stefka SN Thompson and C S Kaetzel ldquoRegulation of the poly-meric immunoglobulin receptor in intestinal epithelial cellsby Enterobacteriaceae implications for mucosal homeostasisrdquoImmunological Investigations vol 39 no 4-5 pp 356ndash382 2010

[159] A L Frantz E W Rogier C R Weber et al ldquoTargeted deletionof MyD88 in intestinal epithelial cells results in compromisedantibacterial immunity associatedwith downregulation of poly-meric immunoglobulin receptor mucin-2 and antibacterialpeptidesrdquoMucosal Immunology vol 5 no 5 pp 501ndash512 2012

[160] E W Rogier A L Frantz M E C Bruno and C S KaetzelldquoSecretory IgA is concentrated in the outer layer of intestinalmucus along with gut bacteriardquo Pathogens In press

[161] M B Geuking K D McCoy and A J Macpherson ldquoThe func-tion of secretory IgA in the context of the intestinal continuumof adaptive immune responses in host-microbial mutualismrdquoSeminars in Immunology vol 24 no 1 pp 36ndash42 2012

20 ISRN Immunology

[162] L VHooper D R Littman andA JMacpherson ldquoInteractionsbetween the microbiota and the immune systemrdquo Science vol336 no 6086 pp 1268ndash1273 2012

[163] A J Macpherson M B Geuking E Slack S Hapfelmeierand K D McCoy ldquoThe habitat double life citizenship andforgetfulness of IgArdquo Immunological Reviews vol 245 no 1 pp132ndash146 2012

Submit your manuscripts athttpwwwhindawicom

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Oxidative Medicine and Cellular Longevity

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The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

2 ISRN Immunology

Vertebrata

Gnathostomata

Osteichthyes

Sarcopterygii

Tetrapoda

Amniota

Placentals

Marsupials

Monotremes

Birds

Crocodilians

Lizards and snakes

Turtles

Frogs

Salamanders

Lungfishes

Coelacanths

Cartilaginous fishes

Lampreys

HagfishesAgnathans

Amphibians

Reptiles

Mammals

IgM

IgT

IgX

IgD

IgD

IgD

IgD

IgY

IgY

IgY

VLR

IgE

IgM

IgGIgA

IgA

IgA

Ray-finned bony fishes

and birds

Lobe-finnedbony fishes IgM

IgM

IgM

IgM

IgM

IgM

IgWD

IgWD

IgWD

IgWD IgNAR

Figure 1 A model for evolution of immunoglobulin isotypes in vertebrates The antigen-binding variable lymphocyte receptors (VLRs)expressed in extant Agnathans are thought to represent the precursors of modern immunoglobulins (Igs) Genes encoding Ig heavy andlight chains apparently emerged prior to the split between cartilaginous and bony fishes resulting in expression of Ig molecules that arecharacteristic of higher vertebrates Cartilaginous fishes express an IgD-like molecule (IgWD) and IgM which is found evenly distributedbetween blood and mucosal secretionsThe first evidence of a dedicated mucosal Ig isotype came with the emergence of IgT in an ancestor ofmodern bony fishes Subsequent duplication of Ig constant region genes and evolution of Ig class switchingmechanisms in a common ancestorof tetrapods allowed the production ofmultiple Ig isotypes during immune responses Color coding indicates the presumed evolution of avianand mammalian IgA from a precursor of amphibian IgX and evolution of mammalian IgG and IgE from a precursor of amphibian IgY

forms the antigen-binding site while the Fc regions of the Igheavy chains (comprising the two most C-terminal constantdomains) confer isotype-specific immune effector functionsSome Ig isotypes can form higher-order polymers of thebasic 4-chain unit thus increasing the number of Ag-bindingsites and enhancing Fc-mediated functions The emergenceof new Ig isotypes during vertebrate evolution allowed fordiversification of Ig-mediated immune functions includingthose specialized for mucosal surfaces (reviewed in [8])Many Ig-mediated immune functions involve interactionswith isotype-specific cellular receptors for the Fc region ofIg heavy chains (Figure 3) The most evolutionarily ancientFc receptor is the polymeric Ig receptor (pIgR) a proteinexpressed selectively bymucosal and glandular epithelial cellsthat transports polymeric Igs into external secretions It hasbeen hypothesized that the complex relationship betweenthe vertebrate host and its resident microbiota provided thedriving force for evolution of the adaptive immune system[1 5] In this review the concept will be explored that animportant consequence of this selective pressure was thecoevolution of mucosal Igs and pIgR

2 Evolution of Mucosal Immunoglobulins

21 Cartilaginous Fishes Primordial Ig-like genes arebelieved to have arisen in a common ancestor of the Gna-thostomata (jawed vertebrates) [2 3] (Figure 1) The most

primitive extant jawed vertebrates comprise the class Chon-drichthyes (cartilaginous fishes) including sharks raysand skates Multiple Ig isotypes have been identified inthe horned shark (Heterodontus francisci) [18] nurse shark(Ginglymostoma cirratum) [19 20] and several species ofskates [21] The primordial IgM of cartilaginous fishes isorthologous to the IgM of higher vertebrates while a secondIg isotype initially called IgW is orthologous to IgD [22] Athird Ig isotype identified in the nurse shark called the Igldquonew antigen receptorrdquo (IgNAR) is homologous to IgM andIgWD but does not have an ortholog in higher vertebrates[19] The IGH and IGL genes are dispersed throughout thegenome of cartilaginous fish in hundreds of clusters eachrepresenting an individual isotype [18 21]

22 Bony Fishes Major changes in the organization of Iggenes occurred during the emergence of the Teleostomithe clade of jawed vertebrates that includes the superclassesOsteichthyes (bony fishes) and Tetrapoda (four-limbed ver-tebrates) (Figure 1) The dispersed IGH loci characteristic ofcartilaginous fishes were replaced with a translocon orga-nization comprising a 51015840 region of VH DH and JH genesegments encoding the Ig heavy chain variable region fol-lowed by tandem CH gene segments encoding Ig heavy chainconstant regions for different isotypes (reviewed in [23])Thistranslocation organization allows a B lymphocyte to ldquoswitchrdquoproduction from one Ig heavy chain isotype to another

ISRN Immunology 3

domain

domain

domain

Hinge region

Fc region

Antigen-binding site

CL

VL

VH

CH1 domain

CH2 domain

CH3 domain

Figure 2 The basic structure of immunoglobulins The basic structural unit of Igs comprises 2 identical light chains (shown in red andblue) and 2 identical heavy chains (shown in red and blue) The polypeptide chains of Ig light and heavy chains consist of repeating unitsof approximately 110 amino acids so-called ldquoIg-likerdquo domains with a characteristic 3-dimensional structure Ig light chains comprise an N-terminal variable (VL) domain followed by a constant (CL) domain of either the 120581 or 120582 type Ig heavy chains comprise an N-terminal variabledomain (VH) followed by 3-4 constant domains (CH1ndashCH3 or 4)The sequence of Ig heavy chain constant regions (designated byGreek letterssuch as 120572 120574 or 120583) defines the Ig class or isotype The structure shown here is characteristic of mammalian IgA IgD and IgG in which theCH1 and CH2 domains of the heavy chains are connected by a short cysteine- and proline-rich hinge region The structure of all Igs in lowervertebrates (as well as IgM and IgE in mammals) differs in that the CH2 domain replaces the hinge region and the Fc region comprises theCH3 and CH4 domains Pairing of VH and VL domains on adjacent Ig heavy and light chains forms the antigen-binding site while the Fcregions of the Ig heavy chains (comprising the two most C-terminal constant domains) confer isotype-specific immune effector functions

during immune responses by a process of DNA rearrange-ment called class switch recombination (CSR) [24ndash26] Mostof the studies of Ig structure and function in bony fisheshave focused on the Actinopterygii (ray-finned bony fishes)which comprise 99 of the over 30000 living species offish mainly within the infraclass Teleostei Early studies inseveral teleost species including plaice (Pleuronectes platessa)[27] common carp (Cyprinus carpio) [28] rainbow trout(Oncorhynchus mykiss) [29] and channel catfish (Ictaluruspunctatus) [30] demonstrated that immunization bymucosalroutes (oral anal and skin) elicited antibody responses in theskin intestinal mucus and bile In 2005 a novel Ig isotypewas described in rainbow trout [31] zebrafish (Danio rerio)[32] and fugu (Fugu rubripes) [33] designated IgT (for teleost)or IgZ (for zebrafish) In the same year an unusual Igisotype described in the common carp which appeared tobe a chimera of IgM and IgZ [34] was identified (Cyprinuscarpio) Subsequent studies in a number of teleost speciesrevealed a common translocon structure in the IGH locuswith tandem gene segments encoding the constant regionsof IgM IgD and IgT(Z) [35ndash37] Functional studies revealed

that the molar ratio of IgT to IgM was 60-fold higher in gutmucus than in serum of rainbow trout and that specific IgTantibodies were induced in the gut following oral infectionwith the parasite Ceratomyxa shasta [38] In this study IgT-expressing lymphocytes were found to represent 543 of allB cells in the intestinal lamina propria Interestingly IgT wasfound as amonomer in serum but as a tetramer in gutmucussuggestive of a selectivemechanism for polymerization of IgTin mucosal B cells similar to that observed for IgA in highervertebrates Thus IgT appears to be the most primitive Igisotype with specialized functions at mucosal surfaces

Although IgT has been identified in most Actinopterygiithus far studied some exceptions have been noted Theabsence of a gene encoding IgT was recently reported in theSiberian sturgeon (Acipenser baerii) a species of the orderAcipenseriformes which occupies a unique phylogeneticniche between the cartilaginous fishes and the Teleostei Theabsence of IgT was also reported in the medaka (Oryziaslatipes) a teleost of the order Beloniformes [39] SurprisinglyIgT is absent in channel catfish a teleost of the order Siluri-formes which is closely related to the order Cypriniformes

4 ISRN Immunology

Ig-like domain

Cysteine-rich domain

Fibronectin type II repeat

C-type lectin-like domain

pIgR

PolymericIgM IgTIgX IgA

Epithelialcells

(CD351)

IgM IgA

B cells

(CD89)

IgA

NeutrophilsMonocytes

Eosinophils

(CD64)

IgG

Monocytes

NeutrophilsEosinophils

(CD32)

IgG

Monocytes

NeutrophilsPlatelets

LangerhansB cells

(CD16)

IgG

NK cells

MonocytesNeutrophilsEosinophils

IgE

Mast cellsBasophils

LangerhansMonocytes

(CD23)

IgE

B cellsT cells

MonocytesEosinophils

FcRn

IgG

Endothelial

Epithelialcells

cells

FcRY

IgY

Endothelialcells

Fc120572120583R

MΦs

Fc120572RI

MΦsMΦs MΦs

MΦs

Fc120574RI Fc120574RII Fc120574RIII

120574120575 T cells

Fc120576RIIFc120576RI

MΦs

1205732m

MHC I-like domain

Figure 3 Fc receptors are Ig isotype- and cell type-specific These schematic diagrams illustrate basic structural features of selectedFc receptors all of which are Type I transmembrane proteins The structures are not to scale and do not imply specific 3-dimensionalconformations All of the structures represent the human homolog of the indicated protein except for FcRY which is from chicken Binding ofthe constant (Fc) region of Igs to cellular receptors initiates transport across epithelial cells or intracellular signaling in cells of hematopoieticorigin The membrane-proximal Ig-like domain of FcRn pairs with the Ig-like domain of soluble 1205732-microglobulin (1205732m) The Ig-bindingsubunits of Fc120572RI Fc120574RI Fc120574RII Fc120574RIII and Fc120576RI (shownhere) pair with other protein subunits (not shown) to initiate signaling pathwaysThis figure was compiled using information from [9ndash15]

that includes the IgT-expressing carp and zebrafish The IGHloci of the few extant species of the class Sarcopterygii (lobe-finned bony fishes including coelacanths and lungfishes)differ from those ofmost of the Actinopterygii (Figure 1)TheAfrican coelacanth (Latimeria chalumnae) one of only twospecies of an ancient class of lobe-finned fishes lacks IgM andhas a single Ig heavy chain gene that resembles the IgWDgene of cartilaginous fishes [40] By contrast the Africanlungfish (Protopterus aethiopicus) expresses both IgM and anisotype resembling IgWD [41] No ortholog of IgT has beenidentified in lobe-finned bony fishes Given the diversity of Iggenes in bony fishes the evolutionary origin of IgT remainsobscure Furthermore while IgT shares many functionalsimilarities with IgA in higher vertebrates the structuralgenes for IgT and IgA are not orthologous [23] Thus thegene encoding IgT appears to be an evolutionary dead-endthat emerged in some lineages of bony fishes in response topressures for immunological protection of mucosal surfaceslikely driven by the resident microbiota as well as mucosalpathogens

23 Amphibians Duplication and diversification of genesegments within the IGH locus in a common ancestor of theTetrapoda (four-limbed vertebrates) led to the appearanceof additional heavy chain Ig isotypes (reviewed in [42])(Figure 1) Most extant species of tetrapods have a single IGHlocus the location of which is syntenic with the human IGHlocus Ectothermic vertebrates of the class Amphibia are themost primitive tetrapods having diverged about 370 millionyears ago from a common ancestor with reptiles birds andmammals Early studies of the structural and immunologicalproperties of Igs from several species of clawed frogs (Xeno-pus) suggested the emergence of two novel Ig isotypes IgXand IgY [43ndash47] (Figure 1) B cells expressing IgX but not IgYwere found abundantly in the intestinal epithelium whereasIgX-positive cells were rarely detected in the spleen and IgXlevels were very low in serum [47] Interestingly thymectomyabolished expression of IgY but not IgM or IgX consistentwith a T-independent role for IgX in the mucosal immunesystem of amphibians Genes encoding IgX and IgY weresubsequently identified in 2 species of salamanders [48 49]

ISRN Immunology 5

suggesting that these Ig isotypes may have emerged in acommon ancestor of amphibians To date no studies havebeen reported on IGH loci in caecilians A recent study inXenopus laevis established the position of amphibian IgX asthe evolutionary precursor of IgA in birds and mammals[50] These investigators found that larval thymectomy didnot affect levels of IgX and did not alter the compositionof the gut microbiota confirming the T-independence ofthe IgX response in Xenopus Phylogenetic comparisons ofIgT in bony fishes and IgX in amphibians suggest that theseIg isotypes evolved independently [23] likely responding tosimilar pressures from the resident microbiota and mucosalpathogens

24 Reptiles and Birds The clade Amniota within the super-class Tetrapoda can be subdivided into the sauropsids (rep-tiles and birds) and synapsids (mammals and their closerelatives) (Figure 1) The distinction between reptiles andbirds is based largely on physical characteristics rather thanphylogeny distinguishing the cold-blooded reptiles withscales from the warm-blooded birds with feathers Earlystudies of Igs in turtles lizards and snakes were basedlargely on their physicochemical and antigenic propertiesrevealing a predominance of IgM and lesser amounts of IgYin bile and gut secretions [51ndash53] Subsequent analyses usingantibodies to chicken IgA failed to detect a cross-reactive Igisotype in reptiles [54 55] The recent availability of wholegenome sequences for 2 species of turtles (Chrysemys pictaand Pelodiscus sinensis) [36 56] and the green anole lizard(Anolis carolinensis) [57] demonstrated the presence of genesegments encoding IgM IgD and multiple subclasses ofIgY but no ortholog of IgX in amphibians or IgA in birdsand mammals The leopard gecko (Eublepharis macularius)expresses IgM IgD and a third Ig isotype that is intermediatein homology between IgA and IgY [50 58] (designatedIgldquoArdquo for the purposes of this review) The recent availabilityof whole genome sequences for 4 crocodilians (Alligatorsinensis Alligator mississippiensis Crocodylus siamensis andCrocodylus porosus) revealed significant differences in theIGH loci compared to other reptiles including multiple sub-classes of IgM IgD and IgA (orthologous to the IgA genes ofbirds and mammals) but no IgY [59 60] Early studies of theimmune systems of birds (class Aves) revealed the presenceof an ortholog of mammalian IgA in mucosal secretionsand an ortholog of IgG (designated IgY) in serum [61ndash69]Mapping of the IGH locus in chickens and ducks revealed aninverted gene segment encoding IgA downstream of the IgMgene segment and upstream of the IgY gene segment andloss of the gene segment encoding IgD [70 71] Availabilityof whole genome sequences for a variety of bird species inthe National Center for Biotechnology Information (NCBI)database demonstrates the consistent presence of IgM IgAand IgY and the absence of IgD A recent analysis of Iggene transcripts in the ostrich (Struthio camelus) revealedsimilarities with chickens ducks and other birds includingthe expression of IgM IgA and IgY and the absence of IgD[72] Because the ostrich is one of the most primitive extantspecies of birds it appears that the distinctive organization

of the IGH locus evolved very early during the divergence ofthe avian lineage Furthermore a phylogenetic comparisonof Ig heavy chain sequences from amphibians with those ofhigher vertebrates demonstrated with high statistical supportthat IgX from amphibians and IgA from birds share arecent common ancestor [50] Taken together the evidenceis consistent with an IGH locus in a common ancestor ofreptiles and birds that included gene segments encoding IgMIgD IgA and IgY Instability in the IGH locus in individuallineages apparently resulted in the selective loss of IgA inmostturtles lizards and snakes IgY in crocodilians and IgD inbirds

25 Mammals The structure of Ig genes and their encodedproteins has been studied extensively in extant species of theclass Mammalia including the egg-laying monotremes thepouch-bearing marsupials and the placentals (eutherians)(reviewed in [8]) The IGH locus in all known mammalsis organized as a translocon with gene segments encodingIgM IgD 2 or more subclasses of IgG 1 or more subclassesof IgA and IgE an isotype unique to mammals (Figure 1)A recent phylogenetic analysis of Ig heavy chain classes intetrapods indicated with high statistical probability that theIgA gene(s) in mammals evolved from an IgX gene in acommon ancestor of all tetrapods while the IgG and IgEgenes evolved more recently from IgY in a common ancestorof amniotes [50] Continuing diversification in the IGH locusinmammals is evidenced by differences in the number of IgGand IgA subclasses and in the structure of Ig heavy chainsUnlike all Ig heavy chains in lower vertebrates comprising 1variable Ig-like domain (VH) and 4 constant Ig-like domains(CH1ndashCH4) the CH2 domain in mammalian IgA IgD andIgG was replaced with a short flexible hinge region richin cysteine and proline residues [73] The heavy chain ofmammalian IgE has retained the prototypic 4 constant Ig-likedomains (as has IgM) suggesting that the evolution of thehinge region in mammalian IgG occurred after the evolutionof IgG and IgE from an ancestral IgY gene (Figure 1)

Determination of the structure of the IGH locus in themonotreme duck-billed platypus (Ornithorhynchus anatinus)revealed the presence of 8 CH genes (including 2 subclassesof IgG and 2 subclasses of IgG) arranged in the order C

120583-

C120575-Co-C1205742-C1205741-C1205721-C120576-C1205722 [74 75] Interestingly the gene

encoding platypus IgD lacks a hinge region and is moresimilar in structure to IgD in lower vertebrates than the IgDof eutherian mammals Downstream of the C

120575gene in the

platypus is a novel Co gene (omicron for Ornithorhynchus)which appears to have evolved from an ancestral IgY geneIn contrast to the platypus only one IgA gene was identifiedin another monotreme the echidna (Tachyglossus aculeatus)and in several species of marsupials [76ndash80] Similarly asingle structural gene for IgA has been identified in 3 speciesof the eutherian order Rodentia mouse (Mus musculus)[81] rat (Rattus norvegicus) (unpublishedGenbank accessionnumber AJ510151) and gerbil (Meriones unguiculatus) [82]By contrast the IGH locus in the European rabbit (Orycto-lagus cuniculus order Lagomorpha) is unique among mam-mals apparently having evolved from a common ancestor

6 ISRN Immunology

prior to the divergence of marsupials and monotremes fromeutherians Distinctive features include a single IgG subclass13 functional IgA subclasses and absence of IgD [83ndash85] Amore typical organization of the IGH locus including singlesubclasses of IgM IgD IgA and IgE and 2 subclasses ofIgG has been reported in mammals of the orders Carnivora[86 87] Cetartiodactyla (even-toed ungulates whales anddolphins) [88ndash91] and Perissodactyla (odd-toed ungulates)[92]

Mammals of the order Primates including humanshave the greatest number and diversity of Ig classes andsubclasses among all of the tetrapods Mapping of IGH locihas now been completed for a number of primate speciesincluding human (Homo sapiens) gorilla (Gorilla gorilla)chimpanzee (Pan troglodytes) orangutan (Pongo pygmaeus)gibbon (Hylobates lar) baboon (Papio anubis) mangabey(Cercocebus torquatus atys) and three species of macaquesthe crab-eating monkey (Macaca fascicularis) pig-tailedmonkey (Macaca nemestrina) and rhesus monkey (Macacamulatta) [93ndash97] A distinguishing feature of primates in thefamily Hominidae (great apes including humans gorillaschimpanzees and orangutans) and the family Hylobatidae(gibbons) is the presence of two IgA subclasses Althoughthe orangutan is a member of the family Hominidae its IGHlocus contains only one IgA subclass gene homologous to theIgA1 gene of other hominoids [95] By contrast primates inthe family Cercopithecidae (Old World monkeys includingbaboons mangabeys and macaques) have a single IgA geneGenetic analysis of the IGH locus of primates suggested thatduplication and diversification of the primordial C

1205741-C1205742-

C120576-C120572region occurred in a common ancestor of the great

apes after the divergence from Old World monkeys [98 99]These events resulted in the current organization of the IGHlocus in extant species of great apes with four IgG subclassesand two IgA subclasses (the duplicated C

120576gene became a

nonfunctional pseudogene hence only one class of IgE isexpressed) The close phylogenetic relationship among theC120572genes in the hominoids and Hylobatidae suggests that

the C1205721

and C1205722

genes evolved from a single C120572gene in a

common ancestor of the great apes and that the C1205722gene was

subsequently lost in the orangutan Evidence of continuingevolution in the IGH locus of humans was demonstrated bythe finding of triplication of the C

1205741-C1205742-C120576-C120572region in

several families [100] Subsequent genetic analyses inmultipleethnic groups revealed that gene duplications and deletionsin the human IGH locus are surprisingly common withfrequencies up to 22 in Japanese and Chinese populations[101]

3 Emergence of the IGJ Gene andEvolution of Polymeric Igs

The ability to produce Igs as both monomers (ie one unitcomprising 2 identical heavy chains and 2 identical lightchains) and polymers (covalently linked aggregates of 2 ormore Ig units) dates to the emergence of primitive Igs incartilaginous fish [23 42 50] Whereas pentameric IgM istypically found in serum as well as secretions the polymeric

forms of IgT IgX and IgA are generally restricted to mucosalsecretions The discovery of a low molecular weight ldquoJrdquo orldquojoiningrdquo chain as a component of polymeric Igs suggesteda potential mechanism for polymerization of individual Igmolecules into highermolecular weight complexes [102ndash104]The most primitive extant vertebrates in which the IGJ genehas been identified are the cartilaginous fish concurrent withthe presence of polymeric IgM Although the IGJ gene hasbeen identified in almost all lineages of jawed vertebratesit is surprisingly absent in some lineages of Osteichthyes(bony fishes) No ortholog of the IGJ gene has been identifiedin any species of the class Actinopterygii (ray-finned bonyfishes) for which the genome has been sequenced and anno-tated including Atlantic cod (Gadus morhua) common carp(Cyprinus carpio) tilapia (Oreochromis niloticus) zebrafish(Danio rerio) medaka (Oryzias latipes) and three-spinedstickleback (Gasterosteus aculeatus) In contrast to the ray-finned bony fishes IGJ genes and functional J chain proteinswere recently identified in two species of the class Sar-copterygii (lobe-finned bony fishes the West Indian Oceancoelacanth (Latimeria chalumnae) and the African lungfish(Protopterus dolloi) [105]) These findings suggest that theIGJ gene was lost during the evolution of the Actinopterygiiafter their divergence from a common ancestor with theSarcopterygii Despite the absence of J chain ray-finned bonyfishes are capable of forming polymeric IgM and IgT that canbe transported into mucosal secretions [38]

4 Evolution of Cellular Receptors for Igs

Theunique structure of vertebrate Igs allows for simultaneousbinding of antigen via the N-terminal variable regions ofthe Ig heavy and light chains and execution of effectorfunctions via the C-terminal constant (Fc) region of the Igheavy chains Evolution of multiple Ig heavy chain isotypesin higher vertebrates expanded the repertoire of Ig-mediatedeffector functions including specialized functions atmucosalsurfaces The simplest effector functions involve neutral-ization of microbes and their toxic byproducts whereaskilling of microbes can be affected by interaction of Igs withsoluble factors found in serumand secretionsThe concurrentemergence of Igs and proteins of the classical complementpathway in cartilaginous fishes is the earliest example of aspecific immune effector function mediated by the Fc regionof Ig heavy chains [106] As the immune system diversifiedduring vertebrate evolution cellular receptors for Ig heavychains (Fc receptors) allowed host cells to bind Igs forthe purpose of internalization transport andor activationof intracellular signaling pathways The most evolutionarilyancient of the vertebrate Fc receptors is the polymeric Igreceptor (pIgR) which first emerged in bony fishes (reviewedin [8]) (Figure 3)Theprimary function of pIgR is to transportpolymeric Igs (IgM IgT IgX and IgA) across glandular andmucosal epithelial cells into external secretions (see below)The fact that the extracellular Ig-binding region of pIgR iscomposed of multiple Ig-like domains suggests that the PIGR

ISRN Immunology 7

gene evolved by duplication of a primordial Ig gene is drivenby the need for an efficient mechanism for transport ofmucosal Igs into external secretions Similar forces may havedriven the evolution of FcRY a receptor first described forits function of transporting IgY from maternal blood tothe embryo yolk sac in chicken [9 107ndash109] FcRY is notstructurally homologous to pIgR or mammalian Fc receptorsbut is instead homologous to mammalian receptors formannose and phospholipase A2 with lectin-like extracellulardomains (Figure 3) A BLAST search of the National Centerfor Biotechnology Information (NCBI) nucleotide databasefor homologs of the gene encoding chicken FcRY (designatedPLA2R1 based on its homology to phospholipase A2 receptor1) revealed homologous genes in many bird species as wellas turtles lizards alligators and mammals However thefunctional significance of FcRYPLA2R1 in the transport ofIgY in reptiles (and possibly IgG in mammals) has not beenexplored A functional equivalent of FcRY in mammals isFcRn which mediates transport of IgG across endothelialand epithelial cells in such tissues as placenta and mucosalepithelia (reviewed in [110 111]) FcRn is homologous in struc-ture to major histocompatibility class (MHC) I moleculescomprising a ligand-binding alpha chain associated withsoluble 1205732-microglobulin (Figure 3)

A unique feature of the mammalian immune system isthe expression of Fc receptors for various Ig isotypes bycells of hematopoietic origin (Figure 3) (reviewed in [10])Engagement of these Fc receptors by Ig (in the presenceor absence of bound antigen depending on the particularFc receptor) initiates intracellular signaling pathways thatcan either augment or inhibit immune responses Withthe exception of Fc120576RII which has a single C-type lectin-like domain the extracellular Ig-binding regions of thesehematopoietic Fc receptors comprise 1 2 or 3 Ig-like domains[10] Genes encoding Fc120572120583R Fc120574RI Fc120574RIII Fc120576RI andFc120576RII are widely distributed among mammalian specieswhereas genes encoding Fc120572RI and Fc120574RII are restricted tothe primate lineage suggesting recent evolutionary originsThe genes encoding the120572120573 andor 120574 chains of Fc120576RI Fc120574RIIand Fc120574RIII are linked in a cluster on the long arm of humanchromosome 1 (1q23) not far removed from the gene for the120572 chain of Fc120574RI at 1q21 This tight linkage is consistent withduplication and diversification of a primordial FcR gene ina common ancestor of mammals The primate-specific genesencoding the 120572 and 120573 chains of Fc120574RII appear to have evolvedmore recently Another cluster of immune-related genes onthe long arm of chromosome 1 includes the genes for pIgR(1q31) and Fc120572120583R (1q32) Although the overall homologybetween pIgR and Fc120572120583R is relatively low they share aconserved binding site for IgA and IgM in the N-terminalIg-like domain Interestingly the genes encoding FcRn andFc120572RI are closely linked on the long arm of chromosome19 (19q133 and 19q1342 resp) although they bear littlehomology beyond the presence of a single Ig-like domain inthe extracellular region Finally the gene for the lectin-likereceptor Fc120576RII is located in an unrelated locus on the shortarm of chromosome 19 (19p133)

PIGR

dIgA

pIgR

Ag

SIgA

Free SC

Figure 4 Transcytosis of pIgR through a polarized epithelial celland formation of secretory Igs A polarized columnar epithelial cellis illustrated with the apical surface at the top and the basolateralsurface at the bottom Newly synthesized pIgR is targeted to thebasolateral surface where it binds polymeric Ig (pIg illustrated hereas dimeric (d)IgA) with or without bound antigen (Ag) Followingreceptor-mediated endocytosis pIg-bound and unoccupied pIgRmolecules are transported through a series of intracellular vesiclesto the apical surface Proteolytic cleavage of pIgR at the extracellularface of the plasma membrane releases free secretory component(SC) and secretory SIg (illustrated here as SIgA) Modified from [13]with permission from John Wiley and sons

5 Unique Biological Functions of pIgR

ThepIgR is expressed on the surface of glandular andmucosalepithelial binds where it binds selectively to polymericIg (pIg) and mediates its transport across epithelial cellsinto external secretions (reviewed in [17 111 112]) Most of

8 ISRN Immunology

02

100

Human IgA1Gorilla IgA1

Gorilla IgA281

6164

Human IgA2

Chimpanzee IgA2Chimpanzee IgA1

Gibbon IgA1Gibbon IgA2

Orangutan IgABaboon IgA

Rhesus macaque IgA53 100

98 69Dog IgA

Pig IgA100 Cattle IgA

52

Horse IgARabbit IgA (13 subclasses)

Mouse IgA57

99

Possum IgA

93

Chicken IgAPlatypus IgA1100

5095

Platypus IgA2

Trout IgTFrog IgX

Gecko IgldquoArdquo

(a)

02

Human pIgR

100Chimpanzee pIgRGorilla pIgR

55Gibbon pIgROrangutan pIgR100

100

100 Baboon pIgRRhesus macaque pIgR

Mouse pIgR

66

96

100 Pig pIgRCattle pIgR

85Horse pIgR

Dog pIgR

74

Rabbit pIgRPossum pIgR

Platypus pIgR

Chicken pIgR

10075

5979

Trout pIgRFrog pIgR

Anole pIgR

71

(b)

Figure 5 Coevolution of mucosal Igs and pIgR Simplified neighbor-joining phylogenetic trees of vertebrate (a) Ig and (b) pIgR proteinsequences with human IgA1 and pIgR denoted as outgroups Horizontal distances are proportional to the degree of divergence followinga multiple alignment of amino acid sequences Numbers at nodes denote bootstrap support for each bifurcation after 100 replicationsAccession numbers for mucosal Ig sequences human (Homo sapiens) IgA1 J00220 IgA2 (allotype m1) J00221 gorilla (Gorilla gorilla) IgA1X53703 IgA2 X53707 chimpanzee (Pan troglodytes) IgA1 X53702 IgA2 X53706 gibbon (Hylobates lar) IgA1 X53708 IgA2 X53709 Borneanorangutan (Pongo pygmaeus) IgA X53704 baboon (Papio anubis) IgA DQ868435 rhesus macaque (Macaca mulatta) AY039245 pig (Susscrofa) IgA U12594 cattle (Bos taurus) IgA AF109167 dog (Canis lupus familiaris) IgA L36871 horse (Equus caballus) IgA AY247966mouse (Mus musculus) IgA D11468 rabbit (Oryctolagus cuniculus) IgA1 X51647 brushtail possum (Trichosurus vulpecula) IgA AF027382duck-billed platypus (Ornithorhynchus anatinus) IgA1 AY055778 IgA2 AY055779 chicken (Gallus gallus) IgA AAB226142 leopard gecko(Eublepharis macularius) IgldquoArdquo (so designated because of its uncertain phylogeny with homology to both IgA and IgY) ABG726841African clawed frog (Xenopus laevis) IgX S03186 rainbow trout (Oncorhynchus mykiss) IgT AAW669811 Accession numbers for pIgRsequences with species that vary from those used for the mucosal Ig alignment in panel A noted in parentheses human NM 002644chimpanzee XM 003308710 gorilla XM 004028295 gibbon XM 003272974 Sumatran orangutan (Pongo abelii) NM 001131626 baboonXM 003893189 rhesus macaque XM 001083307 pig NM 214159 cattle NM 174143 dog XM 537133 horse XM 001492298 mouseNM 011082 rabbit NM 001171045 brushtail possum AF091137 duck-billed platypus XM 001508602 chicken NM 001044644 green anole(Anolis carolinensis) XM 003224013 African clawed frog EF079076 rainbow trout FJ940682

ISRN Immunology 9

our knowledge of pIgR-mediated transcytosis of mucosalIgs is derived from studies of mammalian secretory IgA(SIgA) as illustrated in Figure 4 Transcription of the PIGRgene and translation of pIgR mRNA is accompanied byinsertion of the nascent protein into the endoplasmic retic-ulum The pIgR undergoes substantial glycosylation duringtransport through the ER and Golgi apparatus and is thentargeted to the basolateral surface of polarized epithelialcells Membrane-bound pIgR binds pIg and pIg-containingimmune complexes which are internalized along with unoc-cupied pIgR via receptor-mediated endocytosis and thentranscytosed through a series of intracellular vesicles to theapical surface During transcytosis intracellular pIg antibod-ies can neutralize bacteria viruses and other antigens thathave gained access to the interior of the epithelial cell Atthe apical surface proteolytic cleavage of the membrane-spanning region of pIgR leads to the release of its extracellulardomain known as secretory component (SC) either in freeform or covalently bound to pIg Secretory Igs can neutralizepathogens and antigens within the mucosal lumen andfacilitate excretion of antigens that were transported throughthe epithelial cell as IgA immune complexes The SC moietyof SIgA has been shown to protect IgA from degradationby host and bacterial proteases and along with free SCconfers additional innate immune functions that protectthe epithelial surface from microbial invasion and limitpotentially damaging host inflammatory responses (reviewedin [113]) The finding of an SC-like polypeptide associatedwith polymeric IgT in rainbow trout [38] polymeric IgXin Xenopus [50] and polymeric IgA in birds [114] suggeststhat all vertebrate pIgRs share the function of transportingpolymeric Igs into external secretions In many mammalianspecies pIgR mediates epithelial transcytosis of both poly-meric IgM and IgA (reviewed in [111]) Although directevidence is not yet available it is reasonable to assume thatpIgR transports IgM in lower vertebrates It will be interestingto investigate whether the SCmoiety of secretory Igs in lowervertebrates mediates additional innate immune functions ashas been demonstrated for mammalian SC

6 Coevolution of pIgR and Mucosal Igs

Molecular cloning of the PIGR gene was first reportedfor mammalian species including eutherians marsupialsand monotremes [115ndash127] Subsequent elucidation of PIGRsequences from diverse species of jawed vertebrates hasallowed a comprehensive analysis of the evolutionary originsof the PIGR gene [38 128 128ndash132] and additional sequencesavailable in the Genbank database Whereas no ortholog ofthe PIGR gene has been found in any species of cartilaginousfish the PIGR gene has been annotated in all species of teleostfish for which the genome has been sequenced No orthologof the PIGR gene has been reported in lobe-finned bonyfishes but further analyses of whole genome sequences willbe required to determine whether the PIGR gene was lostfollowing the split of the Sarcopterygii It thus appears thatthe PIGR gene emerged in a common ancestor of highervertebrates after the split of cartilaginous fish and prior

to the evolution of modern teleosts likely driven by theselective pressure to provide a mechanism for transport ofpolymeric Igs such as IgM and IgT into mucosal secretionsThis hypothesis is supported by a comparison of phylogenetictrees based on amino acid sequences for IgT IgX and IgAheavy chains and pIgR (Figure 5)The predicted evolutionarydistance between trout IgT and frog IgX is similar to thedistance between trout and frog pIgR suggesting that thetransition from IgT to IgX as the dominantmucosal Ig isotypewas accompanied by adaptations in pIgR structure Similarparallels can be seen in the transition from IgX to IgA inreptiles birds and mammals and the concurrent evolutionof pIgR

Alignments of the amino acid sequences of mucosal Igheavy chains and pIgR from 10 representative vertebratespecies provide further support for the theory of coevolutionof mucosal IGH and PIGR genes (Figure 6) A commonfeature of Ig and pIgR proteins is the presence of repeatingIg-like domains (see Figure 2 for the basic structure of thesedomains) The structure of IgT IgX and IgA heavy chainsfrom fish amphibians reptiles and birds is similar to thatof IgM with 4 constant Ig-like domains In mammalianIgA (and IgG) the exon for the 2nd constant region wastruncated to encode a short ldquohingerdquo region which confersgreater mobility to the antigen-binding region at the N-terminusThus the CH3 domain of IgT IgX and IgA in lowervertebrates is structurally and functionally homologous tothe CH2 domain of mammalian IgA The heavy chains ofIgT IgX and IgA have retained a characteristic feature ofthe IgM heavy chain that is the presence of a conservedcysteine residue in the tailpiece that allows disulfide bondingbetween heavy chains of individual Ig proteins to formhigher molecular weight polymers These large Ig structurescontaining multiple antigen-binding sites are particularlywell suited for immune clearance of large antigens found atmucosal surfaces such as intact microbes and food particlesIn mucosal Igs from most vertebrate orders the J chainprotein initiates this polymerization process by disulfidebonding with 2 Ig heavy chains remaining associated withthe polymeric Ig at a stoichiometric ratio of 1 J chain subunitper 2 3 4 or 5 Ig units Despite the absence of J chainthe predominant form of IgM and IgT in mucus secretionsin rainbow trout was found to be polymeric in contrastto monomeric forms of IgM and IgT in the blood [38] Inmammals IgM is mainly found as a pentamer whereas theshorter heavy chain ofmammalian IgA restricts its polymericforms to dimers trimers and tetramers Further studies willbe required to characterize the polymeric structures of IgMIgT IgX and IgA in lower vertebrates

Alignment of pIgR amino acid sequences from 10 rep-resentative vertebrate species reveals structural changes thatwere evolved in parallel with structural changes in mucosalIgs (Figure 6(b)) All pIgR proteins have an N-terminalhydrophobic leader peptide required for targeting of thenascent protein into the ER The extracellular region ofpIgR protein is characterized by repeating ldquoIg-likerdquo domainssimilar to Ig heavy chains [115 133] Interestingly the num-ber of extracellular Ig-like domains has increased duringvertebrate evolution culminating with a total of 5 domains

10 ISRN Immunology

TailpieceHinge

Tailpiece

Mammalian IgA

VVVVVVVVVV

200121 300 400 4721

Human IgA1Rhesus IgA

Cattle IgAMouse IgA

Possum IgAPlatypus IgAChicken IgA

Frog IgXTrout IgT

Premammalian IgTXA

Gecko IgldquoArdquo

CH1

CH1

CH2

CH2

CH3

CH3

CH4

(a)

Leader 1 2 3 4 5

Ig homology extracellular domains

Linker CytoplasmicTM

1001 200 300 400 500 600 700 764

HumanRhesus

CattleMouse

PossumPlatypusChicken

AnoleFrog

Trout

(b)

Figure 6 Interspecies similarity in mucosal Ig and pIgR protein sequences from 10 representative vertebrate species Alignments in aminoacid sequences correspond to the phylogenetic trees shown in Figure 5 (a) Numbering ofmucosal Ig amino acids corresponds to the sequenceof human IgA1 beginning with the first residue of the variable domain CH heavy chain constant region domain (b) Numbering of pIgRamino acids corresponds to the sequence of human pIgR beginning with the first residue of the leader peptide TM transmembrane Forboth alignments the intensity of shading at each position signifies the degree of similarity amongmucosal Ig or pIgR sequences from differentspecies Gaps in sequence alignments signify regions of limited interspecies homology Approximate boundaries are noted of key structuralelements in mucosal Ig and pIgR proteins

in mammalian pIgR By contrast pIgR from amphibiansreptiles and birds contains 4 extracellular domains lackinga homolog of domain 2 of mammalian pIgR The mostprimitive form of pIgR found in teleost fish contains only2 extracellular domains homologous to domains 1 and 5of mammalian pIgR Interspecies homology is greatest indomain 1 which has been shown to be critical for binding ofmammalian pIgR to polymeric Igs (reviewed in [111]) Highlyconserved internal disulfide bonds are found in all the Ig-like domains of pIgR characteristic of the immunoglobulinfold An additional disulfide bond is found in domain 5 ofpIgR frommammals birds reptiles and amphibians but notfish In human SIgA this ldquoextrardquo disulfide bond in domain 5has been shown to rearrange to form a disulfide bond with

cysteine residues in one of the heavy chains of polymericIgA [134] Although the structure of SIgA has not beenfully characterized for lower vertebrates it is reasonable toassume that similar disulfide bonds form between domain 5of pIgR and polymeric IgA or IgX from birds reptiles andamphibians The linker region connecting domain 5 of pIgRto the transmembrane domain has a random structure that ispoorly conserved across species Proteolytic cleavage of pIgRwithin this domain leads to the release of SC from the apicalsurface of epithelial cells either free or bound to polymericIg The cytoplasmic domain of mammalian pIgR containsa number of intracellular sorting motifs that interact withcytoplasmic proteins to direct pIgR through the transcytoticpathway (reviewed in [111]) These motifs are reasonably

ISRN Immunology 11

Linker

TMCytoplasmic

J chain

Hinge 1

2

34

5

CL

VLVH

C1205721C1205722 C1205723

(a)

Linker

TMCytoplasmic

J chain

1

3 4

5

CL

VL

VH

C1205941205721

C1205941205722C1205941205723 C1205941205724

(b)

11

5

LinkerTM

Cytoplasmic

5

CL

VL

VH

C1205911C1205912

C1205913 C1205914

pIgR Ig-like domain

H chain Ig-like domain

L chain Ig-like domain

J chain

Disulfide bond

(c)

Figure 7 Theoretical model for changes in the structure of secretory Igs during evolution (a) The structure for mammalian SIgA is adaptedfrom the model of Woof and Russell [16] for human SIgA1 with permission from Nature Publishing Group (b) and (c) Theoretical modelsfor the structure of IgXA from amphibians and birds and SIgT from teleost fish respectively are predicted from alignment of Ig heavy chainand pIgR sequences with mammalian homologs

well conserved in pIgR from birds and reptiles but not inpIgR from amphibians and fish suggesting that complexmechanisms of intracellular trafficking of pIgR coevolvedwith the increasing complexity of the mucosal immunesystem

7 Hypothetical Models for Changes inSecretory Ig Structure during Coevolutionof Mucosal Igs and pIgR

A large number of structural and functional analyses overthe past 30 years allowed the development of detailed modelsfor the structure of mammalian SIgA (reviewed in [111 135])(Figure 7(a)) Domains 1 and 5 of pIgR the most highlyconserved Ig-like domains associate with theC1205722 subunits oftwo adjacent IgA heavy chains in a near-planar structure [136137] During transcytosis a disulfide bond forms betweenhighly conserved cysteine residues in domain 5 of pIgRand the C1205722 domain of one of the IgA heavy chains [134]Domains 2 3 and 4 allow mammalian pIgR to assume aflexible extended structure which is thought to wrap aroundthe IgA heavy chains and protect against degradation fromhost and microbial proteases Binding of mammalian pIgRto polymeric IgA or IgM requires the presence of J chain

connecting the Ig subunits (reviewed in [138]) and J chain-deficient mice fail to transport IgA and IgM into externalsecretions [139ndash141] Structure-function studies usingmutantforms of human J chain suggested that J chain binds directlyto pIgR and also maintains polymeric Ig in an optimalconformation for pIgR binding and transcytosis [142] Theunstructured linker region connecting domain 5 of pIgRto the transmembrane (TM) region gives membrane-boundpIgR the flexibility to bind large polymeric Igs (with orwithout associated antigens) and provides an exposed site forproteolytic cleavage of pIgR to SC The C-terminal region ofpIgR extends past the cytoplasmic face of the plasma mem-brane allowing association with cytoplasmic factors thatregulate trafficking of pIgR with or without bound polymericIg

Although detailed structural studies have not yet beenperformed on secretory Igs from lower vertebrates hypo-thetical models can be constructed based on alignmentswith their mammalian homologs A model for secretoryIgXA in birds reptiles and amphibians is illustrated inFigure 7(b) showing the C

1205941205722 domain in place of the hinge

region ofmammalian IgAThenumbering of the extracellulardomains of pIgR corresponds to the homologous domainsin mammalian pIgR noting the absence of domain 2 In

12 ISRN Immunology

this model the C120594120572

3 domains of two adjacent IgXA heavychains (homologous to the C

1205722 domain of mammalian IgA)

bind to the highly conserved domains 1 and 5 of pIgRGiven the conservation of the analogous cysteine residuesin domain 5 of pIgR and the C

1205941205723 domain of IgXA it

is assumed that a disulfide bond forms between pIgR andpolymeric Ig during epithelial transcytosis in birds reptilesand amphibiansThe absence of domain 2 in pIgR from thesevertebrate orders necessitates a more rigid structure thanthat of mammalian pIgR with a corresponding decrease inits ability to wrap around the IgXA heavy chains and pro-vide protection against proteoltyic degradation Despite theshorter length of pIgR in birds reptiles and amphibians theassociation with the J chain subunit of polymeric IgXA stillappears to be required Recombinant pIgR from the Africanfrog (Xenopus laevis) was shown to bind with moderatelyhigh affinity to human polymeric IgA containing J chain butnot to monomeric IgA [125] The affinity of Xenopus pIgRfor human pIgA was improved when Xenopus J chain wassubstituted for human J chain in a chimeric polymeric IgAmolecule The lack of sequence conservation across speciesin the linker region connecting domain 5 of pIgR to the TMregion suggests that it acts as a nonspecific ldquospacerrdquo As statedabove the cytoplasmic region of pIgR appears to have evolvedover time to provide enhanced regulation of pIgR trafficking

The hypothetical structure of secretory IgT from teleostfish in Figure 7(c) illustrates how the most primitive form ofpIgR comprising only extracellular domains 1 and 5 couldassociate with polymeric Ig and mediate epithelial transcy-tosis Association of pIgR domain 1 with the C

1205913 domain of

IgT would preserve the functional homology with secretoryIgs in higher vertebrates The short length of teleost pIgRwould necessitate the association of domain 5 with a C

1205913

domain on one of the heavy chains of the same IgT ratherthan spanning across to the adjaent IgT subunit While thismodel preserves the highly conserved association of pIgRdomain 1 with the orthologous domain of the IgT heavychain it does not explain the selectivity of teleost pIgR forpolymeric rather than monomeric IgT Although there is noexperimental evidence to support this model it could behypothesized that dimerization of two pIgR molecules in theplasmamembrane is required for high affinity binding of IgTas illustrated in the model in Figure 7(c) This hypotheticalmodel would also explain the lack of a necessity for J chainin polymeric IgT since each subunit in the pIgR dimer wouldonly be in contact with one IgT subunit The unstructuredlinker region connecting domain 5 of pIgR to the TM regionwould provide flexibility for association of 2 membrane-bound pIgR molecules with a large polymeric IgT molecule

Taken together the structural models for secretory Igsshown in Figure 7 are consistent with the selection of a morefunctional pIgR molecule over evolutionary time Duplica-tion and diversification of the extracellular Ig-like domainsof pIgR would provide a longer more flexible surface forbinding to polymeric Igs with higher affinity and protectingthe Ig heavy chains against proteolytic attack Expansion ofthe cytoplasmic domain of pIgR and incorporation of motifsfor binding cytoplasmic proteins would allow regulated

trafficking of pIgR and polymeric Igs across mucosal andglandular epithelial cells Importantly these models illustratea potential path for coevolution of IGH and PIGR genesdriven by the common selective pressure to provide antigen-specific humoral immune responses at mucosal surfaces

8 Evidence that the CommensalMicrobiota Provided the Driving Force forCoevolution of Mucosal Igs and pIgR

From the earliest evolution of vertebrate animals mucosal Igshave been an integral part of the emerging adaptive immunesystem Clearly many environmental factors served as driv-ing forces for the evolution of the adaptive immune systemin vertebrates including a longer lifespan thanmany (but notall) invertebrates and amore diverse diet that could introducea broader range of potential gut pathogens However it hasbeen proposed that the most significant force may havebeen the dramatic increase in the numbers and complexityof the resident microbiota in the evolution of vertebratesfrom their invertebrate ancestors [1 143 144] Antibodiesin mucosal secretions contribute to immune homeostasis bylimiting access of microbes and their products to the bodyproper maintaining the integrity of the epithelial barrier andshaping the composition of the commensal microbiota infavor of metabolically beneficial microorganisms [145] Thepredominance of polymeric Igs in these secretions promotesthese functions by providing multiple antigen-binding sitesper Ig complex thus increasing the overall avidity of antigen-antibody interactions Structural and functional refinementsin mucosal Igs culminating with the multifunctional secre-tory IgA molecule in mammals have further enhanced theirability to enhance immune homeostasis

The early emergence of pIgR in vertebrate evolutionprovided a mechanism for efficient transport of mucosal Igsinto external secretions It is well documented that crosstalkbetween mucosal epithelial cells and the resident microbiotamodulates expression of pIgR (reviewed in [17 111 112]) andit is reasonable to assume that these host-microbe interac-tions provided a driving force for evolution of the PIGR genein vertebrates The first demonstration that gut bacteria maymodulate pIgR expression in epithelial cells was the findingthat butyrate a bacterial fermentation product and importantenergy source in the colon upregulated expression of pIgRin the human colonic epithelial cell line HT-29 [146] A rolefor commensal bacteria in pIgR regulation was subsequentlydemonstrated by the observation that pIgR expression wasincreased when germ-free mice were colonized with Bacteri-oides thetaiotaomicron a prominent organism of the normalmouse and human intestinal microbiota [147] Amore recentstudy using a model of reversible colonization of germ-free mice with a nondividing mutant of Escherichia colidemonstrated that a long-lived SIgA response could besustained that specifically recognized the inducing bacteria[148] However exposure of E coli-colonized mice to otherbacteria limited the duration of the SIgA response against theoriginal colonizer suggesting a dynamic equilibriumbetweenmembers of the gut microbial community and host SIgA A

ISRN Immunology 13

study from the laboratory of Finn-Eirik Johansen demon-strated that diversity of the bacterial community in the cecallumen was reduced in pIgR-knockoutmice supporting a rolefor SIgA in limiting overgrowth of selected species [149] Incontrast the community of bacteria adherent to the epithelialsurface was more diverse in pIgR-knockout mice than inwild-typemice and these adherent bacteria caused enhancedexpression of several epithelial antimicrobial peptides Thesefindings suggest that bacteria-specific SIgA anchored in themucus layer restricts adhesion of bacteria to the epithelialsurface and limits bacterial stimulation of host epithelial cellsA recent study from the authorrsquos laboratory employing abreeding scheme in which119875119894119892119903minusminus damswere bred to119875119894119892119903+minusmales and vice versa demonstrated that SIgA antibodiesin breast milk promote long-term intestinal homeostasis byregulating the gut microbiota and gene expression in colonicepithelial cells [150]

A direct role for commensal andor pathogenic bacteriain the regulation of pIgR expression suggests that the innateimmune system may ldquoprimerdquo epithelial cells for transportof polymeric Ig produced during the adaptive immuneresponse Host cells mediate innate immune responses tomicrobial components through toll-like receptor (TLR) sig-naling (reviewed in [151 152]) Intestinal epithelial cells havebeen shown to express a wide variety of TLRs the expressionof which is upregulated during intestinal inflammation [153ndash155] Significantly expression of pIgR was shown to beupregulated in the HT-29 human intestinal epithelial cellline by bacterial LPS a ligand for TLR4 [156 157] Similarinduction of PIGR gene transcription was seen followingdirect binding of bacteria of the family Enterobacteriaceaewhich express a form of LPS that stimulates TLR4 [158]A recent study from the authorrsquos laboratory demonstratedthat shRNA-mediated knockdown of myeloid differentiationprimary response protein 88 (MyD88) a cytoplasmic adapterprotein that transduces signals from cell surface TLR4blocked the induction of PIGR gene transcription by LPS inHT-29 cells [159] The in vivo significance was confirmed bythe finding that mice with a targeted deletion of the Myd88gene only in intestinal epithelial cells had reduced expressionof pIgR compared to wild-type littermates [159] Mice withtargeted depletion of MyD88 in intestinal epithelial cells alsoexhibited reduced expression of mucin-2 the major compo-nent of the intestinal mucus layer and several antimicrobialpeptides and decreased transmucosal electrical resistanceThese alterations in epithelial barrier function were accom-panied by significant changes in the composition of the fecalmicrobiota increased numbers of bacteria adherent to theintestinal mucus layer and a dramatic increase in transloca-tion of gut bacteria into the drainingmesenteric lymphnodesincluding the opportunistic pathogen Klebsiella pneumoniaeThese findings demonstrate that MyD88-mediated crosstalkbetween the gut microbiota and intestinal epithelial cells iscrucial for optimal expression of pIgR production of SIgAdevelopment of a healthy gut microbiota and maintenanceof intestinal homeostasis

A model can be proposed in which continuous stimu-lation of intestinal epithelial cells by gut bacteria regulates

Lumen

Mucus

Epithelium

Lamina

PIGR

TLRs

MyD88

Bacteria

Plasma cells

propria

Polymeric Ig

Polymeric Ig receptor

Secretory component

Figure 8 Crosstalk between the polymeric immunoglobulin recep-tor secretory immunoglobulins and the gut microbiotaThe single-layered epithelium that lines the gastrointestinal tract is coveredwith a thick mucus layer which physically excludes members ofthe resident microbiota but allows diffusion of shed components ofmicrobial cells Stimulation of epithelial toll-like receptors (TLRs)with microbial products engages the cytoplasmic adaptor proteinMyD88 and initiates NF120581B-dependent signaling pathways Translo-cation of activated NF120581B and other transcription factors to thenucleus enhances transcription of thePIGR gene Activation of TLRsmay also stimulate pIgR transcytosis Polymeric Igs secreted bylamina propria plasma cells bind to pIgRon the basolateral surface ofepithelial cells and are transcytosed to the apical surface along withunoccupied pIgR Proteolytic cleavage of pIgR at the apical surfacereleases secretory SIg and free secretory component (SC) Binding ofSIg and SC to luminal bacteria promotes association with themucuslayer and prevents direct access of bacteria to the epithelial surfaceOver time the continuous crosstalk with SIg shapes the compositionof the gut microbiota Modified from [17] under terms of authorrsquoscopyright with Nature Publishing Group

pIgR expression and transport of SIgA and promotes immuneexclusion of resident and pathogenic bacteria (Figure 8) Adense layer of mucus which increases in thickness fromthe proximal to the distal colon serves to separate bacteriafrom direct contact with the epithelial surface Secretionof microbial-associated molecular patterns (MAMPs) bycommensal bacteria stimulates MyD88-dependent TLR sig-naling leading to enhanced expression of pIgR and antimi-crobial peptides and increased mucus production Bindingof pIgA to pIgR and possibly also signaling via MAMPs

14 ISRN Immunology

enhances transcytosis of pIgA pIgA-containing immunecomplexes and unoccupied pIgR which promotes clearanceof antigens and pathogens from the lamina propria intra-cellular neutralization and release of SIgA and SC at theluminal surface SIgA and SC serve to trap bacteria in themucus layer limiting their access to the epithelial surface Inmice with a targeted deletion of the Muc2 gene which havea severely depleted mucus layer in the colon SIgA and SCfail to associate with the surface of colonic epithelial cells[160] The presence of SIgA in the intestinal lumen whetherderived passively frommaternalmilk or actively via epithelialtranscytosis shapes the composition of the gut microbiotaand modulates intestinal epithelial gene expression

9 Concluding Remarks

The first microbes that emerged on Earth almost 4 billionyears ago encountered a hostile world where nutrients werescarce hazards were everywhere and life was short Withthe evolution of multicellular organisms about 3 billion yearslater a select group ofmicrobes chose to sacrifice an indepen-dent existence for the benefits of a mutualistic relationshipwith eukaryotic hosts Prokaryotic-eukaryotic mutualismreached its apex some 500 million years ago with theemergence of primitive vertebrates whose gastrointestinaltracts were populated by an abundant and diverse commensalmicrobiota In humans the large intestine is home to some100 trillion microorganisms 10 times more than the totalnumber of eukaryotic cells in the entire body The microbesthat inhabit the vertebrate GI tract provide many benefitsto the eukaryotic host including digestion of complex foodmolecules synthesis of vitamins and production of solublefactors that enhance the development of the host immunesystem In return the eukaryotic host provides the microbeswith a warm moist place to live abundant food low oxygentension and a soft bed of mucus on which to form biofilmsWhen this mutually beneficial arrangement is challenged bypathogenicmicrobes the eukaryotic host and the commensalmicrobiota join forces to battle the pathogens and protectthe body from invasion The vertebrate immune system isequipped with a well-trained army of immune cells and asophisticated arsenal of weapons (cell surface molecules andsecreted factors) that protect the host from all but the mostvirulent pathogens This immune ldquoarmyrdquo also serves as aconstant reminder to the commensal microbes that whilethey are free to enjoy the amenities of the mucosal surfacesthey are not welcome in the body proper The emergence ofantigen-specific Igs and T-cell receptors in jawed vertebratesbegan a process of immunological diversification that led tothe development of a specialized mucosal immune systemin higher vertebrates in which secretory Igs play a centralrole The relationship between host and microbiota is clearlyreciprocal the mucosal Igs that evolved in response toselective pressure from the commensal microbiota play acentral role throughout life in shaping the compositiongenetics andmetabolic activity of themicrobiota [1 161 162]

The epithelial layer lining mucosal surfaces provides aphysical and innate immune barrier against penetration of

the body proper by microbes undigested food antigens andpotentially noxious environmental substances The evolu-tionary challenge of transporting mucosal Igs into externalsecretions without compromising the epithelial barrier wasmet by the emergence of the PIGR gene in an ancestor ofbony fishes encoding an epithelial-specific transmembraneprotein that actively transports polymeric Igs across mucosaland glandular epithelia (Figure 4) Structural similaritiesbetween Igs and the extracellular Ig-binding domains of pIgR(Figure 6) suggest that duplication and diversification of agene encoding primordial Ig-like domain may have givenrise to the PIGR gene in a primitive vertebrate ancestorParallel refinement of the structures of mucosal Igs andpIgR during tetrapod evolution (Figures 6 and 7) culminatedin the evolution of the multifunctional SIgA molecule inmammals in which the pIgR-derived SC subunit providesinnate immune functions and protects the antigen-bindingIgA polymer from proteolytic degradation In addition toacting as a powerful force during vertebrate evolution thereciprocal relationship between pIgR mucosal Igs and thecommensal microbiota provides benefits throughout thelife of the individual Microbial colonization of newbornvertebrates stimulates development of mucosal B cells andclass switching to mucosal Ig isotypes [1 163] Microbialfactors upregulate expression of pIgR enhancing transportof mucosal Igs into external secretions where they in turnregulate the microbiotaThis beautifully orchestrated processallows us to maintain a healthy relationship with our resi-dent microbiota while providing mutual protection againstpathogens

Conflict of Interests

The author declares that there is no conflict of interestsregarding the publication of this paper

Acknowledgments

This work was supported by Grant no AI069027 from theNational Institutes of Health of the United States of America(and an associatedAmerican Recovery andReinvestmentActsupplement) and a Senior Research Award from the Crohnrsquosand Colitis Foundation of America

References

[1] C L Maynard C O Elson R D Hatton and C T WeaverldquoReciprocal interactions of the intestinal microbiota andimmune systemrdquo Nature vol 489 no 7415 pp 231ndash241 2012

[2] M F Flajnik and M Kasahara ldquoOrigin and evolution of theadaptive immune system genetic events and selective pres-suresrdquo Nature Reviews Genetics vol 11 no 1 pp 47ndash59 2010

[3] M F Flajnik and L du Pasquier ldquoEvolution of the immunesystemrdquo in Fundamental Immunology W E Paul Ed chapter4 pp 67ndash128 Lippincott Williams ampWilkins Philadelphia PaUSA 2012

[4] M Hirano S Das P Guo and M D Cooper ldquoThe evolutionof adaptive immunity in vertebratesrdquo Advances in Immunologyvol 109 pp 125ndash157 2011

ISRN Immunology 15

[5] T BoehmNMcCurley Y SutohM SchorppMKasahara andM D Cooper ldquoVLR-based adaptive immunityrdquo Annual Reviewof Immunology vol 30 pp 203ndash220 2012

[6] T Hunkapiller and L Hood ldquoImmunology the growing immu-noglobulin gene superfamilyrdquoNature vol 323 no 6083 pp 15ndash16 1986

[7] P Bork L Holm and C Sander ldquoThe immunoglobulin foldstructural classification sequence patterns and common corerdquoJournal of Molecular Biology vol 242 no 4 pp 309ndash320 1994

[8] C S Kaetzel and M W Russell ldquoPhylogeny and comparativephysiology of IgArdquo in Mucosal Immunology J Mestecky WStrober H Cheroutre B Kelsall B N Lambrecht and M WRussell Eds chapter 19 Academic PressElsevier WalthamMass USA 2014

[9] Y He and P J Bjorkman ldquoStructure of FcRY an avian immu-noglobulin receptor related to mammalian mannose receptorsand its complex with IgYrdquo Proceedings of the National Academyof Sciences of the United States of America vol 108 no 30 pp12431ndash12436 2011

[10] J M Woof and D R Burton ldquoHuman antibody-Fc receptorinteractions illuminated by crystal structuresrdquo Nature ReviewsImmunology vol 4 no 2 pp 89ndash99 2004

[11] W L Martin A P West Jr L Gan and P J Bjorkman ldquoCrystalstructure at 28 A of an FcRnheterodimeric Fc complexmechanism of pH-dependent bindingrdquo Molecular Cell vol 7no 4 pp 867ndash877 2001

[12] E S Ward ldquoAcquiring maternal immunoglobulin differentreceptors similar functionsrdquo Immunity vol 20 no 5 pp 507ndash508 2004

[13] C S Kaetzel ldquoThe polymeric immunoglobulin receptor bridg-ing innate and adaptive immune responses atmucosal surfacesrdquoImmunological Reviews vol 206 no 1 pp 83ndash99 2005

[14] M Acharya G Borland A L Edkins et al ldquoCD23Fc120576RIImolecular multi-taskingrdquo Clinical and Experimental Immunol-ogy vol 162 no 1 pp 12ndash23 2010

[15] V B Klimovich ldquoIgM and its receptors structural and func-tional aspectsrdquo Biochemistry vol 76 no 5 pp 534ndash549 2011

[16] J MWoof andMW Russell ldquoStructure and function relation-ships in IgArdquo Mucosal Immunology vol 4 no 6 pp 590ndash5972011

[17] F-E Johansen and C S Kaetzel ldquoRegulation of the polymericimmunoglobulin receptor and IgA transport new advances inenvironmental factors that stimulate pIgR expression and itsrole in mucosal immunityrdquo Mucosal Immunology vol 4 no 6pp 598ndash602 2011

[18] F Kokubu K Hinds R Litman M J Shamblott and G WLitman ldquoExtensive families of constant region genes in a phy-logenetically primitive vertebrate indicate an additional levelof immunoglobulin complexityrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 84 no16 pp 5868ndash5872 1987

[19] A S Greenberg A L Hughes J Guo D Avila E CMcKinneyand M F Flajnik ldquoA novel ldquochimericrdquo antibody class in carti-laginous fish IgMmay not be the primordial immunoglobulinrdquoEuropean Journal of Immunology vol 26 no 5 pp 1123ndash11291996

[20] H Dooley and M F Flajnik ldquoShark immunity bites back affin-ity maturation and memory response in the nurse shark Ging-lymostoma cirratumrdquo European Journal of Immunology vol 35no 3 pp 936ndash945 2005

[21] S F Schluter R M Bernstein and J J Marchalonis ldquoMolecularorigins and evolution of immunoglobulin heavy-chain genes ofjawed vertebratesrdquo Immunology Today vol 18 no 11 pp 543ndash549 1997

[22] Y Ohta and M Flajnik ldquoIgD like IgM is a primordial immu-noglobulin class perpetuated in most jawed vertebratesrdquo Pro-ceedings of the National Academy of Sciences of the United Statesof America vol 103 no 28 pp 10723ndash10728 2006

[23] S Fillatreau A Six S Magadan R Castro J O Sunyer andP Boudinot ldquoThe astonishing diversity of Ig classes and B cellrepertoires in teleost fishrdquo Frontiers in Immunology vol 4 no28 2013

[24] W Harriman H Volk N Defranoux and M Wabl ldquoImmu-noglobulin class switch recombinationrdquo Annual Review ofImmunology vol 11 pp 361ndash384 1993

[25] J Stavnezer and C T Amemiya ldquoEvolution of isotype switch-ingrdquo Seminars in Immunology vol 16 no 4 pp 257ndash275 2004

[26] V M Barreto Q Pan-Hammarstrom Y Zhao L Ham-marstrom Z Misulovin and M C Nussenzweig ldquoAID frombony fish catalyzes class switch recombinationrdquo Journal ofExperimental Medicine vol 202 no 6 pp 733ndash738 2005

[27] T C Fletcher and AWhite ldquoAntibody production in the plaice(Pleuronectes platessa L) after oral and parenteral immuniza-tion with Vibrio anguillarum antigensrdquo Aquaculture vol 1 pp417ndash428 1972

[28] J W H M Rombout L J Blok C H J Lamers and E EgbertsldquoImmunization of carp (Cyprinus carpio) with a Vibrio anguil-larum bacterin indications for a common mucosal immunesystemrdquo Developmental and Comparative Immunology vol 10no 3 pp 341ndash351 1986

[29] U Georgopoulou and J-M Vernier ldquoLocal immunologicalresponse in the posterior intestinal segment of the rainbowtrout after oral administration of macromoleculesrdquo Develop-mental andComparative Immunology vol 10 no 4 pp 529ndash5371986

[30] C J Lobb ldquoSecretory immunity induced in catfish Ictaluruspunctatus following bath immunizationrdquo Developmental andComparative Immunology vol 11 no 4 pp 727ndash738 1987

[31] J D Hansen E D Landis and R B Phillips ldquoDiscovery ofa unique Ig heavy-chain (IgT) in rainbow trout implicationsfor a distinctive B cell developmental pathway in teleost fishrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 102 no 19 pp 6919ndash6924 2005

[32] N Danilova J Bussmann K Jekosch and L A Steiner ldquoTheimmunoglobulin heavy-chain locus in zebrafish identificationand expression of a previously unknown isotype immunoglob-ulin Zrdquo Nature Immunology vol 6 no 3 pp 295ndash302 2005

[33] R Savan A Aman K Sato R Yamaguchi and M Sakai ldquoDis-covery of a new class of immunoglobulin heavy chain fromfugurdquo European Journal of Immunology vol 35 no 11 pp 3320ndash3331 2005

[34] R Savan A AmanMNakao HWatanuki andM Sakai ldquoDis-covery of a novel immunoglobulin heavy chain gene chimerafrom common carp (Cyprinus carpio L)rdquo Immunogenetics vol57 no 6 pp 458ndash463 2005

[35] F Gambon-Deza C Sanchez-Espinel and S Magadan-Mompo ldquoPresence of an unique IgT on the IGH locus in three-spined stickleback fish (Gasterosteus aculeatus) and the veryrecent generation of a repertoire of VH genesrdquo Developmentaland Comparative Immunology vol 34 no 2 pp 114ndash122 2010

[36] T M Tadiso K K Lie and I Hordvik ldquoMolecular cloning ofIgT fromAtlantic salmon and analysis of the relative expression

16 ISRN Immunology

of 120591 120583 and 120575 in different tissuesrdquo Veterinary Immunology andImmunopathology vol 139 no 1 pp 17ndash26 2011

[37] S Mashoof C Pohlenz P L Chen et al ldquoExpressed IgH 120583and 120591 transcripts share diversity segment in ranched Thunnusorientalisrdquo Developmental and Comparative Immunology vol43 no 1 pp 76ndash86 2014

[38] Y-A Zhang I Salinas J Li et al ldquoIgT a primitive immunoglob-ulin class specialized in mucosal immunityrdquo Nature Immunol-ogy vol 11 no 9 pp 827ndash835 2010

[39] S Magadan-Mompo C Sanchez-Espinel and F Gambon-Deza ldquoImmunoglobulin heavy chains in medaka (Oryziaslatipes)rdquo BMC Evolutionary Biology vol 11 no 1 article 1652011

[40] C T Amemiya J Alfoldi A P Lee et al ldquoThe African coela-canth genome provides insights into tetrapod evolutionrdquoNature vol 496 no 7445 pp 311ndash316 2013

[41] T Ota J P Rast G W Litman and C T Amemiya ldquoLineage-restricted retention of a primitive immunoglobulin heavy chainisotype within the Dipnoi reveals an evolutionary paradoxrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 100 no 5 pp 2501ndash2506 2003

[42] Y Sun Z Wei N Li and Y Zhao ldquoA comparative overview ofimmunoglobulin genes and the generation of their diversity intetrapodsrdquo Developmental and Comparative Immunology vol39 no 1-2 pp 103ndash109 2013

[43] I Hadji-Azimi ldquoAnuran immunoglobulins a reviewrdquo Develop-mental and Comparative Immunology vol 3 no 2 pp 223ndash2431979

[44] E Hsu M F Flajnik and L du Pasquier ldquoA third immunoglob-ulin class in amphibiansrdquo The Journal of Immunology vol 135no 3 pp 1998ndash2004 1985

[45] C T Amemiya R N Haire and G W Litman ldquoNucleotidesequence of a cDNA encoding a third distinct Xenopusimmunoglobulin heavy chain isotyperdquo Nucleic Acids Researchvol 17 no 13 p 5388 1989

[46] R Muszligmann M Wilson A Marcuz M Courtet and L duPasquier ldquoMembrane exon sequences of the three Xenopus Igclasses explain the evolutionary origin of mammalian isotypesrdquoEuropean Journal of Immunology vol 26 no 2 pp 409ndash4141996

[47] R Muszligmann L du Pasquier and E Hsu ldquoIs Xenopus IgX ananalog of IgArdquo European Journal of Immunology vol 26 no12 pp 2823ndash2830 1996

[48] B Schaerlinger and J-P Frippiat ldquoIgX antibodies in the urodeleamphibian Ambystoma mexicanumrdquo Developmental and Com-parative Immunology vol 32 no 8 pp 908ndash915 2008

[49] B Schaerlinger M Bascove and J-P Frippiat ldquoA new isotypeof immunoglobulin heavy chain in the urodele amphibianPleurodeles waltl predominantly expressed in larvaerdquoMolecularImmunology vol 45 no 3 pp 776ndash786 2008

[50] S Mashoof A Goodroe C C Du et al ldquoAncient T-independence of mucosal IgXA gut microbiota unaffected bylarval thymectomy in Xenopus laevisrdquo Mucosal Immunologyvol 6 no 2 pp 358ndash368 2013

[51] J P Vaerman J Picard and J F Heremans ldquoStructural dataon chicken IgA and failure to identify the IgA of the tortoiserdquoin Immunologic Phylogeny vol 64 of Advances in ExperimentalMedicine and Biology pp 185ndash195 Springer New York NYUSA 1975

[52] J L Portis and J E Coe ldquoIgM the secretory immunoglobulinof reptiles and amphibiansrdquo Nature vol 258 no 5535 pp 547ndash548 1975

[53] J E Coe D Leong J L Portis and L A Thomas ldquoImmuneresponse in the garter snake (Thamnophis ordinoides)rdquo Immu-nology vol 31 no 3 pp 417ndash424 1976

[54] D Hadge and H Ambrosius ldquoEvolution of low molecularweight immunoglobulinsmdashIV IgY-like immunoglobulins ofbirds reptiles and amphibians precursors of mammalian IgArdquoMolecular Immunology vol 21 no 8 pp 699ndash707 1984

[55] D Hadge and H Ambrosius ldquoEvolution of low molecularweight immunoglobulins V Degree of antigenic relationshipbetween the 7S immunoglobulins ofmammals birds and lowervertebrates to the turkey IgYrdquo Developmental and ComparativeImmunology vol 10 no 3 pp 377ndash385 1986

[56] S Magadan-Mompo C Sanchez-Espinel and F Gambon-Deza ldquoImmunoglobulin genes of the turtlesrdquo Immunogeneticsvol 65 no 3 pp 227ndash237 2013

[57] Z Wei Q Wu L Ren et al ldquoExpression of IgM IgD and IgYin a reptile Anolis carolinensisrdquoThe Journal of Immunology vol183 no 6 pp 3858ndash3864 2009

[58] F Gambon-Deza C Sanchez-Espinel and J V Beneitez ldquoAnovel IgA-like immunoglobulin in the reptile Eublepharis mac-ulariusrdquo Developmental and Comparative Immunology vol 31no 6 pp 596ndash605 2007

[59] G Cheng Y Gao T Wang et al ldquoExtensive diversification ofIgH subclass-encoding genes and IgM subclass switching incrocodiliansrdquo Nature Communications vol 4 article 1337 2013

[60] S Magadan-Mompo C Sanchez-Espinel and F Gambon-Deza ldquoIgH loci of American alligator and saltwater crocodileshed light on IgA evolutionrdquo Immunogenetics vol 65 no 7 pp531ndash541 2013

[61] E Orlans and M E Rose ldquoAn IgA-like immunoglobulin in thefowlrdquo Immunochemistry vol 9 no 8 pp 833ndash838 1972

[62] G A Leslie and L N Martin ldquoStudies on the secretory immu-nologic system of fowl 3 Serum and secretory IgA of thechickenrdquoThe Journal of Immunology vol 110 no 1 pp 1ndash9 1973

[63] J Bienenstock D Y Perey J Gauldie and B J UnderdownldquoChicken 120574A physicochemical and immunochemical charac-teristicsrdquoThe Journal of Immunology vol 110 no 2 pp 524ndash5331973

[64] A M Lebacq-Verheyden J P Vaerman and J F HeremansldquoQuantification and distribution of chicken immunoglobulinsIgA IgM and IgG in serum and secretionsrdquo Immunology vol27 no 4 pp 683ndash692 1974

[65] J Goudswaard A Noordzij R H van Dam J A vanderDonk and J P Vaerman ldquoThe immunoglobulins of the turkey(Meleagris gallopavo) Isolation and characterization of IgGIgM and IgA in body fluids eggs and intraocular tissuesrdquoPoultry science vol 56 no 6 pp 1847ndash1851 1977

[66] D Hadge and H Ambrosius ldquoComparative studies on thestructure of biliary immunoglobulins of some avian speciesII Antigenic properties of the biliary immunoglobulins ofchicken turkey duck and gooserdquo Developmental and Compar-ative Immunology vol 12 no 2 pp 319ndash329 1988

[67] J Goudswaard J P Vaerman and J F Heremans ldquoThreeimmunoglobulin classes in the pigeon (Columbia livia)rdquo Inter-national Archives of Allergy andApplied Immunology vol 53 no5 pp 409ndash419 1977

[68] P L K Ng and D A Higgins ldquoBile immunoglobulin of theduck (Anas platyrhynchos) I Preliminary characterization andontogenyrdquo Immunology vol 58 no 2 pp 323ndash327 1986

[69] K E Magor G W Warr Y Bando D L Middleton and DA Higgins ldquoSecretory immune system of the duck (Anas

ISRN Immunology 17

platyrhynchos) Identification and expression of the genesencoding IgA and IgM heavy chainsrdquo European Journal ofImmunology vol 28 no 3 pp 1063ndash1068 1998

[70] Y Zhao H Rabbani A Shimizu and L Hammarstrom ldquoMap-ping of the chicken immunoglobulin heavy-chain constantregion gene locus reveals an inverted 120572 gene upstream of acondensed 120592 generdquo Immunology vol 101 no 3 pp 348ndash3532000

[71] M L Lundqvist D L Middleton S Hazard and G W WarrldquoThe immunoglobulin heavy chain locus of the duck genomicorganization and expression of D J and C region genesrdquo TheJournal of Biological Chemistry vol 276 no 50 pp 46729ndash46736 2001

[72] T HuangM Zhang ZWei et al ldquoAnalysis of immunoglobulintranscripts in the ostrich Struthio camelus a primitive avianspeciesrdquo PLoS ONE vol 7 no 3 Article ID e34346 2012

[73] K H Roux ldquoImmunoglobulin structure and function asrevealed by electron microscopyrdquo International Archives ofAllergy and Immunology vol 120 no 2 pp 85ndash99 1999

[74] F Gambon-Deza C Sanchez-Espinel and S Magadan-Mompo ldquoThe immunoglobulin heavy chain locus in the platy-pus (Ornithorhynchus anatinus)rdquo Molecular Immunology vol46 no 13 pp 2515ndash2523 2009

[75] Y Zhao H Cui C M Whittington et al ldquoOrnithorhynchusanatinus (platypus) links the evolution of immunoglobulingenes in eutherian mammals and nonmammalian tetrapodsrdquoThe Journal of Immunology vol 183 no 5 pp 3285ndash3293 2009

[76] M Aveskogh and L Hellman ldquoEvidence for an early appear-ance of modern post-switch isotypes in mammalian evolutioncloning of IgE IgG and IgA from the marsupial Monodelphisdomesticardquo European Journal of Immunology vol 28 no 9 pp2738ndash2750 1998

[77] K Belov G A Harrison and DW Cooper ldquoMolecular cloningof the cDNA encoding the constant region of the immunoglob-ulin a heavy chain (C120572) from amarsupialTrichosurus vulpecula(common brushtail possum)rdquo Immunology Letters vol 60 no2-3 pp 165ndash170 1998

[78] K Belov K R Zenger L Hellman and DW Cooper ldquoEchidnaIgA supports mammalian unity and traditional Therian rela-tionshiprdquo Mammalian Genome vol 13 no 11 pp 656ndash6632002

[79] K Belov and L Hellman ldquoImmunoglobulin genetics of Orni-thorhynchus anatinus (platypus) and Tachyglossus aculeatus(short-beaked echidna)rdquo Comparative Biochemistry and Phys-iology vol 136 no 4 pp 811ndash819 2003

[80] M VernerssonM Aveskogh BMunday and L Hellman ldquoEvi-dence for an early appearance of modern post-switch immu-noglobulin isotypes in mammalian evolution (II) cloning ofIgE IgG1 and IgG2 fromamonotreme the duck-billed platypusOrnithorhynchus anatinusrdquo European Journal of Immunologyvol 32 no 8 pp 2145ndash2155 2002

[81] C Auffray R Nageotte and J L Sikorav ldquoMouse immunoglob-ulin A nucleotide sequence of the structural gene for the 120572heavy chain derived from cloned cDNAsrdquo Gene vol 13 no 4pp 365ndash374 1981

[82] T Ukaji D Sumiyama and O Kai ldquoSequence determinationof the heavy-chain constant region in four immunoglobulinclasses of Mongolian gerbils (Meriones unguiculatus)rdquo Experi-mental Animals vol 61 no 2 pp 99ndash107 2012

[83] R C Burnett W C Hanly S K Zhai and K L Knight ldquoTheIgA heavy chain gene family in rabbit cloning and sequence

analysis of 13 C120572 genesrdquo The EMBO Journal vol 8 no 13 pp4041ndash4047 1989

[84] D K Lanning S-K Zhai and K L Knight ldquoAnalysis of the 31015840C120583 region of the rabbit Ig heavy chain locusrdquoGene vol 309 no2 pp 135ndash144 2003

[85] F Ros J Puels N Reichenberger W van Schooten R Buelowand J Platzer ldquoSequence analysis of 05Mb of the rabbitgermline immunoglobulin heavy chain locusrdquo Gene vol 330no 1-2 pp 49ndash59 2004

[86] M Patel D Selinger G E Mark G J Hickey and G FHollis ldquoSequence of the dog immunoglobulin alpha and epsilonconstant region genesrdquo Immunogenetics vol 41 no 5 pp 282ndash286 1995

[87] Z Zhao Y Zhao Q Pan-Hammarstrom et al ldquoPhysical map-ping of the giant panda immunoglobulin heavy chain constantregion genesrdquo Developmental and Comparative Immunologyvol 31 no 10 pp 1034ndash1049 2007

[88] W R Brown and J E Butler ldquoCharacterization of a C120572 gene ofswinerdquoMolecular Immunology vol 31 no 8 pp 633ndash642 1994

[89] W R Brown H Rabbani J E Butler and L HammarstromldquoCharacterization of the bovine C120572 generdquo Immunology vol 91no 1 pp 1ndash6 1997

[90] G PWhite P Roche M R Brandon S E Newton and E N TMeeusen ldquoCloning and characterization of sheep (Ovis aries)immunoglobulin 120572 chainrdquo Immunogenetics vol 48 no 5 pp359ndash362 1998

[91] AMancia T A Romano H A Gefroh et al ldquoCharacterizationof the immunoglobulin A heavy chain gene of the Atlantic bot-tlenose dolphin (Tursiops truncatus)rdquo Veterinary Immunologyand Immunopathology vol 118 no 3-4 pp 304ndash309 2007

[92] B Wagner I Greiser-Wilke and D F Antczak ldquoCharacteriza-tion of the horse [Equus caballus] IGHA generdquo Immunogeneticsvol 55 no 8 pp 552ndash560 2003

[93] N Takahashi S Ueda and M Obata ldquoStructure of humanimmunoglobulin gamma genes implications for evolution of agene familyrdquo Cell vol 29 no 2 pp 671ndash679 1982

[94] J G Flanagan M-P Lefranc and T H Rabbitts ldquoMechanismsof divergence and convergence of the human immunoglobulin1205721 and 1205722 constant region gene sequencesrdquo Cell vol 36 no 3pp 681ndash688 1984

[95] S Kawamura K Omoto and S Ueda ldquoEvolutionary hypervari-ability in the hinge region of the immunoglobulin alpha generdquoJournal of Molecular Biology vol 215 no 2 pp 201ndash206 1990

[96] F Scinicariello F Masseoud L Jayashankar and R AttanasioldquoSooty mangabey (Cercocebus torquatus atys) IGHG and IGHAgenesrdquo Immunogenetics vol 58 no 12 pp 955ndash965 2006

[97] K A Rogers L Jayashankar F Scinicariello and R AttanasioldquoNonhuman primate IgA genetic heterogeneity and interac-tions with CD89rdquoThe Journal of Immunology vol 180 no 7 pp4816ndash4824 2008

[98] S Kawamura N Saitou and S Ueda ldquoConcerted evolution ofthe primate immunoglobulin 120572-gene through gene conversionrdquoThe Journal of Biological Chemistry vol 267 no 11 pp 7359ndash7367 1992

[99] S Kawamura and S Ueda ldquoImmunoglobulin C119867gene family in

hominoids and its evolutionary historyrdquo Genomics vol 13 no1 pp 194ndash200 1992

[100] A Brusco U Cariota A Bottaro et al ldquoStructural andimmunologic analysis of gene triplications in the Ig heavy chainconstant region locusrdquoThe Journal of Immunology vol 152 no1 pp 129ndash135 1994

18 ISRN Immunology

[101] H Rabbani Q Pan N Kondo C I E Smith and L Ham-marstrom ldquoDuplications and deletions of the human IGHClocus evolutionary implicationsrdquo Immunogenetics vol 45 no2 pp 136ndash141 1996

[102] P F Weinheimer J Mestecky and R T Acton ldquoSpecies distri-bution of J chainrdquoThe Journal of Immunology vol 107 no 4 pp1211ndash1212 1971

[103] F P Inman and J Mestecky ldquoThe J chain of polymeric immu-noglobulinsrdquo inContemporary Topics inMolecular Immunologyvol 3 pp 111ndash141 Springer New York NY USA 1974

[104] P Brandtzaeg ldquoPresence of J chain in human immunocytescontaining various immunoglobulin classesrdquo Nature vol 252no 5482 pp 418ndash420 1974

[105] L Tacchi E Larragoite and I Salinas ldquoDiscovery of J chain inAfrican lungfish (Protopterus dolloi Sarcopterygii) using highthroughput transcriptome sequencing implications in mucosalimmunityrdquo PLoS ONE vol 8 no 8 Article ID e70650 2013

[106] I K Zarkadis D Mastellos and J D Lambris ldquoPhylogeneticaspects of the complement systemrdquo Developmental and Com-parative Immunology vol 25 no 8-9 pp 745ndash762 2001

[107] A P West Jr A B Herr and P J Bjorkman ldquoThe chickenyolk sac IgY receptor a functional equivalent of themammalianMHC-related Fc receptor is a phospholipase A

2receptor

homologrdquo Immunity vol 20 no 5 pp 601ndash610 2004[108] D B Tesar E J Cheung and P J Bjorkman ldquoThe chicken

yolk sac IgY receptor a mammalian mannose receptor familymember transcytoses IgY across polarized epithelial cellsrdquoMolecular Biology of the Cell vol 19 no 4 pp 1587ndash1593 2008

[109] A I Taylor R L Beavil B J Sutton and R A Calvert ldquoAmonomeric chicken IgY receptor binds IgY with 21 stoichiom-etryrdquo The Journal of Biological Chemistry vol 284 no 36 pp24168ndash24175 2009

[110] K Baker S-W Qiao T Kuo et al ldquoImmune and non-immunefunctions of the (not so) neonatal Fc receptor FcRnrdquo Seminarsin Immunopathology vol 31 no 2 pp 223ndash236 2009

[111] K Baker R S Blumberg and C S Kaetzel ldquoImmunoglob-ulin transport and immunoglobulin receptorsrdquo in MucosalImmunology J Mestecky W Strober H Cheroutre B KelsallB N Lambrecht andMW Russell Eds chapter 20 AcademicPressElsevier Waltham Mass USA 2014

[112] C S Kaetzel ldquoThepolymeric immunoglobulin receptorrdquo in eLSJohn Wiley amp Sons Chichester UK 2013

[113] N J Mantis N Rol and B Corthesy ldquoSecretory IgArsquos complexroles in immunity andmucosal homeostasis in the gutrdquoMucosalImmunology vol 4 no 6 pp 603ndash611 2011

[114] J V Peppard M E Rose and P Hesketh ldquoA functional homo-logue of mammalian secretory component exists in chickensrdquoEuropean Journal of Immunology vol 13 no 7 pp 566ndash5701983

[115] K E Mostov M Friedlander and G Blobel ldquoThe receptorfor transepithelial transport of IgA and IgM contains multipleimmunoglobulin-like domainsrdquo Nature vol 308 no 5954 pp37ndash43 1984

[116] P Krajci R Solberg M Sandberg O Oyen T Jahnsen and PBrandtzaeg ldquoMolecular cloning of the human transmembranesecretory component (poly-Ig receptor) and its mRNA expres-sion in human tissuesrdquo Biochemical and Biophysical ResearchCommunications vol 158 no 3 pp 783ndash789 1989

[117] P Krajci D Kvale K Tasken and P Brandtzaeg ldquoMolecularcloning and exon-intron mapping of the gene encoding humantransmembrane secretory component (the poly-Ig receptor)rdquo

European Journal of Immunology vol 22 no 9 pp 2309ndash23151992

[118] J F Piskurich J A France C M Tamer C A Willmer CS Kaetzel and D M Kaetzel ldquoInterferon-120574 induces polymericimmunoglobulin receptormRNA in human intestinal epithelialcells by a protein synthesis dependent mechanismrdquo MolecularImmunology vol 30 no 4 pp 413ndash421 1993

[119] J F Piskurich M H Blanchard K R Youngman J A Franceand C S Kaetzel ldquoMolecular cloning of the mouse polymericIg receptor functional regions of the molecule are conservedamong five mammalian speciesrdquo The Journal of Immunologyvol 154 no 4 pp 1735ndash1747 1995

[120] M A Kulseth P Krajci O Myklebost and S RogneldquoCloning and characterization of two forms of bovine polymericimmunoglobulin receptor cDNArdquo DNA and Cell Biology vol14 no 3 pp 251ndash256 1995

[121] K S Koch A S Gleiberman T Aoki et al ldquoDiscordant expres-sion and variable numbers of neighboring GGA- and GAA-richtriplet repeats in the 31015840 untranslated regions of two groups ofmessenger RNAs encoded by the rat polymeric immunoglob-ulin receptor generdquo Nucleic Acids Research vol 23 no 7 pp1098ndash1112 1995

[122] F M Adamski and J Demmer ldquoTwo stages of increased IgAtransfer during lactation in themarsupialTrichosurus vulpecula(brushtail possum)rdquoThe Journal of Immunology vol 162 no 10pp 6009ndash6015 1999

[123] H Kumura T Sone K-I Shimazaki and E KobayashildquoSequence analysis of porcine polymeric immunoglobulinreceptor from mammary epithelial cells present in colostrumrdquoThe Journal of Dairy Research vol 67 no 4 pp 631ndash636 2000

[124] C L Taylor G A Harrison C M Watson and E M DeaneldquocDNA cloning of the polymeric immunoglobulin receptor ofthe marsupial Macropus eugenii (tammar wallaby)rdquo EuropeanJournal of Immunogenetics vol 29 no 2 pp 87ndash93 2002

[125] R Braathen V S Hohman P Brandtzaeg and F-E JohansenldquoSecretory antibody formation conserved binding interactionsbetween J chain and polymeric Ig receptor from humans andamphibiansrdquo The Journal of Immunology vol 178 no 3 pp1589ndash1597 2007

[126] M J Lewis BWagner R M Irvine and J MWoof ldquoIgA in thehorse cloning of equine polymeric Ig receptor and J chain andcharacterization of recombinant forms of equine IgArdquoMucosalImmunology vol 3 no 6 pp 610ndash621 2010

[127] A J Leon D Banner L Xu et al ldquoSequencing annotation andcharacterization of the influenza ferret infectomerdquo Journal ofVirology vol 87 no 4 pp 1957ndash1966 2013

[128] W H Wieland D Orzaez A Lammers H K ParmentierM W A Verstegen and A Schots ldquoA functional polymericimmunoglobulin receptor in chicken (Gallus gallus) indicatesancient role of secretory IgA inmucosal immunityrdquoBiochemicalJournal vol 380 no 3 pp 669ndash676 2004

[129] K Hamuro H Suetake N R Saha K Kikuchi and YSuzuki ldquoA teleost polymeric Ig receptor exhibiting two Ig-likedomains transports tetrameric IgM into the skinrdquo The Journalof Immunology vol 178 no 9 pp 5682ndash5689 2007

[130] J H W M Rombout S J L van der Tuin G Yang et alldquoExpression of the polymeric immunoglobulin receptor (pIgR)in mucosal tissues of common carp (Cyprinus carpio L)rdquo Fishand Shellfish Immunology vol 24 no 5 pp 620ndash628 2008

[131] L-N Feng D-Q Lu J-X Bei et al ldquoMolecular cloning andfunctional analysis of polymeric immunoglobulin receptor gene

ISRN Immunology 19

in orange-spotted grouper (Epinephelus coioides)rdquo ComparativeBiochemistry and Physiology B vol 154 no 3 pp 282ndash289 2009

[132] A E Oslashstergaard S A M Martin T Wang R J M Stet andC J Secombes ldquoRainbow trout (Oncorhynchus mykiss) pos-sessmultiple novel immunoglobulin-like transcripts containingeither an ITAM or ITIMsrdquo Developmental and ComparativeImmunology vol 33 no 4 pp 525ndash532 2009

[133] H Eiffert E Quentin and J Decker ldquoThe primary structureof the human free secretory component and the arrangementof disulfide bondsrdquo Hoppe-Seylerrsquos Zeitschrift fur PhysiologischeChemie vol 365 no 12 pp 1489ndash1495 1984

[134] E Fallgreen-Gebauer W Gebauer A Bastian et al ldquoThe cova-lent linkage of secretory component to IgA Structure of sIgArdquoBiological Chemistry Hoppe-Seyler vol 374 no 11 pp 1023ndash1028 1993

[135] J MWoof ldquoThe structure of IgArdquo inMucosal Immune DefenseImmunoglobulin A C S Kaetzel Ed chapter 1 pp 1ndash24Springer New York NY USA 2007

[136] A Bonner A Almogren P B Furtado M A Kerr and S JPerkins ldquoLocation of secretory component on the Fc edge ofdimeric IgA1 reveals insight into the role of secretory IgA1 inmucosal immunityrdquoMucosal Immunology vol 2 no 1 pp 74ndash84 2009

[137] A Bonner A Almogren P B Furtado M A Kerr and S JPerkins ldquoThe nonplanar secretory IgA2 and near planar secre-tory IgA1 solution structures rationalize their different mucosalimmune responsesrdquo The Journal of Biological Chemistry vol284 no 8 pp 5077ndash5087 2009

[138] J Johansen B Braathen and P Brandtzaeg ldquoRole of J chain insecretory immunoglobulin formationrdquo Scandinavian Journal ofImmunology vol 52 no 3 pp 240ndash248 2000

[139] B A Hendrickson D A Conner D J Ladd et al ldquoAlteredhepatic transport of immunoglobulin A in mice lacking the Jchainrdquo Journal of Experimental Medicine vol 182 no 6 pp1905ndash1911 1995

[140] B A Hendrickson L Rindisbacher B Corthesy et al ldquoLackof association of secretory component with IgA in J chain-deficient micerdquo The Journal of Immunology vol 157 no 2 pp750ndash754 1996

[141] N Lycke L Erlandsson L Ekman K Schon and T Lean-derson ldquoLack of J chain inhibits the transport of gut IgA andabrogates the development of intestinal antitoxic protectionrdquoThe Journal of Immunology vol 163 no 2 pp 913ndash919 1999

[142] F-E Johansen R Braathen and P Brandtzaeg ldquoThe J chainis essential for polymeric Ig receptor-mediated epithelial trans-port of IgArdquoThe Journal of Immunology vol 167 no 9 pp 5185ndash5192 2001

[143] R E Ley D A Peterson and J I Gordon ldquoEcological andevolutionary forces shaping microbial diversity in the humanintestinerdquo Cell vol 124 no 4 pp 837ndash848 2006

[144] M McFall-Ngai ldquoAdaptive immunity care for the communityrdquoNature vol 445 no 7124 p 153 2007

[145] A J Macpherson K D McCoy F-E Johansen and PBrandtzaeg ldquoThe immune geography of IgA induction andfunctionrdquoMucosal Immunology vol 1 no 1 pp 11ndash22 2008

[146] D Kvale and P Brandtzaeg ldquoConstitutive and cytokine inducedexpression of HLA molecules secretory component and inter-cellular adhesion molecule-1 is modulated by butyrate in thecolonic epithelial cell line HT-29rdquo Gut vol 36 no 5 pp 737ndash742 1995

[147] L VHooperMHWong AThelin L Hansson P G Falk andJ I Gordon ldquoMolecular analysis of commensal host-microbialrelationships in the intestinerdquo Science vol 291 no 5505 pp 881ndash884 2001

[148] S Hapfelmeier M A E Lawson E Slack et al ldquoReversiblemicrobial colonization of germ-free mice reveals the dynamicsof IgA immune responsesrdquo Science vol 328 no 5986 pp 1705ndash1709 2010

[149] DH ReikvamMDerrien R Islam et al ldquoEpithelial-microbialcross-talk in polymeric Ig receptor deficient micerdquo EuropeanJournal of Immunology vol 42 no 11 pp 2959ndash2970 2012

[150] EW Rogier A L Frantz M E C Bruno et al ldquoSecretory anti-bodies in breast milk promote long-term intestinal homeostasisby regulating the gut microbiota and host gene expressionrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 111 no 8 pp 3074ndash3079 2014

[151] G M Barton and R Medzhitov ldquoToll-like receptor signalingpathwaysrdquo Science vol 300 no 5625 pp 1524ndash1525 2003

[152] K Takeda and S Akira ldquoToll receptors and pathogen resis-tancerdquo Cellular Microbiology vol 5 no 3 pp 143ndash153 2003

[153] E Cario andD K Podolsky ldquoDifferential alteration in intestinalepithelial cell expression of Toll-like receptor 3 (TLR3) andTLR4 in inflammatory bowel diseaserdquo Infection and Immunityvol 68 no 12 pp 7010ndash7017 2000

[154] M Hausmann S Kiessling S Mestermann et al ldquoToll-likereceptors 2 and 4 are up-regulated during intestinal inflamma-tionrdquo Gastroenterology vol 122 no 7 pp 1987ndash2000 2002

[155] M T Abreu L S Thomas S Y Tesfay et al ldquoRegulation ofTLR4 and MD-2 in the intestinal epithelium evidence for dys-regulated LPS signaling in human inflammatory bowel diseaserdquoin Proceedings of the 90th Annual Meeting of the AmericanAssociation for Immunologists Abstract 3634 Denver ColoUSA 2003

[156] T A Schneeman M E C Bruno H Schjerven F-E JohansenL Chady and C S Kaetzel ldquoRegulation of the polymeric Igreceptor by signaling through TLRs 3 and 4 linking innate andadaptive immune responsesrdquo The Journal of Immunology vol175 no 1 pp 376ndash384 2005

[157] M E C Bruno A L Frantz E W Rogier F-E Johansen andC S Kaetzel ldquoRegulation of the polymeric immunoglobulinreceptor by the classical and alternative NF-120581B pathways inintestinal epithelial cellsrdquoMucosal Immunology vol 4 no 4 pp468ndash478 2011

[158] M E C Bruno E W Rogier A L Frantz A T Stefka SN Thompson and C S Kaetzel ldquoRegulation of the poly-meric immunoglobulin receptor in intestinal epithelial cellsby Enterobacteriaceae implications for mucosal homeostasisrdquoImmunological Investigations vol 39 no 4-5 pp 356ndash382 2010

[159] A L Frantz E W Rogier C R Weber et al ldquoTargeted deletionof MyD88 in intestinal epithelial cells results in compromisedantibacterial immunity associatedwith downregulation of poly-meric immunoglobulin receptor mucin-2 and antibacterialpeptidesrdquoMucosal Immunology vol 5 no 5 pp 501ndash512 2012

[160] E W Rogier A L Frantz M E C Bruno and C S KaetzelldquoSecretory IgA is concentrated in the outer layer of intestinalmucus along with gut bacteriardquo Pathogens In press

[161] M B Geuking K D McCoy and A J Macpherson ldquoThe func-tion of secretory IgA in the context of the intestinal continuumof adaptive immune responses in host-microbial mutualismrdquoSeminars in Immunology vol 24 no 1 pp 36ndash42 2012

20 ISRN Immunology

[162] L VHooper D R Littman andA JMacpherson ldquoInteractionsbetween the microbiota and the immune systemrdquo Science vol336 no 6086 pp 1268ndash1273 2012

[163] A J Macpherson M B Geuking E Slack S Hapfelmeierand K D McCoy ldquoThe habitat double life citizenship andforgetfulness of IgArdquo Immunological Reviews vol 245 no 1 pp132ndash146 2012

Submit your manuscripts athttpwwwhindawicom

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

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Diabetes ResearchJournal of

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Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

ISRN Immunology 3

domain

domain

domain

Hinge region

Fc region

Antigen-binding site

CL

VL

VH

CH1 domain

CH2 domain

CH3 domain

Figure 2 The basic structure of immunoglobulins The basic structural unit of Igs comprises 2 identical light chains (shown in red andblue) and 2 identical heavy chains (shown in red and blue) The polypeptide chains of Ig light and heavy chains consist of repeating unitsof approximately 110 amino acids so-called ldquoIg-likerdquo domains with a characteristic 3-dimensional structure Ig light chains comprise an N-terminal variable (VL) domain followed by a constant (CL) domain of either the 120581 or 120582 type Ig heavy chains comprise an N-terminal variabledomain (VH) followed by 3-4 constant domains (CH1ndashCH3 or 4)The sequence of Ig heavy chain constant regions (designated byGreek letterssuch as 120572 120574 or 120583) defines the Ig class or isotype The structure shown here is characteristic of mammalian IgA IgD and IgG in which theCH1 and CH2 domains of the heavy chains are connected by a short cysteine- and proline-rich hinge region The structure of all Igs in lowervertebrates (as well as IgM and IgE in mammals) differs in that the CH2 domain replaces the hinge region and the Fc region comprises theCH3 and CH4 domains Pairing of VH and VL domains on adjacent Ig heavy and light chains forms the antigen-binding site while the Fcregions of the Ig heavy chains (comprising the two most C-terminal constant domains) confer isotype-specific immune effector functions

during immune responses by a process of DNA rearrange-ment called class switch recombination (CSR) [24ndash26] Mostof the studies of Ig structure and function in bony fisheshave focused on the Actinopterygii (ray-finned bony fishes)which comprise 99 of the over 30000 living species offish mainly within the infraclass Teleostei Early studies inseveral teleost species including plaice (Pleuronectes platessa)[27] common carp (Cyprinus carpio) [28] rainbow trout(Oncorhynchus mykiss) [29] and channel catfish (Ictaluruspunctatus) [30] demonstrated that immunization bymucosalroutes (oral anal and skin) elicited antibody responses in theskin intestinal mucus and bile In 2005 a novel Ig isotypewas described in rainbow trout [31] zebrafish (Danio rerio)[32] and fugu (Fugu rubripes) [33] designated IgT (for teleost)or IgZ (for zebrafish) In the same year an unusual Igisotype described in the common carp which appeared tobe a chimera of IgM and IgZ [34] was identified (Cyprinuscarpio) Subsequent studies in a number of teleost speciesrevealed a common translocon structure in the IGH locuswith tandem gene segments encoding the constant regionsof IgM IgD and IgT(Z) [35ndash37] Functional studies revealed

that the molar ratio of IgT to IgM was 60-fold higher in gutmucus than in serum of rainbow trout and that specific IgTantibodies were induced in the gut following oral infectionwith the parasite Ceratomyxa shasta [38] In this study IgT-expressing lymphocytes were found to represent 543 of allB cells in the intestinal lamina propria Interestingly IgT wasfound as amonomer in serum but as a tetramer in gutmucussuggestive of a selectivemechanism for polymerization of IgTin mucosal B cells similar to that observed for IgA in highervertebrates Thus IgT appears to be the most primitive Igisotype with specialized functions at mucosal surfaces

Although IgT has been identified in most Actinopterygiithus far studied some exceptions have been noted Theabsence of a gene encoding IgT was recently reported in theSiberian sturgeon (Acipenser baerii) a species of the orderAcipenseriformes which occupies a unique phylogeneticniche between the cartilaginous fishes and the Teleostei Theabsence of IgT was also reported in the medaka (Oryziaslatipes) a teleost of the order Beloniformes [39] SurprisinglyIgT is absent in channel catfish a teleost of the order Siluri-formes which is closely related to the order Cypriniformes

4 ISRN Immunology

Ig-like domain

Cysteine-rich domain

Fibronectin type II repeat

C-type lectin-like domain

pIgR

PolymericIgM IgTIgX IgA

Epithelialcells

(CD351)

IgM IgA

B cells

(CD89)

IgA

NeutrophilsMonocytes

Eosinophils

(CD64)

IgG

Monocytes

NeutrophilsEosinophils

(CD32)

IgG

Monocytes

NeutrophilsPlatelets

LangerhansB cells

(CD16)

IgG

NK cells

MonocytesNeutrophilsEosinophils

IgE

Mast cellsBasophils

LangerhansMonocytes

(CD23)

IgE

B cellsT cells

MonocytesEosinophils

FcRn

IgG

Endothelial

Epithelialcells

cells

FcRY

IgY

Endothelialcells

Fc120572120583R

MΦs

Fc120572RI

MΦsMΦs MΦs

MΦs

Fc120574RI Fc120574RII Fc120574RIII

120574120575 T cells

Fc120576RIIFc120576RI

MΦs

1205732m

MHC I-like domain

Figure 3 Fc receptors are Ig isotype- and cell type-specific These schematic diagrams illustrate basic structural features of selectedFc receptors all of which are Type I transmembrane proteins The structures are not to scale and do not imply specific 3-dimensionalconformations All of the structures represent the human homolog of the indicated protein except for FcRY which is from chicken Binding ofthe constant (Fc) region of Igs to cellular receptors initiates transport across epithelial cells or intracellular signaling in cells of hematopoieticorigin The membrane-proximal Ig-like domain of FcRn pairs with the Ig-like domain of soluble 1205732-microglobulin (1205732m) The Ig-bindingsubunits of Fc120572RI Fc120574RI Fc120574RII Fc120574RIII and Fc120576RI (shownhere) pair with other protein subunits (not shown) to initiate signaling pathwaysThis figure was compiled using information from [9ndash15]

that includes the IgT-expressing carp and zebrafish The IGHloci of the few extant species of the class Sarcopterygii (lobe-finned bony fishes including coelacanths and lungfishes)differ from those ofmost of the Actinopterygii (Figure 1)TheAfrican coelacanth (Latimeria chalumnae) one of only twospecies of an ancient class of lobe-finned fishes lacks IgM andhas a single Ig heavy chain gene that resembles the IgWDgene of cartilaginous fishes [40] By contrast the Africanlungfish (Protopterus aethiopicus) expresses both IgM and anisotype resembling IgWD [41] No ortholog of IgT has beenidentified in lobe-finned bony fishes Given the diversity of Iggenes in bony fishes the evolutionary origin of IgT remainsobscure Furthermore while IgT shares many functionalsimilarities with IgA in higher vertebrates the structuralgenes for IgT and IgA are not orthologous [23] Thus thegene encoding IgT appears to be an evolutionary dead-endthat emerged in some lineages of bony fishes in response topressures for immunological protection of mucosal surfaceslikely driven by the resident microbiota as well as mucosalpathogens

23 Amphibians Duplication and diversification of genesegments within the IGH locus in a common ancestor of theTetrapoda (four-limbed vertebrates) led to the appearanceof additional heavy chain Ig isotypes (reviewed in [42])(Figure 1) Most extant species of tetrapods have a single IGHlocus the location of which is syntenic with the human IGHlocus Ectothermic vertebrates of the class Amphibia are themost primitive tetrapods having diverged about 370 millionyears ago from a common ancestor with reptiles birds andmammals Early studies of the structural and immunologicalproperties of Igs from several species of clawed frogs (Xeno-pus) suggested the emergence of two novel Ig isotypes IgXand IgY [43ndash47] (Figure 1) B cells expressing IgX but not IgYwere found abundantly in the intestinal epithelium whereasIgX-positive cells were rarely detected in the spleen and IgXlevels were very low in serum [47] Interestingly thymectomyabolished expression of IgY but not IgM or IgX consistentwith a T-independent role for IgX in the mucosal immunesystem of amphibians Genes encoding IgX and IgY weresubsequently identified in 2 species of salamanders [48 49]

ISRN Immunology 5

suggesting that these Ig isotypes may have emerged in acommon ancestor of amphibians To date no studies havebeen reported on IGH loci in caecilians A recent study inXenopus laevis established the position of amphibian IgX asthe evolutionary precursor of IgA in birds and mammals[50] These investigators found that larval thymectomy didnot affect levels of IgX and did not alter the compositionof the gut microbiota confirming the T-independence ofthe IgX response in Xenopus Phylogenetic comparisons ofIgT in bony fishes and IgX in amphibians suggest that theseIg isotypes evolved independently [23] likely responding tosimilar pressures from the resident microbiota and mucosalpathogens

24 Reptiles and Birds The clade Amniota within the super-class Tetrapoda can be subdivided into the sauropsids (rep-tiles and birds) and synapsids (mammals and their closerelatives) (Figure 1) The distinction between reptiles andbirds is based largely on physical characteristics rather thanphylogeny distinguishing the cold-blooded reptiles withscales from the warm-blooded birds with feathers Earlystudies of Igs in turtles lizards and snakes were basedlargely on their physicochemical and antigenic propertiesrevealing a predominance of IgM and lesser amounts of IgYin bile and gut secretions [51ndash53] Subsequent analyses usingantibodies to chicken IgA failed to detect a cross-reactive Igisotype in reptiles [54 55] The recent availability of wholegenome sequences for 2 species of turtles (Chrysemys pictaand Pelodiscus sinensis) [36 56] and the green anole lizard(Anolis carolinensis) [57] demonstrated the presence of genesegments encoding IgM IgD and multiple subclasses ofIgY but no ortholog of IgX in amphibians or IgA in birdsand mammals The leopard gecko (Eublepharis macularius)expresses IgM IgD and a third Ig isotype that is intermediatein homology between IgA and IgY [50 58] (designatedIgldquoArdquo for the purposes of this review) The recent availabilityof whole genome sequences for 4 crocodilians (Alligatorsinensis Alligator mississippiensis Crocodylus siamensis andCrocodylus porosus) revealed significant differences in theIGH loci compared to other reptiles including multiple sub-classes of IgM IgD and IgA (orthologous to the IgA genes ofbirds and mammals) but no IgY [59 60] Early studies of theimmune systems of birds (class Aves) revealed the presenceof an ortholog of mammalian IgA in mucosal secretionsand an ortholog of IgG (designated IgY) in serum [61ndash69]Mapping of the IGH locus in chickens and ducks revealed aninverted gene segment encoding IgA downstream of the IgMgene segment and upstream of the IgY gene segment andloss of the gene segment encoding IgD [70 71] Availabilityof whole genome sequences for a variety of bird species inthe National Center for Biotechnology Information (NCBI)database demonstrates the consistent presence of IgM IgAand IgY and the absence of IgD A recent analysis of Iggene transcripts in the ostrich (Struthio camelus) revealedsimilarities with chickens ducks and other birds includingthe expression of IgM IgA and IgY and the absence of IgD[72] Because the ostrich is one of the most primitive extantspecies of birds it appears that the distinctive organization

of the IGH locus evolved very early during the divergence ofthe avian lineage Furthermore a phylogenetic comparisonof Ig heavy chain sequences from amphibians with those ofhigher vertebrates demonstrated with high statistical supportthat IgX from amphibians and IgA from birds share arecent common ancestor [50] Taken together the evidenceis consistent with an IGH locus in a common ancestor ofreptiles and birds that included gene segments encoding IgMIgD IgA and IgY Instability in the IGH locus in individuallineages apparently resulted in the selective loss of IgA inmostturtles lizards and snakes IgY in crocodilians and IgD inbirds

25 Mammals The structure of Ig genes and their encodedproteins has been studied extensively in extant species of theclass Mammalia including the egg-laying monotremes thepouch-bearing marsupials and the placentals (eutherians)(reviewed in [8]) The IGH locus in all known mammalsis organized as a translocon with gene segments encodingIgM IgD 2 or more subclasses of IgG 1 or more subclassesof IgA and IgE an isotype unique to mammals (Figure 1)A recent phylogenetic analysis of Ig heavy chain classes intetrapods indicated with high statistical probability that theIgA gene(s) in mammals evolved from an IgX gene in acommon ancestor of all tetrapods while the IgG and IgEgenes evolved more recently from IgY in a common ancestorof amniotes [50] Continuing diversification in the IGH locusinmammals is evidenced by differences in the number of IgGand IgA subclasses and in the structure of Ig heavy chainsUnlike all Ig heavy chains in lower vertebrates comprising 1variable Ig-like domain (VH) and 4 constant Ig-like domains(CH1ndashCH4) the CH2 domain in mammalian IgA IgD andIgG was replaced with a short flexible hinge region richin cysteine and proline residues [73] The heavy chain ofmammalian IgE has retained the prototypic 4 constant Ig-likedomains (as has IgM) suggesting that the evolution of thehinge region in mammalian IgG occurred after the evolutionof IgG and IgE from an ancestral IgY gene (Figure 1)

Determination of the structure of the IGH locus in themonotreme duck-billed platypus (Ornithorhynchus anatinus)revealed the presence of 8 CH genes (including 2 subclassesof IgG and 2 subclasses of IgG) arranged in the order C

120583-

C120575-Co-C1205742-C1205741-C1205721-C120576-C1205722 [74 75] Interestingly the gene

encoding platypus IgD lacks a hinge region and is moresimilar in structure to IgD in lower vertebrates than the IgDof eutherian mammals Downstream of the C

120575gene in the

platypus is a novel Co gene (omicron for Ornithorhynchus)which appears to have evolved from an ancestral IgY geneIn contrast to the platypus only one IgA gene was identifiedin another monotreme the echidna (Tachyglossus aculeatus)and in several species of marsupials [76ndash80] Similarly asingle structural gene for IgA has been identified in 3 speciesof the eutherian order Rodentia mouse (Mus musculus)[81] rat (Rattus norvegicus) (unpublishedGenbank accessionnumber AJ510151) and gerbil (Meriones unguiculatus) [82]By contrast the IGH locus in the European rabbit (Orycto-lagus cuniculus order Lagomorpha) is unique among mam-mals apparently having evolved from a common ancestor

6 ISRN Immunology

prior to the divergence of marsupials and monotremes fromeutherians Distinctive features include a single IgG subclass13 functional IgA subclasses and absence of IgD [83ndash85] Amore typical organization of the IGH locus including singlesubclasses of IgM IgD IgA and IgE and 2 subclasses ofIgG has been reported in mammals of the orders Carnivora[86 87] Cetartiodactyla (even-toed ungulates whales anddolphins) [88ndash91] and Perissodactyla (odd-toed ungulates)[92]

Mammals of the order Primates including humanshave the greatest number and diversity of Ig classes andsubclasses among all of the tetrapods Mapping of IGH locihas now been completed for a number of primate speciesincluding human (Homo sapiens) gorilla (Gorilla gorilla)chimpanzee (Pan troglodytes) orangutan (Pongo pygmaeus)gibbon (Hylobates lar) baboon (Papio anubis) mangabey(Cercocebus torquatus atys) and three species of macaquesthe crab-eating monkey (Macaca fascicularis) pig-tailedmonkey (Macaca nemestrina) and rhesus monkey (Macacamulatta) [93ndash97] A distinguishing feature of primates in thefamily Hominidae (great apes including humans gorillaschimpanzees and orangutans) and the family Hylobatidae(gibbons) is the presence of two IgA subclasses Althoughthe orangutan is a member of the family Hominidae its IGHlocus contains only one IgA subclass gene homologous to theIgA1 gene of other hominoids [95] By contrast primates inthe family Cercopithecidae (Old World monkeys includingbaboons mangabeys and macaques) have a single IgA geneGenetic analysis of the IGH locus of primates suggested thatduplication and diversification of the primordial C

1205741-C1205742-

C120576-C120572region occurred in a common ancestor of the great

apes after the divergence from Old World monkeys [98 99]These events resulted in the current organization of the IGHlocus in extant species of great apes with four IgG subclassesand two IgA subclasses (the duplicated C

120576gene became a

nonfunctional pseudogene hence only one class of IgE isexpressed) The close phylogenetic relationship among theC120572genes in the hominoids and Hylobatidae suggests that

the C1205721

and C1205722

genes evolved from a single C120572gene in a

common ancestor of the great apes and that the C1205722gene was

subsequently lost in the orangutan Evidence of continuingevolution in the IGH locus of humans was demonstrated bythe finding of triplication of the C

1205741-C1205742-C120576-C120572region in

several families [100] Subsequent genetic analyses inmultipleethnic groups revealed that gene duplications and deletionsin the human IGH locus are surprisingly common withfrequencies up to 22 in Japanese and Chinese populations[101]

3 Emergence of the IGJ Gene andEvolution of Polymeric Igs

The ability to produce Igs as both monomers (ie one unitcomprising 2 identical heavy chains and 2 identical lightchains) and polymers (covalently linked aggregates of 2 ormore Ig units) dates to the emergence of primitive Igs incartilaginous fish [23 42 50] Whereas pentameric IgM istypically found in serum as well as secretions the polymeric

forms of IgT IgX and IgA are generally restricted to mucosalsecretions The discovery of a low molecular weight ldquoJrdquo orldquojoiningrdquo chain as a component of polymeric Igs suggesteda potential mechanism for polymerization of individual Igmolecules into highermolecular weight complexes [102ndash104]The most primitive extant vertebrates in which the IGJ genehas been identified are the cartilaginous fish concurrent withthe presence of polymeric IgM Although the IGJ gene hasbeen identified in almost all lineages of jawed vertebratesit is surprisingly absent in some lineages of Osteichthyes(bony fishes) No ortholog of the IGJ gene has been identifiedin any species of the class Actinopterygii (ray-finned bonyfishes) for which the genome has been sequenced and anno-tated including Atlantic cod (Gadus morhua) common carp(Cyprinus carpio) tilapia (Oreochromis niloticus) zebrafish(Danio rerio) medaka (Oryzias latipes) and three-spinedstickleback (Gasterosteus aculeatus) In contrast to the ray-finned bony fishes IGJ genes and functional J chain proteinswere recently identified in two species of the class Sar-copterygii (lobe-finned bony fishes the West Indian Oceancoelacanth (Latimeria chalumnae) and the African lungfish(Protopterus dolloi) [105]) These findings suggest that theIGJ gene was lost during the evolution of the Actinopterygiiafter their divergence from a common ancestor with theSarcopterygii Despite the absence of J chain ray-finned bonyfishes are capable of forming polymeric IgM and IgT that canbe transported into mucosal secretions [38]

4 Evolution of Cellular Receptors for Igs

Theunique structure of vertebrate Igs allows for simultaneousbinding of antigen via the N-terminal variable regions ofthe Ig heavy and light chains and execution of effectorfunctions via the C-terminal constant (Fc) region of the Igheavy chains Evolution of multiple Ig heavy chain isotypesin higher vertebrates expanded the repertoire of Ig-mediatedeffector functions including specialized functions atmucosalsurfaces The simplest effector functions involve neutral-ization of microbes and their toxic byproducts whereaskilling of microbes can be affected by interaction of Igs withsoluble factors found in serumand secretionsThe concurrentemergence of Igs and proteins of the classical complementpathway in cartilaginous fishes is the earliest example of aspecific immune effector function mediated by the Fc regionof Ig heavy chains [106] As the immune system diversifiedduring vertebrate evolution cellular receptors for Ig heavychains (Fc receptors) allowed host cells to bind Igs forthe purpose of internalization transport andor activationof intracellular signaling pathways The most evolutionarilyancient of the vertebrate Fc receptors is the polymeric Igreceptor (pIgR) which first emerged in bony fishes (reviewedin [8]) (Figure 3)Theprimary function of pIgR is to transportpolymeric Igs (IgM IgT IgX and IgA) across glandular andmucosal epithelial cells into external secretions (see below)The fact that the extracellular Ig-binding region of pIgR iscomposed of multiple Ig-like domains suggests that the PIGR

ISRN Immunology 7

gene evolved by duplication of a primordial Ig gene is drivenby the need for an efficient mechanism for transport ofmucosal Igs into external secretions Similar forces may havedriven the evolution of FcRY a receptor first described forits function of transporting IgY from maternal blood tothe embryo yolk sac in chicken [9 107ndash109] FcRY is notstructurally homologous to pIgR or mammalian Fc receptorsbut is instead homologous to mammalian receptors formannose and phospholipase A2 with lectin-like extracellulardomains (Figure 3) A BLAST search of the National Centerfor Biotechnology Information (NCBI) nucleotide databasefor homologs of the gene encoding chicken FcRY (designatedPLA2R1 based on its homology to phospholipase A2 receptor1) revealed homologous genes in many bird species as wellas turtles lizards alligators and mammals However thefunctional significance of FcRYPLA2R1 in the transport ofIgY in reptiles (and possibly IgG in mammals) has not beenexplored A functional equivalent of FcRY in mammals isFcRn which mediates transport of IgG across endothelialand epithelial cells in such tissues as placenta and mucosalepithelia (reviewed in [110 111]) FcRn is homologous in struc-ture to major histocompatibility class (MHC) I moleculescomprising a ligand-binding alpha chain associated withsoluble 1205732-microglobulin (Figure 3)

A unique feature of the mammalian immune system isthe expression of Fc receptors for various Ig isotypes bycells of hematopoietic origin (Figure 3) (reviewed in [10])Engagement of these Fc receptors by Ig (in the presenceor absence of bound antigen depending on the particularFc receptor) initiates intracellular signaling pathways thatcan either augment or inhibit immune responses Withthe exception of Fc120576RII which has a single C-type lectin-like domain the extracellular Ig-binding regions of thesehematopoietic Fc receptors comprise 1 2 or 3 Ig-like domains[10] Genes encoding Fc120572120583R Fc120574RI Fc120574RIII Fc120576RI andFc120576RII are widely distributed among mammalian specieswhereas genes encoding Fc120572RI and Fc120574RII are restricted tothe primate lineage suggesting recent evolutionary originsThe genes encoding the120572120573 andor 120574 chains of Fc120576RI Fc120574RIIand Fc120574RIII are linked in a cluster on the long arm of humanchromosome 1 (1q23) not far removed from the gene for the120572 chain of Fc120574RI at 1q21 This tight linkage is consistent withduplication and diversification of a primordial FcR gene ina common ancestor of mammals The primate-specific genesencoding the 120572 and 120573 chains of Fc120574RII appear to have evolvedmore recently Another cluster of immune-related genes onthe long arm of chromosome 1 includes the genes for pIgR(1q31) and Fc120572120583R (1q32) Although the overall homologybetween pIgR and Fc120572120583R is relatively low they share aconserved binding site for IgA and IgM in the N-terminalIg-like domain Interestingly the genes encoding FcRn andFc120572RI are closely linked on the long arm of chromosome19 (19q133 and 19q1342 resp) although they bear littlehomology beyond the presence of a single Ig-like domain inthe extracellular region Finally the gene for the lectin-likereceptor Fc120576RII is located in an unrelated locus on the shortarm of chromosome 19 (19p133)

PIGR

dIgA

pIgR

Ag

SIgA

Free SC

Figure 4 Transcytosis of pIgR through a polarized epithelial celland formation of secretory Igs A polarized columnar epithelial cellis illustrated with the apical surface at the top and the basolateralsurface at the bottom Newly synthesized pIgR is targeted to thebasolateral surface where it binds polymeric Ig (pIg illustrated hereas dimeric (d)IgA) with or without bound antigen (Ag) Followingreceptor-mediated endocytosis pIg-bound and unoccupied pIgRmolecules are transported through a series of intracellular vesiclesto the apical surface Proteolytic cleavage of pIgR at the extracellularface of the plasma membrane releases free secretory component(SC) and secretory SIg (illustrated here as SIgA) Modified from [13]with permission from John Wiley and sons

5 Unique Biological Functions of pIgR

ThepIgR is expressed on the surface of glandular andmucosalepithelial binds where it binds selectively to polymericIg (pIg) and mediates its transport across epithelial cellsinto external secretions (reviewed in [17 111 112]) Most of

8 ISRN Immunology

02

100

Human IgA1Gorilla IgA1

Gorilla IgA281

6164

Human IgA2

Chimpanzee IgA2Chimpanzee IgA1

Gibbon IgA1Gibbon IgA2

Orangutan IgABaboon IgA

Rhesus macaque IgA53 100

98 69Dog IgA

Pig IgA100 Cattle IgA

52

Horse IgARabbit IgA (13 subclasses)

Mouse IgA57

99

Possum IgA

93

Chicken IgAPlatypus IgA1100

5095

Platypus IgA2

Trout IgTFrog IgX

Gecko IgldquoArdquo

(a)

02

Human pIgR

100Chimpanzee pIgRGorilla pIgR

55Gibbon pIgROrangutan pIgR100

100

100 Baboon pIgRRhesus macaque pIgR

Mouse pIgR

66

96

100 Pig pIgRCattle pIgR

85Horse pIgR

Dog pIgR

74

Rabbit pIgRPossum pIgR

Platypus pIgR

Chicken pIgR

10075

5979

Trout pIgRFrog pIgR

Anole pIgR

71

(b)

Figure 5 Coevolution of mucosal Igs and pIgR Simplified neighbor-joining phylogenetic trees of vertebrate (a) Ig and (b) pIgR proteinsequences with human IgA1 and pIgR denoted as outgroups Horizontal distances are proportional to the degree of divergence followinga multiple alignment of amino acid sequences Numbers at nodes denote bootstrap support for each bifurcation after 100 replicationsAccession numbers for mucosal Ig sequences human (Homo sapiens) IgA1 J00220 IgA2 (allotype m1) J00221 gorilla (Gorilla gorilla) IgA1X53703 IgA2 X53707 chimpanzee (Pan troglodytes) IgA1 X53702 IgA2 X53706 gibbon (Hylobates lar) IgA1 X53708 IgA2 X53709 Borneanorangutan (Pongo pygmaeus) IgA X53704 baboon (Papio anubis) IgA DQ868435 rhesus macaque (Macaca mulatta) AY039245 pig (Susscrofa) IgA U12594 cattle (Bos taurus) IgA AF109167 dog (Canis lupus familiaris) IgA L36871 horse (Equus caballus) IgA AY247966mouse (Mus musculus) IgA D11468 rabbit (Oryctolagus cuniculus) IgA1 X51647 brushtail possum (Trichosurus vulpecula) IgA AF027382duck-billed platypus (Ornithorhynchus anatinus) IgA1 AY055778 IgA2 AY055779 chicken (Gallus gallus) IgA AAB226142 leopard gecko(Eublepharis macularius) IgldquoArdquo (so designated because of its uncertain phylogeny with homology to both IgA and IgY) ABG726841African clawed frog (Xenopus laevis) IgX S03186 rainbow trout (Oncorhynchus mykiss) IgT AAW669811 Accession numbers for pIgRsequences with species that vary from those used for the mucosal Ig alignment in panel A noted in parentheses human NM 002644chimpanzee XM 003308710 gorilla XM 004028295 gibbon XM 003272974 Sumatran orangutan (Pongo abelii) NM 001131626 baboonXM 003893189 rhesus macaque XM 001083307 pig NM 214159 cattle NM 174143 dog XM 537133 horse XM 001492298 mouseNM 011082 rabbit NM 001171045 brushtail possum AF091137 duck-billed platypus XM 001508602 chicken NM 001044644 green anole(Anolis carolinensis) XM 003224013 African clawed frog EF079076 rainbow trout FJ940682

ISRN Immunology 9

our knowledge of pIgR-mediated transcytosis of mucosalIgs is derived from studies of mammalian secretory IgA(SIgA) as illustrated in Figure 4 Transcription of the PIGRgene and translation of pIgR mRNA is accompanied byinsertion of the nascent protein into the endoplasmic retic-ulum The pIgR undergoes substantial glycosylation duringtransport through the ER and Golgi apparatus and is thentargeted to the basolateral surface of polarized epithelialcells Membrane-bound pIgR binds pIg and pIg-containingimmune complexes which are internalized along with unoc-cupied pIgR via receptor-mediated endocytosis and thentranscytosed through a series of intracellular vesicles to theapical surface During transcytosis intracellular pIg antibod-ies can neutralize bacteria viruses and other antigens thathave gained access to the interior of the epithelial cell Atthe apical surface proteolytic cleavage of the membrane-spanning region of pIgR leads to the release of its extracellulardomain known as secretory component (SC) either in freeform or covalently bound to pIg Secretory Igs can neutralizepathogens and antigens within the mucosal lumen andfacilitate excretion of antigens that were transported throughthe epithelial cell as IgA immune complexes The SC moietyof SIgA has been shown to protect IgA from degradationby host and bacterial proteases and along with free SCconfers additional innate immune functions that protectthe epithelial surface from microbial invasion and limitpotentially damaging host inflammatory responses (reviewedin [113]) The finding of an SC-like polypeptide associatedwith polymeric IgT in rainbow trout [38] polymeric IgXin Xenopus [50] and polymeric IgA in birds [114] suggeststhat all vertebrate pIgRs share the function of transportingpolymeric Igs into external secretions In many mammalianspecies pIgR mediates epithelial transcytosis of both poly-meric IgM and IgA (reviewed in [111]) Although directevidence is not yet available it is reasonable to assume thatpIgR transports IgM in lower vertebrates It will be interestingto investigate whether the SCmoiety of secretory Igs in lowervertebrates mediates additional innate immune functions ashas been demonstrated for mammalian SC

6 Coevolution of pIgR and Mucosal Igs

Molecular cloning of the PIGR gene was first reportedfor mammalian species including eutherians marsupialsand monotremes [115ndash127] Subsequent elucidation of PIGRsequences from diverse species of jawed vertebrates hasallowed a comprehensive analysis of the evolutionary originsof the PIGR gene [38 128 128ndash132] and additional sequencesavailable in the Genbank database Whereas no ortholog ofthe PIGR gene has been found in any species of cartilaginousfish the PIGR gene has been annotated in all species of teleostfish for which the genome has been sequenced No orthologof the PIGR gene has been reported in lobe-finned bonyfishes but further analyses of whole genome sequences willbe required to determine whether the PIGR gene was lostfollowing the split of the Sarcopterygii It thus appears thatthe PIGR gene emerged in a common ancestor of highervertebrates after the split of cartilaginous fish and prior

to the evolution of modern teleosts likely driven by theselective pressure to provide a mechanism for transport ofpolymeric Igs such as IgM and IgT into mucosal secretionsThis hypothesis is supported by a comparison of phylogenetictrees based on amino acid sequences for IgT IgX and IgAheavy chains and pIgR (Figure 5)The predicted evolutionarydistance between trout IgT and frog IgX is similar to thedistance between trout and frog pIgR suggesting that thetransition from IgT to IgX as the dominantmucosal Ig isotypewas accompanied by adaptations in pIgR structure Similarparallels can be seen in the transition from IgX to IgA inreptiles birds and mammals and the concurrent evolutionof pIgR

Alignments of the amino acid sequences of mucosal Igheavy chains and pIgR from 10 representative vertebratespecies provide further support for the theory of coevolutionof mucosal IGH and PIGR genes (Figure 6) A commonfeature of Ig and pIgR proteins is the presence of repeatingIg-like domains (see Figure 2 for the basic structure of thesedomains) The structure of IgT IgX and IgA heavy chainsfrom fish amphibians reptiles and birds is similar to thatof IgM with 4 constant Ig-like domains In mammalianIgA (and IgG) the exon for the 2nd constant region wastruncated to encode a short ldquohingerdquo region which confersgreater mobility to the antigen-binding region at the N-terminusThus the CH3 domain of IgT IgX and IgA in lowervertebrates is structurally and functionally homologous tothe CH2 domain of mammalian IgA The heavy chains ofIgT IgX and IgA have retained a characteristic feature ofthe IgM heavy chain that is the presence of a conservedcysteine residue in the tailpiece that allows disulfide bondingbetween heavy chains of individual Ig proteins to formhigher molecular weight polymers These large Ig structurescontaining multiple antigen-binding sites are particularlywell suited for immune clearance of large antigens found atmucosal surfaces such as intact microbes and food particlesIn mucosal Igs from most vertebrate orders the J chainprotein initiates this polymerization process by disulfidebonding with 2 Ig heavy chains remaining associated withthe polymeric Ig at a stoichiometric ratio of 1 J chain subunitper 2 3 4 or 5 Ig units Despite the absence of J chainthe predominant form of IgM and IgT in mucus secretionsin rainbow trout was found to be polymeric in contrastto monomeric forms of IgM and IgT in the blood [38] Inmammals IgM is mainly found as a pentamer whereas theshorter heavy chain ofmammalian IgA restricts its polymericforms to dimers trimers and tetramers Further studies willbe required to characterize the polymeric structures of IgMIgT IgX and IgA in lower vertebrates

Alignment of pIgR amino acid sequences from 10 rep-resentative vertebrate species reveals structural changes thatwere evolved in parallel with structural changes in mucosalIgs (Figure 6(b)) All pIgR proteins have an N-terminalhydrophobic leader peptide required for targeting of thenascent protein into the ER The extracellular region ofpIgR protein is characterized by repeating ldquoIg-likerdquo domainssimilar to Ig heavy chains [115 133] Interestingly the num-ber of extracellular Ig-like domains has increased duringvertebrate evolution culminating with a total of 5 domains

10 ISRN Immunology

TailpieceHinge

Tailpiece

Mammalian IgA

VVVVVVVVVV

200121 300 400 4721

Human IgA1Rhesus IgA

Cattle IgAMouse IgA

Possum IgAPlatypus IgAChicken IgA

Frog IgXTrout IgT

Premammalian IgTXA

Gecko IgldquoArdquo

CH1

CH1

CH2

CH2

CH3

CH3

CH4

(a)

Leader 1 2 3 4 5

Ig homology extracellular domains

Linker CytoplasmicTM

1001 200 300 400 500 600 700 764

HumanRhesus

CattleMouse

PossumPlatypusChicken

AnoleFrog

Trout

(b)

Figure 6 Interspecies similarity in mucosal Ig and pIgR protein sequences from 10 representative vertebrate species Alignments in aminoacid sequences correspond to the phylogenetic trees shown in Figure 5 (a) Numbering ofmucosal Ig amino acids corresponds to the sequenceof human IgA1 beginning with the first residue of the variable domain CH heavy chain constant region domain (b) Numbering of pIgRamino acids corresponds to the sequence of human pIgR beginning with the first residue of the leader peptide TM transmembrane Forboth alignments the intensity of shading at each position signifies the degree of similarity amongmucosal Ig or pIgR sequences from differentspecies Gaps in sequence alignments signify regions of limited interspecies homology Approximate boundaries are noted of key structuralelements in mucosal Ig and pIgR proteins

in mammalian pIgR By contrast pIgR from amphibiansreptiles and birds contains 4 extracellular domains lackinga homolog of domain 2 of mammalian pIgR The mostprimitive form of pIgR found in teleost fish contains only2 extracellular domains homologous to domains 1 and 5of mammalian pIgR Interspecies homology is greatest indomain 1 which has been shown to be critical for binding ofmammalian pIgR to polymeric Igs (reviewed in [111]) Highlyconserved internal disulfide bonds are found in all the Ig-like domains of pIgR characteristic of the immunoglobulinfold An additional disulfide bond is found in domain 5 ofpIgR frommammals birds reptiles and amphibians but notfish In human SIgA this ldquoextrardquo disulfide bond in domain 5has been shown to rearrange to form a disulfide bond with

cysteine residues in one of the heavy chains of polymericIgA [134] Although the structure of SIgA has not beenfully characterized for lower vertebrates it is reasonable toassume that similar disulfide bonds form between domain 5of pIgR and polymeric IgA or IgX from birds reptiles andamphibians The linker region connecting domain 5 of pIgRto the transmembrane domain has a random structure that ispoorly conserved across species Proteolytic cleavage of pIgRwithin this domain leads to the release of SC from the apicalsurface of epithelial cells either free or bound to polymericIg The cytoplasmic domain of mammalian pIgR containsa number of intracellular sorting motifs that interact withcytoplasmic proteins to direct pIgR through the transcytoticpathway (reviewed in [111]) These motifs are reasonably

ISRN Immunology 11

Linker

TMCytoplasmic

J chain

Hinge 1

2

34

5

CL

VLVH

C1205721C1205722 C1205723

(a)

Linker

TMCytoplasmic

J chain

1

3 4

5

CL

VL

VH

C1205941205721

C1205941205722C1205941205723 C1205941205724

(b)

11

5

LinkerTM

Cytoplasmic

5

CL

VL

VH

C1205911C1205912

C1205913 C1205914

pIgR Ig-like domain

H chain Ig-like domain

L chain Ig-like domain

J chain

Disulfide bond

(c)

Figure 7 Theoretical model for changes in the structure of secretory Igs during evolution (a) The structure for mammalian SIgA is adaptedfrom the model of Woof and Russell [16] for human SIgA1 with permission from Nature Publishing Group (b) and (c) Theoretical modelsfor the structure of IgXA from amphibians and birds and SIgT from teleost fish respectively are predicted from alignment of Ig heavy chainand pIgR sequences with mammalian homologs

well conserved in pIgR from birds and reptiles but not inpIgR from amphibians and fish suggesting that complexmechanisms of intracellular trafficking of pIgR coevolvedwith the increasing complexity of the mucosal immunesystem

7 Hypothetical Models for Changes inSecretory Ig Structure during Coevolutionof Mucosal Igs and pIgR

A large number of structural and functional analyses overthe past 30 years allowed the development of detailed modelsfor the structure of mammalian SIgA (reviewed in [111 135])(Figure 7(a)) Domains 1 and 5 of pIgR the most highlyconserved Ig-like domains associate with theC1205722 subunits oftwo adjacent IgA heavy chains in a near-planar structure [136137] During transcytosis a disulfide bond forms betweenhighly conserved cysteine residues in domain 5 of pIgRand the C1205722 domain of one of the IgA heavy chains [134]Domains 2 3 and 4 allow mammalian pIgR to assume aflexible extended structure which is thought to wrap aroundthe IgA heavy chains and protect against degradation fromhost and microbial proteases Binding of mammalian pIgRto polymeric IgA or IgM requires the presence of J chain

connecting the Ig subunits (reviewed in [138]) and J chain-deficient mice fail to transport IgA and IgM into externalsecretions [139ndash141] Structure-function studies usingmutantforms of human J chain suggested that J chain binds directlyto pIgR and also maintains polymeric Ig in an optimalconformation for pIgR binding and transcytosis [142] Theunstructured linker region connecting domain 5 of pIgRto the transmembrane (TM) region gives membrane-boundpIgR the flexibility to bind large polymeric Igs (with orwithout associated antigens) and provides an exposed site forproteolytic cleavage of pIgR to SC The C-terminal region ofpIgR extends past the cytoplasmic face of the plasma mem-brane allowing association with cytoplasmic factors thatregulate trafficking of pIgR with or without bound polymericIg

Although detailed structural studies have not yet beenperformed on secretory Igs from lower vertebrates hypo-thetical models can be constructed based on alignmentswith their mammalian homologs A model for secretoryIgXA in birds reptiles and amphibians is illustrated inFigure 7(b) showing the C

1205941205722 domain in place of the hinge

region ofmammalian IgAThenumbering of the extracellulardomains of pIgR corresponds to the homologous domainsin mammalian pIgR noting the absence of domain 2 In

12 ISRN Immunology

this model the C120594120572

3 domains of two adjacent IgXA heavychains (homologous to the C

1205722 domain of mammalian IgA)

bind to the highly conserved domains 1 and 5 of pIgRGiven the conservation of the analogous cysteine residuesin domain 5 of pIgR and the C

1205941205723 domain of IgXA it

is assumed that a disulfide bond forms between pIgR andpolymeric Ig during epithelial transcytosis in birds reptilesand amphibiansThe absence of domain 2 in pIgR from thesevertebrate orders necessitates a more rigid structure thanthat of mammalian pIgR with a corresponding decrease inits ability to wrap around the IgXA heavy chains and pro-vide protection against proteoltyic degradation Despite theshorter length of pIgR in birds reptiles and amphibians theassociation with the J chain subunit of polymeric IgXA stillappears to be required Recombinant pIgR from the Africanfrog (Xenopus laevis) was shown to bind with moderatelyhigh affinity to human polymeric IgA containing J chain butnot to monomeric IgA [125] The affinity of Xenopus pIgRfor human pIgA was improved when Xenopus J chain wassubstituted for human J chain in a chimeric polymeric IgAmolecule The lack of sequence conservation across speciesin the linker region connecting domain 5 of pIgR to the TMregion suggests that it acts as a nonspecific ldquospacerrdquo As statedabove the cytoplasmic region of pIgR appears to have evolvedover time to provide enhanced regulation of pIgR trafficking

The hypothetical structure of secretory IgT from teleostfish in Figure 7(c) illustrates how the most primitive form ofpIgR comprising only extracellular domains 1 and 5 couldassociate with polymeric Ig and mediate epithelial transcy-tosis Association of pIgR domain 1 with the C

1205913 domain of

IgT would preserve the functional homology with secretoryIgs in higher vertebrates The short length of teleost pIgRwould necessitate the association of domain 5 with a C

1205913

domain on one of the heavy chains of the same IgT ratherthan spanning across to the adjaent IgT subunit While thismodel preserves the highly conserved association of pIgRdomain 1 with the orthologous domain of the IgT heavychain it does not explain the selectivity of teleost pIgR forpolymeric rather than monomeric IgT Although there is noexperimental evidence to support this model it could behypothesized that dimerization of two pIgR molecules in theplasmamembrane is required for high affinity binding of IgTas illustrated in the model in Figure 7(c) This hypotheticalmodel would also explain the lack of a necessity for J chainin polymeric IgT since each subunit in the pIgR dimer wouldonly be in contact with one IgT subunit The unstructuredlinker region connecting domain 5 of pIgR to the TM regionwould provide flexibility for association of 2 membrane-bound pIgR molecules with a large polymeric IgT molecule

Taken together the structural models for secretory Igsshown in Figure 7 are consistent with the selection of a morefunctional pIgR molecule over evolutionary time Duplica-tion and diversification of the extracellular Ig-like domainsof pIgR would provide a longer more flexible surface forbinding to polymeric Igs with higher affinity and protectingthe Ig heavy chains against proteolytic attack Expansion ofthe cytoplasmic domain of pIgR and incorporation of motifsfor binding cytoplasmic proteins would allow regulated

trafficking of pIgR and polymeric Igs across mucosal andglandular epithelial cells Importantly these models illustratea potential path for coevolution of IGH and PIGR genesdriven by the common selective pressure to provide antigen-specific humoral immune responses at mucosal surfaces

8 Evidence that the CommensalMicrobiota Provided the Driving Force forCoevolution of Mucosal Igs and pIgR

From the earliest evolution of vertebrate animals mucosal Igshave been an integral part of the emerging adaptive immunesystem Clearly many environmental factors served as driv-ing forces for the evolution of the adaptive immune systemin vertebrates including a longer lifespan thanmany (but notall) invertebrates and amore diverse diet that could introducea broader range of potential gut pathogens However it hasbeen proposed that the most significant force may havebeen the dramatic increase in the numbers and complexityof the resident microbiota in the evolution of vertebratesfrom their invertebrate ancestors [1 143 144] Antibodiesin mucosal secretions contribute to immune homeostasis bylimiting access of microbes and their products to the bodyproper maintaining the integrity of the epithelial barrier andshaping the composition of the commensal microbiota infavor of metabolically beneficial microorganisms [145] Thepredominance of polymeric Igs in these secretions promotesthese functions by providing multiple antigen-binding sitesper Ig complex thus increasing the overall avidity of antigen-antibody interactions Structural and functional refinementsin mucosal Igs culminating with the multifunctional secre-tory IgA molecule in mammals have further enhanced theirability to enhance immune homeostasis

The early emergence of pIgR in vertebrate evolutionprovided a mechanism for efficient transport of mucosal Igsinto external secretions It is well documented that crosstalkbetween mucosal epithelial cells and the resident microbiotamodulates expression of pIgR (reviewed in [17 111 112]) andit is reasonable to assume that these host-microbe interac-tions provided a driving force for evolution of the PIGR genein vertebrates The first demonstration that gut bacteria maymodulate pIgR expression in epithelial cells was the findingthat butyrate a bacterial fermentation product and importantenergy source in the colon upregulated expression of pIgRin the human colonic epithelial cell line HT-29 [146] A rolefor commensal bacteria in pIgR regulation was subsequentlydemonstrated by the observation that pIgR expression wasincreased when germ-free mice were colonized with Bacteri-oides thetaiotaomicron a prominent organism of the normalmouse and human intestinal microbiota [147] Amore recentstudy using a model of reversible colonization of germ-free mice with a nondividing mutant of Escherichia colidemonstrated that a long-lived SIgA response could besustained that specifically recognized the inducing bacteria[148] However exposure of E coli-colonized mice to otherbacteria limited the duration of the SIgA response against theoriginal colonizer suggesting a dynamic equilibriumbetweenmembers of the gut microbial community and host SIgA A

ISRN Immunology 13

study from the laboratory of Finn-Eirik Johansen demon-strated that diversity of the bacterial community in the cecallumen was reduced in pIgR-knockoutmice supporting a rolefor SIgA in limiting overgrowth of selected species [149] Incontrast the community of bacteria adherent to the epithelialsurface was more diverse in pIgR-knockout mice than inwild-typemice and these adherent bacteria caused enhancedexpression of several epithelial antimicrobial peptides Thesefindings suggest that bacteria-specific SIgA anchored in themucus layer restricts adhesion of bacteria to the epithelialsurface and limits bacterial stimulation of host epithelial cellsA recent study from the authorrsquos laboratory employing abreeding scheme in which119875119894119892119903minusminus damswere bred to119875119894119892119903+minusmales and vice versa demonstrated that SIgA antibodiesin breast milk promote long-term intestinal homeostasis byregulating the gut microbiota and gene expression in colonicepithelial cells [150]

A direct role for commensal andor pathogenic bacteriain the regulation of pIgR expression suggests that the innateimmune system may ldquoprimerdquo epithelial cells for transportof polymeric Ig produced during the adaptive immuneresponse Host cells mediate innate immune responses tomicrobial components through toll-like receptor (TLR) sig-naling (reviewed in [151 152]) Intestinal epithelial cells havebeen shown to express a wide variety of TLRs the expressionof which is upregulated during intestinal inflammation [153ndash155] Significantly expression of pIgR was shown to beupregulated in the HT-29 human intestinal epithelial cellline by bacterial LPS a ligand for TLR4 [156 157] Similarinduction of PIGR gene transcription was seen followingdirect binding of bacteria of the family Enterobacteriaceaewhich express a form of LPS that stimulates TLR4 [158]A recent study from the authorrsquos laboratory demonstratedthat shRNA-mediated knockdown of myeloid differentiationprimary response protein 88 (MyD88) a cytoplasmic adapterprotein that transduces signals from cell surface TLR4blocked the induction of PIGR gene transcription by LPS inHT-29 cells [159] The in vivo significance was confirmed bythe finding that mice with a targeted deletion of the Myd88gene only in intestinal epithelial cells had reduced expressionof pIgR compared to wild-type littermates [159] Mice withtargeted depletion of MyD88 in intestinal epithelial cells alsoexhibited reduced expression of mucin-2 the major compo-nent of the intestinal mucus layer and several antimicrobialpeptides and decreased transmucosal electrical resistanceThese alterations in epithelial barrier function were accom-panied by significant changes in the composition of the fecalmicrobiota increased numbers of bacteria adherent to theintestinal mucus layer and a dramatic increase in transloca-tion of gut bacteria into the drainingmesenteric lymphnodesincluding the opportunistic pathogen Klebsiella pneumoniaeThese findings demonstrate that MyD88-mediated crosstalkbetween the gut microbiota and intestinal epithelial cells iscrucial for optimal expression of pIgR production of SIgAdevelopment of a healthy gut microbiota and maintenanceof intestinal homeostasis

A model can be proposed in which continuous stimu-lation of intestinal epithelial cells by gut bacteria regulates

Lumen

Mucus

Epithelium

Lamina

PIGR

TLRs

MyD88

Bacteria

Plasma cells

propria

Polymeric Ig

Polymeric Ig receptor

Secretory component

Figure 8 Crosstalk between the polymeric immunoglobulin recep-tor secretory immunoglobulins and the gut microbiotaThe single-layered epithelium that lines the gastrointestinal tract is coveredwith a thick mucus layer which physically excludes members ofthe resident microbiota but allows diffusion of shed components ofmicrobial cells Stimulation of epithelial toll-like receptors (TLRs)with microbial products engages the cytoplasmic adaptor proteinMyD88 and initiates NF120581B-dependent signaling pathways Translo-cation of activated NF120581B and other transcription factors to thenucleus enhances transcription of thePIGR gene Activation of TLRsmay also stimulate pIgR transcytosis Polymeric Igs secreted bylamina propria plasma cells bind to pIgRon the basolateral surface ofepithelial cells and are transcytosed to the apical surface along withunoccupied pIgR Proteolytic cleavage of pIgR at the apical surfacereleases secretory SIg and free secretory component (SC) Binding ofSIg and SC to luminal bacteria promotes association with themucuslayer and prevents direct access of bacteria to the epithelial surfaceOver time the continuous crosstalk with SIg shapes the compositionof the gut microbiota Modified from [17] under terms of authorrsquoscopyright with Nature Publishing Group

pIgR expression and transport of SIgA and promotes immuneexclusion of resident and pathogenic bacteria (Figure 8) Adense layer of mucus which increases in thickness fromthe proximal to the distal colon serves to separate bacteriafrom direct contact with the epithelial surface Secretionof microbial-associated molecular patterns (MAMPs) bycommensal bacteria stimulates MyD88-dependent TLR sig-naling leading to enhanced expression of pIgR and antimi-crobial peptides and increased mucus production Bindingof pIgA to pIgR and possibly also signaling via MAMPs

14 ISRN Immunology

enhances transcytosis of pIgA pIgA-containing immunecomplexes and unoccupied pIgR which promotes clearanceof antigens and pathogens from the lamina propria intra-cellular neutralization and release of SIgA and SC at theluminal surface SIgA and SC serve to trap bacteria in themucus layer limiting their access to the epithelial surface Inmice with a targeted deletion of the Muc2 gene which havea severely depleted mucus layer in the colon SIgA and SCfail to associate with the surface of colonic epithelial cells[160] The presence of SIgA in the intestinal lumen whetherderived passively frommaternalmilk or actively via epithelialtranscytosis shapes the composition of the gut microbiotaand modulates intestinal epithelial gene expression

9 Concluding Remarks

The first microbes that emerged on Earth almost 4 billionyears ago encountered a hostile world where nutrients werescarce hazards were everywhere and life was short Withthe evolution of multicellular organisms about 3 billion yearslater a select group ofmicrobes chose to sacrifice an indepen-dent existence for the benefits of a mutualistic relationshipwith eukaryotic hosts Prokaryotic-eukaryotic mutualismreached its apex some 500 million years ago with theemergence of primitive vertebrates whose gastrointestinaltracts were populated by an abundant and diverse commensalmicrobiota In humans the large intestine is home to some100 trillion microorganisms 10 times more than the totalnumber of eukaryotic cells in the entire body The microbesthat inhabit the vertebrate GI tract provide many benefitsto the eukaryotic host including digestion of complex foodmolecules synthesis of vitamins and production of solublefactors that enhance the development of the host immunesystem In return the eukaryotic host provides the microbeswith a warm moist place to live abundant food low oxygentension and a soft bed of mucus on which to form biofilmsWhen this mutually beneficial arrangement is challenged bypathogenicmicrobes the eukaryotic host and the commensalmicrobiota join forces to battle the pathogens and protectthe body from invasion The vertebrate immune system isequipped with a well-trained army of immune cells and asophisticated arsenal of weapons (cell surface molecules andsecreted factors) that protect the host from all but the mostvirulent pathogens This immune ldquoarmyrdquo also serves as aconstant reminder to the commensal microbes that whilethey are free to enjoy the amenities of the mucosal surfacesthey are not welcome in the body proper The emergence ofantigen-specific Igs and T-cell receptors in jawed vertebratesbegan a process of immunological diversification that led tothe development of a specialized mucosal immune systemin higher vertebrates in which secretory Igs play a centralrole The relationship between host and microbiota is clearlyreciprocal the mucosal Igs that evolved in response toselective pressure from the commensal microbiota play acentral role throughout life in shaping the compositiongenetics andmetabolic activity of themicrobiota [1 161 162]

The epithelial layer lining mucosal surfaces provides aphysical and innate immune barrier against penetration of

the body proper by microbes undigested food antigens andpotentially noxious environmental substances The evolu-tionary challenge of transporting mucosal Igs into externalsecretions without compromising the epithelial barrier wasmet by the emergence of the PIGR gene in an ancestor ofbony fishes encoding an epithelial-specific transmembraneprotein that actively transports polymeric Igs across mucosaland glandular epithelia (Figure 4) Structural similaritiesbetween Igs and the extracellular Ig-binding domains of pIgR(Figure 6) suggest that duplication and diversification of agene encoding primordial Ig-like domain may have givenrise to the PIGR gene in a primitive vertebrate ancestorParallel refinement of the structures of mucosal Igs andpIgR during tetrapod evolution (Figures 6 and 7) culminatedin the evolution of the multifunctional SIgA molecule inmammals in which the pIgR-derived SC subunit providesinnate immune functions and protects the antigen-bindingIgA polymer from proteolytic degradation In addition toacting as a powerful force during vertebrate evolution thereciprocal relationship between pIgR mucosal Igs and thecommensal microbiota provides benefits throughout thelife of the individual Microbial colonization of newbornvertebrates stimulates development of mucosal B cells andclass switching to mucosal Ig isotypes [1 163] Microbialfactors upregulate expression of pIgR enhancing transportof mucosal Igs into external secretions where they in turnregulate the microbiotaThis beautifully orchestrated processallows us to maintain a healthy relationship with our resi-dent microbiota while providing mutual protection againstpathogens

Conflict of Interests

The author declares that there is no conflict of interestsregarding the publication of this paper

Acknowledgments

This work was supported by Grant no AI069027 from theNational Institutes of Health of the United States of America(and an associatedAmerican Recovery andReinvestmentActsupplement) and a Senior Research Award from the Crohnrsquosand Colitis Foundation of America

References

[1] C L Maynard C O Elson R D Hatton and C T WeaverldquoReciprocal interactions of the intestinal microbiota andimmune systemrdquo Nature vol 489 no 7415 pp 231ndash241 2012

[2] M F Flajnik and M Kasahara ldquoOrigin and evolution of theadaptive immune system genetic events and selective pres-suresrdquo Nature Reviews Genetics vol 11 no 1 pp 47ndash59 2010

[3] M F Flajnik and L du Pasquier ldquoEvolution of the immunesystemrdquo in Fundamental Immunology W E Paul Ed chapter4 pp 67ndash128 Lippincott Williams ampWilkins Philadelphia PaUSA 2012

[4] M Hirano S Das P Guo and M D Cooper ldquoThe evolutionof adaptive immunity in vertebratesrdquo Advances in Immunologyvol 109 pp 125ndash157 2011

ISRN Immunology 15

[5] T BoehmNMcCurley Y SutohM SchorppMKasahara andM D Cooper ldquoVLR-based adaptive immunityrdquo Annual Reviewof Immunology vol 30 pp 203ndash220 2012

[6] T Hunkapiller and L Hood ldquoImmunology the growing immu-noglobulin gene superfamilyrdquoNature vol 323 no 6083 pp 15ndash16 1986

[7] P Bork L Holm and C Sander ldquoThe immunoglobulin foldstructural classification sequence patterns and common corerdquoJournal of Molecular Biology vol 242 no 4 pp 309ndash320 1994

[8] C S Kaetzel and M W Russell ldquoPhylogeny and comparativephysiology of IgArdquo in Mucosal Immunology J Mestecky WStrober H Cheroutre B Kelsall B N Lambrecht and M WRussell Eds chapter 19 Academic PressElsevier WalthamMass USA 2014

[9] Y He and P J Bjorkman ldquoStructure of FcRY an avian immu-noglobulin receptor related to mammalian mannose receptorsand its complex with IgYrdquo Proceedings of the National Academyof Sciences of the United States of America vol 108 no 30 pp12431ndash12436 2011

[10] J M Woof and D R Burton ldquoHuman antibody-Fc receptorinteractions illuminated by crystal structuresrdquo Nature ReviewsImmunology vol 4 no 2 pp 89ndash99 2004

[11] W L Martin A P West Jr L Gan and P J Bjorkman ldquoCrystalstructure at 28 A of an FcRnheterodimeric Fc complexmechanism of pH-dependent bindingrdquo Molecular Cell vol 7no 4 pp 867ndash877 2001

[12] E S Ward ldquoAcquiring maternal immunoglobulin differentreceptors similar functionsrdquo Immunity vol 20 no 5 pp 507ndash508 2004

[13] C S Kaetzel ldquoThe polymeric immunoglobulin receptor bridg-ing innate and adaptive immune responses atmucosal surfacesrdquoImmunological Reviews vol 206 no 1 pp 83ndash99 2005

[14] M Acharya G Borland A L Edkins et al ldquoCD23Fc120576RIImolecular multi-taskingrdquo Clinical and Experimental Immunol-ogy vol 162 no 1 pp 12ndash23 2010

[15] V B Klimovich ldquoIgM and its receptors structural and func-tional aspectsrdquo Biochemistry vol 76 no 5 pp 534ndash549 2011

[16] J MWoof andMW Russell ldquoStructure and function relation-ships in IgArdquo Mucosal Immunology vol 4 no 6 pp 590ndash5972011

[17] F-E Johansen and C S Kaetzel ldquoRegulation of the polymericimmunoglobulin receptor and IgA transport new advances inenvironmental factors that stimulate pIgR expression and itsrole in mucosal immunityrdquo Mucosal Immunology vol 4 no 6pp 598ndash602 2011

[18] F Kokubu K Hinds R Litman M J Shamblott and G WLitman ldquoExtensive families of constant region genes in a phy-logenetically primitive vertebrate indicate an additional levelof immunoglobulin complexityrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 84 no16 pp 5868ndash5872 1987

[19] A S Greenberg A L Hughes J Guo D Avila E CMcKinneyand M F Flajnik ldquoA novel ldquochimericrdquo antibody class in carti-laginous fish IgMmay not be the primordial immunoglobulinrdquoEuropean Journal of Immunology vol 26 no 5 pp 1123ndash11291996

[20] H Dooley and M F Flajnik ldquoShark immunity bites back affin-ity maturation and memory response in the nurse shark Ging-lymostoma cirratumrdquo European Journal of Immunology vol 35no 3 pp 936ndash945 2005

[21] S F Schluter R M Bernstein and J J Marchalonis ldquoMolecularorigins and evolution of immunoglobulin heavy-chain genes ofjawed vertebratesrdquo Immunology Today vol 18 no 11 pp 543ndash549 1997

[22] Y Ohta and M Flajnik ldquoIgD like IgM is a primordial immu-noglobulin class perpetuated in most jawed vertebratesrdquo Pro-ceedings of the National Academy of Sciences of the United Statesof America vol 103 no 28 pp 10723ndash10728 2006

[23] S Fillatreau A Six S Magadan R Castro J O Sunyer andP Boudinot ldquoThe astonishing diversity of Ig classes and B cellrepertoires in teleost fishrdquo Frontiers in Immunology vol 4 no28 2013

[24] W Harriman H Volk N Defranoux and M Wabl ldquoImmu-noglobulin class switch recombinationrdquo Annual Review ofImmunology vol 11 pp 361ndash384 1993

[25] J Stavnezer and C T Amemiya ldquoEvolution of isotype switch-ingrdquo Seminars in Immunology vol 16 no 4 pp 257ndash275 2004

[26] V M Barreto Q Pan-Hammarstrom Y Zhao L Ham-marstrom Z Misulovin and M C Nussenzweig ldquoAID frombony fish catalyzes class switch recombinationrdquo Journal ofExperimental Medicine vol 202 no 6 pp 733ndash738 2005

[27] T C Fletcher and AWhite ldquoAntibody production in the plaice(Pleuronectes platessa L) after oral and parenteral immuniza-tion with Vibrio anguillarum antigensrdquo Aquaculture vol 1 pp417ndash428 1972

[28] J W H M Rombout L J Blok C H J Lamers and E EgbertsldquoImmunization of carp (Cyprinus carpio) with a Vibrio anguil-larum bacterin indications for a common mucosal immunesystemrdquo Developmental and Comparative Immunology vol 10no 3 pp 341ndash351 1986

[29] U Georgopoulou and J-M Vernier ldquoLocal immunologicalresponse in the posterior intestinal segment of the rainbowtrout after oral administration of macromoleculesrdquo Develop-mental andComparative Immunology vol 10 no 4 pp 529ndash5371986

[30] C J Lobb ldquoSecretory immunity induced in catfish Ictaluruspunctatus following bath immunizationrdquo Developmental andComparative Immunology vol 11 no 4 pp 727ndash738 1987

[31] J D Hansen E D Landis and R B Phillips ldquoDiscovery ofa unique Ig heavy-chain (IgT) in rainbow trout implicationsfor a distinctive B cell developmental pathway in teleost fishrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 102 no 19 pp 6919ndash6924 2005

[32] N Danilova J Bussmann K Jekosch and L A Steiner ldquoTheimmunoglobulin heavy-chain locus in zebrafish identificationand expression of a previously unknown isotype immunoglob-ulin Zrdquo Nature Immunology vol 6 no 3 pp 295ndash302 2005

[33] R Savan A Aman K Sato R Yamaguchi and M Sakai ldquoDis-covery of a new class of immunoglobulin heavy chain fromfugurdquo European Journal of Immunology vol 35 no 11 pp 3320ndash3331 2005

[34] R Savan A AmanMNakao HWatanuki andM Sakai ldquoDis-covery of a novel immunoglobulin heavy chain gene chimerafrom common carp (Cyprinus carpio L)rdquo Immunogenetics vol57 no 6 pp 458ndash463 2005

[35] F Gambon-Deza C Sanchez-Espinel and S Magadan-Mompo ldquoPresence of an unique IgT on the IGH locus in three-spined stickleback fish (Gasterosteus aculeatus) and the veryrecent generation of a repertoire of VH genesrdquo Developmentaland Comparative Immunology vol 34 no 2 pp 114ndash122 2010

[36] T M Tadiso K K Lie and I Hordvik ldquoMolecular cloning ofIgT fromAtlantic salmon and analysis of the relative expression

16 ISRN Immunology

of 120591 120583 and 120575 in different tissuesrdquo Veterinary Immunology andImmunopathology vol 139 no 1 pp 17ndash26 2011

[37] S Mashoof C Pohlenz P L Chen et al ldquoExpressed IgH 120583and 120591 transcripts share diversity segment in ranched Thunnusorientalisrdquo Developmental and Comparative Immunology vol43 no 1 pp 76ndash86 2014

[38] Y-A Zhang I Salinas J Li et al ldquoIgT a primitive immunoglob-ulin class specialized in mucosal immunityrdquo Nature Immunol-ogy vol 11 no 9 pp 827ndash835 2010

[39] S Magadan-Mompo C Sanchez-Espinel and F Gambon-Deza ldquoImmunoglobulin heavy chains in medaka (Oryziaslatipes)rdquo BMC Evolutionary Biology vol 11 no 1 article 1652011

[40] C T Amemiya J Alfoldi A P Lee et al ldquoThe African coela-canth genome provides insights into tetrapod evolutionrdquoNature vol 496 no 7445 pp 311ndash316 2013

[41] T Ota J P Rast G W Litman and C T Amemiya ldquoLineage-restricted retention of a primitive immunoglobulin heavy chainisotype within the Dipnoi reveals an evolutionary paradoxrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 100 no 5 pp 2501ndash2506 2003

[42] Y Sun Z Wei N Li and Y Zhao ldquoA comparative overview ofimmunoglobulin genes and the generation of their diversity intetrapodsrdquo Developmental and Comparative Immunology vol39 no 1-2 pp 103ndash109 2013

[43] I Hadji-Azimi ldquoAnuran immunoglobulins a reviewrdquo Develop-mental and Comparative Immunology vol 3 no 2 pp 223ndash2431979

[44] E Hsu M F Flajnik and L du Pasquier ldquoA third immunoglob-ulin class in amphibiansrdquo The Journal of Immunology vol 135no 3 pp 1998ndash2004 1985

[45] C T Amemiya R N Haire and G W Litman ldquoNucleotidesequence of a cDNA encoding a third distinct Xenopusimmunoglobulin heavy chain isotyperdquo Nucleic Acids Researchvol 17 no 13 p 5388 1989

[46] R Muszligmann M Wilson A Marcuz M Courtet and L duPasquier ldquoMembrane exon sequences of the three Xenopus Igclasses explain the evolutionary origin of mammalian isotypesrdquoEuropean Journal of Immunology vol 26 no 2 pp 409ndash4141996

[47] R Muszligmann L du Pasquier and E Hsu ldquoIs Xenopus IgX ananalog of IgArdquo European Journal of Immunology vol 26 no12 pp 2823ndash2830 1996

[48] B Schaerlinger and J-P Frippiat ldquoIgX antibodies in the urodeleamphibian Ambystoma mexicanumrdquo Developmental and Com-parative Immunology vol 32 no 8 pp 908ndash915 2008

[49] B Schaerlinger M Bascove and J-P Frippiat ldquoA new isotypeof immunoglobulin heavy chain in the urodele amphibianPleurodeles waltl predominantly expressed in larvaerdquoMolecularImmunology vol 45 no 3 pp 776ndash786 2008

[50] S Mashoof A Goodroe C C Du et al ldquoAncient T-independence of mucosal IgXA gut microbiota unaffected bylarval thymectomy in Xenopus laevisrdquo Mucosal Immunologyvol 6 no 2 pp 358ndash368 2013

[51] J P Vaerman J Picard and J F Heremans ldquoStructural dataon chicken IgA and failure to identify the IgA of the tortoiserdquoin Immunologic Phylogeny vol 64 of Advances in ExperimentalMedicine and Biology pp 185ndash195 Springer New York NYUSA 1975

[52] J L Portis and J E Coe ldquoIgM the secretory immunoglobulinof reptiles and amphibiansrdquo Nature vol 258 no 5535 pp 547ndash548 1975

[53] J E Coe D Leong J L Portis and L A Thomas ldquoImmuneresponse in the garter snake (Thamnophis ordinoides)rdquo Immu-nology vol 31 no 3 pp 417ndash424 1976

[54] D Hadge and H Ambrosius ldquoEvolution of low molecularweight immunoglobulinsmdashIV IgY-like immunoglobulins ofbirds reptiles and amphibians precursors of mammalian IgArdquoMolecular Immunology vol 21 no 8 pp 699ndash707 1984

[55] D Hadge and H Ambrosius ldquoEvolution of low molecularweight immunoglobulins V Degree of antigenic relationshipbetween the 7S immunoglobulins ofmammals birds and lowervertebrates to the turkey IgYrdquo Developmental and ComparativeImmunology vol 10 no 3 pp 377ndash385 1986

[56] S Magadan-Mompo C Sanchez-Espinel and F Gambon-Deza ldquoImmunoglobulin genes of the turtlesrdquo Immunogeneticsvol 65 no 3 pp 227ndash237 2013

[57] Z Wei Q Wu L Ren et al ldquoExpression of IgM IgD and IgYin a reptile Anolis carolinensisrdquoThe Journal of Immunology vol183 no 6 pp 3858ndash3864 2009

[58] F Gambon-Deza C Sanchez-Espinel and J V Beneitez ldquoAnovel IgA-like immunoglobulin in the reptile Eublepharis mac-ulariusrdquo Developmental and Comparative Immunology vol 31no 6 pp 596ndash605 2007

[59] G Cheng Y Gao T Wang et al ldquoExtensive diversification ofIgH subclass-encoding genes and IgM subclass switching incrocodiliansrdquo Nature Communications vol 4 article 1337 2013

[60] S Magadan-Mompo C Sanchez-Espinel and F Gambon-Deza ldquoIgH loci of American alligator and saltwater crocodileshed light on IgA evolutionrdquo Immunogenetics vol 65 no 7 pp531ndash541 2013

[61] E Orlans and M E Rose ldquoAn IgA-like immunoglobulin in thefowlrdquo Immunochemistry vol 9 no 8 pp 833ndash838 1972

[62] G A Leslie and L N Martin ldquoStudies on the secretory immu-nologic system of fowl 3 Serum and secretory IgA of thechickenrdquoThe Journal of Immunology vol 110 no 1 pp 1ndash9 1973

[63] J Bienenstock D Y Perey J Gauldie and B J UnderdownldquoChicken 120574A physicochemical and immunochemical charac-teristicsrdquoThe Journal of Immunology vol 110 no 2 pp 524ndash5331973

[64] A M Lebacq-Verheyden J P Vaerman and J F HeremansldquoQuantification and distribution of chicken immunoglobulinsIgA IgM and IgG in serum and secretionsrdquo Immunology vol27 no 4 pp 683ndash692 1974

[65] J Goudswaard A Noordzij R H van Dam J A vanderDonk and J P Vaerman ldquoThe immunoglobulins of the turkey(Meleagris gallopavo) Isolation and characterization of IgGIgM and IgA in body fluids eggs and intraocular tissuesrdquoPoultry science vol 56 no 6 pp 1847ndash1851 1977

[66] D Hadge and H Ambrosius ldquoComparative studies on thestructure of biliary immunoglobulins of some avian speciesII Antigenic properties of the biliary immunoglobulins ofchicken turkey duck and gooserdquo Developmental and Compar-ative Immunology vol 12 no 2 pp 319ndash329 1988

[67] J Goudswaard J P Vaerman and J F Heremans ldquoThreeimmunoglobulin classes in the pigeon (Columbia livia)rdquo Inter-national Archives of Allergy andApplied Immunology vol 53 no5 pp 409ndash419 1977

[68] P L K Ng and D A Higgins ldquoBile immunoglobulin of theduck (Anas platyrhynchos) I Preliminary characterization andontogenyrdquo Immunology vol 58 no 2 pp 323ndash327 1986

[69] K E Magor G W Warr Y Bando D L Middleton and DA Higgins ldquoSecretory immune system of the duck (Anas

ISRN Immunology 17

platyrhynchos) Identification and expression of the genesencoding IgA and IgM heavy chainsrdquo European Journal ofImmunology vol 28 no 3 pp 1063ndash1068 1998

[70] Y Zhao H Rabbani A Shimizu and L Hammarstrom ldquoMap-ping of the chicken immunoglobulin heavy-chain constantregion gene locus reveals an inverted 120572 gene upstream of acondensed 120592 generdquo Immunology vol 101 no 3 pp 348ndash3532000

[71] M L Lundqvist D L Middleton S Hazard and G W WarrldquoThe immunoglobulin heavy chain locus of the duck genomicorganization and expression of D J and C region genesrdquo TheJournal of Biological Chemistry vol 276 no 50 pp 46729ndash46736 2001

[72] T HuangM Zhang ZWei et al ldquoAnalysis of immunoglobulintranscripts in the ostrich Struthio camelus a primitive avianspeciesrdquo PLoS ONE vol 7 no 3 Article ID e34346 2012

[73] K H Roux ldquoImmunoglobulin structure and function asrevealed by electron microscopyrdquo International Archives ofAllergy and Immunology vol 120 no 2 pp 85ndash99 1999

[74] F Gambon-Deza C Sanchez-Espinel and S Magadan-Mompo ldquoThe immunoglobulin heavy chain locus in the platy-pus (Ornithorhynchus anatinus)rdquo Molecular Immunology vol46 no 13 pp 2515ndash2523 2009

[75] Y Zhao H Cui C M Whittington et al ldquoOrnithorhynchusanatinus (platypus) links the evolution of immunoglobulingenes in eutherian mammals and nonmammalian tetrapodsrdquoThe Journal of Immunology vol 183 no 5 pp 3285ndash3293 2009

[76] M Aveskogh and L Hellman ldquoEvidence for an early appear-ance of modern post-switch isotypes in mammalian evolutioncloning of IgE IgG and IgA from the marsupial Monodelphisdomesticardquo European Journal of Immunology vol 28 no 9 pp2738ndash2750 1998

[77] K Belov G A Harrison and DW Cooper ldquoMolecular cloningof the cDNA encoding the constant region of the immunoglob-ulin a heavy chain (C120572) from amarsupialTrichosurus vulpecula(common brushtail possum)rdquo Immunology Letters vol 60 no2-3 pp 165ndash170 1998

[78] K Belov K R Zenger L Hellman and DW Cooper ldquoEchidnaIgA supports mammalian unity and traditional Therian rela-tionshiprdquo Mammalian Genome vol 13 no 11 pp 656ndash6632002

[79] K Belov and L Hellman ldquoImmunoglobulin genetics of Orni-thorhynchus anatinus (platypus) and Tachyglossus aculeatus(short-beaked echidna)rdquo Comparative Biochemistry and Phys-iology vol 136 no 4 pp 811ndash819 2003

[80] M VernerssonM Aveskogh BMunday and L Hellman ldquoEvi-dence for an early appearance of modern post-switch immu-noglobulin isotypes in mammalian evolution (II) cloning ofIgE IgG1 and IgG2 fromamonotreme the duck-billed platypusOrnithorhynchus anatinusrdquo European Journal of Immunologyvol 32 no 8 pp 2145ndash2155 2002

[81] C Auffray R Nageotte and J L Sikorav ldquoMouse immunoglob-ulin A nucleotide sequence of the structural gene for the 120572heavy chain derived from cloned cDNAsrdquo Gene vol 13 no 4pp 365ndash374 1981

[82] T Ukaji D Sumiyama and O Kai ldquoSequence determinationof the heavy-chain constant region in four immunoglobulinclasses of Mongolian gerbils (Meriones unguiculatus)rdquo Experi-mental Animals vol 61 no 2 pp 99ndash107 2012

[83] R C Burnett W C Hanly S K Zhai and K L Knight ldquoTheIgA heavy chain gene family in rabbit cloning and sequence

analysis of 13 C120572 genesrdquo The EMBO Journal vol 8 no 13 pp4041ndash4047 1989

[84] D K Lanning S-K Zhai and K L Knight ldquoAnalysis of the 31015840C120583 region of the rabbit Ig heavy chain locusrdquoGene vol 309 no2 pp 135ndash144 2003

[85] F Ros J Puels N Reichenberger W van Schooten R Buelowand J Platzer ldquoSequence analysis of 05Mb of the rabbitgermline immunoglobulin heavy chain locusrdquo Gene vol 330no 1-2 pp 49ndash59 2004

[86] M Patel D Selinger G E Mark G J Hickey and G FHollis ldquoSequence of the dog immunoglobulin alpha and epsilonconstant region genesrdquo Immunogenetics vol 41 no 5 pp 282ndash286 1995

[87] Z Zhao Y Zhao Q Pan-Hammarstrom et al ldquoPhysical map-ping of the giant panda immunoglobulin heavy chain constantregion genesrdquo Developmental and Comparative Immunologyvol 31 no 10 pp 1034ndash1049 2007

[88] W R Brown and J E Butler ldquoCharacterization of a C120572 gene ofswinerdquoMolecular Immunology vol 31 no 8 pp 633ndash642 1994

[89] W R Brown H Rabbani J E Butler and L HammarstromldquoCharacterization of the bovine C120572 generdquo Immunology vol 91no 1 pp 1ndash6 1997

[90] G PWhite P Roche M R Brandon S E Newton and E N TMeeusen ldquoCloning and characterization of sheep (Ovis aries)immunoglobulin 120572 chainrdquo Immunogenetics vol 48 no 5 pp359ndash362 1998

[91] AMancia T A Romano H A Gefroh et al ldquoCharacterizationof the immunoglobulin A heavy chain gene of the Atlantic bot-tlenose dolphin (Tursiops truncatus)rdquo Veterinary Immunologyand Immunopathology vol 118 no 3-4 pp 304ndash309 2007

[92] B Wagner I Greiser-Wilke and D F Antczak ldquoCharacteriza-tion of the horse [Equus caballus] IGHA generdquo Immunogeneticsvol 55 no 8 pp 552ndash560 2003

[93] N Takahashi S Ueda and M Obata ldquoStructure of humanimmunoglobulin gamma genes implications for evolution of agene familyrdquo Cell vol 29 no 2 pp 671ndash679 1982

[94] J G Flanagan M-P Lefranc and T H Rabbitts ldquoMechanismsof divergence and convergence of the human immunoglobulin1205721 and 1205722 constant region gene sequencesrdquo Cell vol 36 no 3pp 681ndash688 1984

[95] S Kawamura K Omoto and S Ueda ldquoEvolutionary hypervari-ability in the hinge region of the immunoglobulin alpha generdquoJournal of Molecular Biology vol 215 no 2 pp 201ndash206 1990

[96] F Scinicariello F Masseoud L Jayashankar and R AttanasioldquoSooty mangabey (Cercocebus torquatus atys) IGHG and IGHAgenesrdquo Immunogenetics vol 58 no 12 pp 955ndash965 2006

[97] K A Rogers L Jayashankar F Scinicariello and R AttanasioldquoNonhuman primate IgA genetic heterogeneity and interac-tions with CD89rdquoThe Journal of Immunology vol 180 no 7 pp4816ndash4824 2008

[98] S Kawamura N Saitou and S Ueda ldquoConcerted evolution ofthe primate immunoglobulin 120572-gene through gene conversionrdquoThe Journal of Biological Chemistry vol 267 no 11 pp 7359ndash7367 1992

[99] S Kawamura and S Ueda ldquoImmunoglobulin C119867gene family in

hominoids and its evolutionary historyrdquo Genomics vol 13 no1 pp 194ndash200 1992

[100] A Brusco U Cariota A Bottaro et al ldquoStructural andimmunologic analysis of gene triplications in the Ig heavy chainconstant region locusrdquoThe Journal of Immunology vol 152 no1 pp 129ndash135 1994

18 ISRN Immunology

[101] H Rabbani Q Pan N Kondo C I E Smith and L Ham-marstrom ldquoDuplications and deletions of the human IGHClocus evolutionary implicationsrdquo Immunogenetics vol 45 no2 pp 136ndash141 1996

[102] P F Weinheimer J Mestecky and R T Acton ldquoSpecies distri-bution of J chainrdquoThe Journal of Immunology vol 107 no 4 pp1211ndash1212 1971

[103] F P Inman and J Mestecky ldquoThe J chain of polymeric immu-noglobulinsrdquo inContemporary Topics inMolecular Immunologyvol 3 pp 111ndash141 Springer New York NY USA 1974

[104] P Brandtzaeg ldquoPresence of J chain in human immunocytescontaining various immunoglobulin classesrdquo Nature vol 252no 5482 pp 418ndash420 1974

[105] L Tacchi E Larragoite and I Salinas ldquoDiscovery of J chain inAfrican lungfish (Protopterus dolloi Sarcopterygii) using highthroughput transcriptome sequencing implications in mucosalimmunityrdquo PLoS ONE vol 8 no 8 Article ID e70650 2013

[106] I K Zarkadis D Mastellos and J D Lambris ldquoPhylogeneticaspects of the complement systemrdquo Developmental and Com-parative Immunology vol 25 no 8-9 pp 745ndash762 2001

[107] A P West Jr A B Herr and P J Bjorkman ldquoThe chickenyolk sac IgY receptor a functional equivalent of themammalianMHC-related Fc receptor is a phospholipase A

2receptor

homologrdquo Immunity vol 20 no 5 pp 601ndash610 2004[108] D B Tesar E J Cheung and P J Bjorkman ldquoThe chicken

yolk sac IgY receptor a mammalian mannose receptor familymember transcytoses IgY across polarized epithelial cellsrdquoMolecular Biology of the Cell vol 19 no 4 pp 1587ndash1593 2008

[109] A I Taylor R L Beavil B J Sutton and R A Calvert ldquoAmonomeric chicken IgY receptor binds IgY with 21 stoichiom-etryrdquo The Journal of Biological Chemistry vol 284 no 36 pp24168ndash24175 2009

[110] K Baker S-W Qiao T Kuo et al ldquoImmune and non-immunefunctions of the (not so) neonatal Fc receptor FcRnrdquo Seminarsin Immunopathology vol 31 no 2 pp 223ndash236 2009

[111] K Baker R S Blumberg and C S Kaetzel ldquoImmunoglob-ulin transport and immunoglobulin receptorsrdquo in MucosalImmunology J Mestecky W Strober H Cheroutre B KelsallB N Lambrecht andMW Russell Eds chapter 20 AcademicPressElsevier Waltham Mass USA 2014

[112] C S Kaetzel ldquoThepolymeric immunoglobulin receptorrdquo in eLSJohn Wiley amp Sons Chichester UK 2013

[113] N J Mantis N Rol and B Corthesy ldquoSecretory IgArsquos complexroles in immunity andmucosal homeostasis in the gutrdquoMucosalImmunology vol 4 no 6 pp 603ndash611 2011

[114] J V Peppard M E Rose and P Hesketh ldquoA functional homo-logue of mammalian secretory component exists in chickensrdquoEuropean Journal of Immunology vol 13 no 7 pp 566ndash5701983

[115] K E Mostov M Friedlander and G Blobel ldquoThe receptorfor transepithelial transport of IgA and IgM contains multipleimmunoglobulin-like domainsrdquo Nature vol 308 no 5954 pp37ndash43 1984

[116] P Krajci R Solberg M Sandberg O Oyen T Jahnsen and PBrandtzaeg ldquoMolecular cloning of the human transmembranesecretory component (poly-Ig receptor) and its mRNA expres-sion in human tissuesrdquo Biochemical and Biophysical ResearchCommunications vol 158 no 3 pp 783ndash789 1989

[117] P Krajci D Kvale K Tasken and P Brandtzaeg ldquoMolecularcloning and exon-intron mapping of the gene encoding humantransmembrane secretory component (the poly-Ig receptor)rdquo

European Journal of Immunology vol 22 no 9 pp 2309ndash23151992

[118] J F Piskurich J A France C M Tamer C A Willmer CS Kaetzel and D M Kaetzel ldquoInterferon-120574 induces polymericimmunoglobulin receptormRNA in human intestinal epithelialcells by a protein synthesis dependent mechanismrdquo MolecularImmunology vol 30 no 4 pp 413ndash421 1993

[119] J F Piskurich M H Blanchard K R Youngman J A Franceand C S Kaetzel ldquoMolecular cloning of the mouse polymericIg receptor functional regions of the molecule are conservedamong five mammalian speciesrdquo The Journal of Immunologyvol 154 no 4 pp 1735ndash1747 1995

[120] M A Kulseth P Krajci O Myklebost and S RogneldquoCloning and characterization of two forms of bovine polymericimmunoglobulin receptor cDNArdquo DNA and Cell Biology vol14 no 3 pp 251ndash256 1995

[121] K S Koch A S Gleiberman T Aoki et al ldquoDiscordant expres-sion and variable numbers of neighboring GGA- and GAA-richtriplet repeats in the 31015840 untranslated regions of two groups ofmessenger RNAs encoded by the rat polymeric immunoglob-ulin receptor generdquo Nucleic Acids Research vol 23 no 7 pp1098ndash1112 1995

[122] F M Adamski and J Demmer ldquoTwo stages of increased IgAtransfer during lactation in themarsupialTrichosurus vulpecula(brushtail possum)rdquoThe Journal of Immunology vol 162 no 10pp 6009ndash6015 1999

[123] H Kumura T Sone K-I Shimazaki and E KobayashildquoSequence analysis of porcine polymeric immunoglobulinreceptor from mammary epithelial cells present in colostrumrdquoThe Journal of Dairy Research vol 67 no 4 pp 631ndash636 2000

[124] C L Taylor G A Harrison C M Watson and E M DeaneldquocDNA cloning of the polymeric immunoglobulin receptor ofthe marsupial Macropus eugenii (tammar wallaby)rdquo EuropeanJournal of Immunogenetics vol 29 no 2 pp 87ndash93 2002

[125] R Braathen V S Hohman P Brandtzaeg and F-E JohansenldquoSecretory antibody formation conserved binding interactionsbetween J chain and polymeric Ig receptor from humans andamphibiansrdquo The Journal of Immunology vol 178 no 3 pp1589ndash1597 2007

[126] M J Lewis BWagner R M Irvine and J MWoof ldquoIgA in thehorse cloning of equine polymeric Ig receptor and J chain andcharacterization of recombinant forms of equine IgArdquoMucosalImmunology vol 3 no 6 pp 610ndash621 2010

[127] A J Leon D Banner L Xu et al ldquoSequencing annotation andcharacterization of the influenza ferret infectomerdquo Journal ofVirology vol 87 no 4 pp 1957ndash1966 2013

[128] W H Wieland D Orzaez A Lammers H K ParmentierM W A Verstegen and A Schots ldquoA functional polymericimmunoglobulin receptor in chicken (Gallus gallus) indicatesancient role of secretory IgA inmucosal immunityrdquoBiochemicalJournal vol 380 no 3 pp 669ndash676 2004

[129] K Hamuro H Suetake N R Saha K Kikuchi and YSuzuki ldquoA teleost polymeric Ig receptor exhibiting two Ig-likedomains transports tetrameric IgM into the skinrdquo The Journalof Immunology vol 178 no 9 pp 5682ndash5689 2007

[130] J H W M Rombout S J L van der Tuin G Yang et alldquoExpression of the polymeric immunoglobulin receptor (pIgR)in mucosal tissues of common carp (Cyprinus carpio L)rdquo Fishand Shellfish Immunology vol 24 no 5 pp 620ndash628 2008

[131] L-N Feng D-Q Lu J-X Bei et al ldquoMolecular cloning andfunctional analysis of polymeric immunoglobulin receptor gene

ISRN Immunology 19

in orange-spotted grouper (Epinephelus coioides)rdquo ComparativeBiochemistry and Physiology B vol 154 no 3 pp 282ndash289 2009

[132] A E Oslashstergaard S A M Martin T Wang R J M Stet andC J Secombes ldquoRainbow trout (Oncorhynchus mykiss) pos-sessmultiple novel immunoglobulin-like transcripts containingeither an ITAM or ITIMsrdquo Developmental and ComparativeImmunology vol 33 no 4 pp 525ndash532 2009

[133] H Eiffert E Quentin and J Decker ldquoThe primary structureof the human free secretory component and the arrangementof disulfide bondsrdquo Hoppe-Seylerrsquos Zeitschrift fur PhysiologischeChemie vol 365 no 12 pp 1489ndash1495 1984

[134] E Fallgreen-Gebauer W Gebauer A Bastian et al ldquoThe cova-lent linkage of secretory component to IgA Structure of sIgArdquoBiological Chemistry Hoppe-Seyler vol 374 no 11 pp 1023ndash1028 1993

[135] J MWoof ldquoThe structure of IgArdquo inMucosal Immune DefenseImmunoglobulin A C S Kaetzel Ed chapter 1 pp 1ndash24Springer New York NY USA 2007

[136] A Bonner A Almogren P B Furtado M A Kerr and S JPerkins ldquoLocation of secretory component on the Fc edge ofdimeric IgA1 reveals insight into the role of secretory IgA1 inmucosal immunityrdquoMucosal Immunology vol 2 no 1 pp 74ndash84 2009

[137] A Bonner A Almogren P B Furtado M A Kerr and S JPerkins ldquoThe nonplanar secretory IgA2 and near planar secre-tory IgA1 solution structures rationalize their different mucosalimmune responsesrdquo The Journal of Biological Chemistry vol284 no 8 pp 5077ndash5087 2009

[138] J Johansen B Braathen and P Brandtzaeg ldquoRole of J chain insecretory immunoglobulin formationrdquo Scandinavian Journal ofImmunology vol 52 no 3 pp 240ndash248 2000

[139] B A Hendrickson D A Conner D J Ladd et al ldquoAlteredhepatic transport of immunoglobulin A in mice lacking the Jchainrdquo Journal of Experimental Medicine vol 182 no 6 pp1905ndash1911 1995

[140] B A Hendrickson L Rindisbacher B Corthesy et al ldquoLackof association of secretory component with IgA in J chain-deficient micerdquo The Journal of Immunology vol 157 no 2 pp750ndash754 1996

[141] N Lycke L Erlandsson L Ekman K Schon and T Lean-derson ldquoLack of J chain inhibits the transport of gut IgA andabrogates the development of intestinal antitoxic protectionrdquoThe Journal of Immunology vol 163 no 2 pp 913ndash919 1999

[142] F-E Johansen R Braathen and P Brandtzaeg ldquoThe J chainis essential for polymeric Ig receptor-mediated epithelial trans-port of IgArdquoThe Journal of Immunology vol 167 no 9 pp 5185ndash5192 2001

[143] R E Ley D A Peterson and J I Gordon ldquoEcological andevolutionary forces shaping microbial diversity in the humanintestinerdquo Cell vol 124 no 4 pp 837ndash848 2006

[144] M McFall-Ngai ldquoAdaptive immunity care for the communityrdquoNature vol 445 no 7124 p 153 2007

[145] A J Macpherson K D McCoy F-E Johansen and PBrandtzaeg ldquoThe immune geography of IgA induction andfunctionrdquoMucosal Immunology vol 1 no 1 pp 11ndash22 2008

[146] D Kvale and P Brandtzaeg ldquoConstitutive and cytokine inducedexpression of HLA molecules secretory component and inter-cellular adhesion molecule-1 is modulated by butyrate in thecolonic epithelial cell line HT-29rdquo Gut vol 36 no 5 pp 737ndash742 1995

[147] L VHooperMHWong AThelin L Hansson P G Falk andJ I Gordon ldquoMolecular analysis of commensal host-microbialrelationships in the intestinerdquo Science vol 291 no 5505 pp 881ndash884 2001

[148] S Hapfelmeier M A E Lawson E Slack et al ldquoReversiblemicrobial colonization of germ-free mice reveals the dynamicsof IgA immune responsesrdquo Science vol 328 no 5986 pp 1705ndash1709 2010

[149] DH ReikvamMDerrien R Islam et al ldquoEpithelial-microbialcross-talk in polymeric Ig receptor deficient micerdquo EuropeanJournal of Immunology vol 42 no 11 pp 2959ndash2970 2012

[150] EW Rogier A L Frantz M E C Bruno et al ldquoSecretory anti-bodies in breast milk promote long-term intestinal homeostasisby regulating the gut microbiota and host gene expressionrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 111 no 8 pp 3074ndash3079 2014

[151] G M Barton and R Medzhitov ldquoToll-like receptor signalingpathwaysrdquo Science vol 300 no 5625 pp 1524ndash1525 2003

[152] K Takeda and S Akira ldquoToll receptors and pathogen resis-tancerdquo Cellular Microbiology vol 5 no 3 pp 143ndash153 2003

[153] E Cario andD K Podolsky ldquoDifferential alteration in intestinalepithelial cell expression of Toll-like receptor 3 (TLR3) andTLR4 in inflammatory bowel diseaserdquo Infection and Immunityvol 68 no 12 pp 7010ndash7017 2000

[154] M Hausmann S Kiessling S Mestermann et al ldquoToll-likereceptors 2 and 4 are up-regulated during intestinal inflamma-tionrdquo Gastroenterology vol 122 no 7 pp 1987ndash2000 2002

[155] M T Abreu L S Thomas S Y Tesfay et al ldquoRegulation ofTLR4 and MD-2 in the intestinal epithelium evidence for dys-regulated LPS signaling in human inflammatory bowel diseaserdquoin Proceedings of the 90th Annual Meeting of the AmericanAssociation for Immunologists Abstract 3634 Denver ColoUSA 2003

[156] T A Schneeman M E C Bruno H Schjerven F-E JohansenL Chady and C S Kaetzel ldquoRegulation of the polymeric Igreceptor by signaling through TLRs 3 and 4 linking innate andadaptive immune responsesrdquo The Journal of Immunology vol175 no 1 pp 376ndash384 2005

[157] M E C Bruno A L Frantz E W Rogier F-E Johansen andC S Kaetzel ldquoRegulation of the polymeric immunoglobulinreceptor by the classical and alternative NF-120581B pathways inintestinal epithelial cellsrdquoMucosal Immunology vol 4 no 4 pp468ndash478 2011

[158] M E C Bruno E W Rogier A L Frantz A T Stefka SN Thompson and C S Kaetzel ldquoRegulation of the poly-meric immunoglobulin receptor in intestinal epithelial cellsby Enterobacteriaceae implications for mucosal homeostasisrdquoImmunological Investigations vol 39 no 4-5 pp 356ndash382 2010

[159] A L Frantz E W Rogier C R Weber et al ldquoTargeted deletionof MyD88 in intestinal epithelial cells results in compromisedantibacterial immunity associatedwith downregulation of poly-meric immunoglobulin receptor mucin-2 and antibacterialpeptidesrdquoMucosal Immunology vol 5 no 5 pp 501ndash512 2012

[160] E W Rogier A L Frantz M E C Bruno and C S KaetzelldquoSecretory IgA is concentrated in the outer layer of intestinalmucus along with gut bacteriardquo Pathogens In press

[161] M B Geuking K D McCoy and A J Macpherson ldquoThe func-tion of secretory IgA in the context of the intestinal continuumof adaptive immune responses in host-microbial mutualismrdquoSeminars in Immunology vol 24 no 1 pp 36ndash42 2012

20 ISRN Immunology

[162] L VHooper D R Littman andA JMacpherson ldquoInteractionsbetween the microbiota and the immune systemrdquo Science vol336 no 6086 pp 1268ndash1273 2012

[163] A J Macpherson M B Geuking E Slack S Hapfelmeierand K D McCoy ldquoThe habitat double life citizenship andforgetfulness of IgArdquo Immunological Reviews vol 245 no 1 pp132ndash146 2012

Submit your manuscripts athttpwwwhindawicom

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

4 ISRN Immunology

Ig-like domain

Cysteine-rich domain

Fibronectin type II repeat

C-type lectin-like domain

pIgR

PolymericIgM IgTIgX IgA

Epithelialcells

(CD351)

IgM IgA

B cells

(CD89)

IgA

NeutrophilsMonocytes

Eosinophils

(CD64)

IgG

Monocytes

NeutrophilsEosinophils

(CD32)

IgG

Monocytes

NeutrophilsPlatelets

LangerhansB cells

(CD16)

IgG

NK cells

MonocytesNeutrophilsEosinophils

IgE

Mast cellsBasophils

LangerhansMonocytes

(CD23)

IgE

B cellsT cells

MonocytesEosinophils

FcRn

IgG

Endothelial

Epithelialcells

cells

FcRY

IgY

Endothelialcells

Fc120572120583R

MΦs

Fc120572RI

MΦsMΦs MΦs

MΦs

Fc120574RI Fc120574RII Fc120574RIII

120574120575 T cells

Fc120576RIIFc120576RI

MΦs

1205732m

MHC I-like domain

Figure 3 Fc receptors are Ig isotype- and cell type-specific These schematic diagrams illustrate basic structural features of selectedFc receptors all of which are Type I transmembrane proteins The structures are not to scale and do not imply specific 3-dimensionalconformations All of the structures represent the human homolog of the indicated protein except for FcRY which is from chicken Binding ofthe constant (Fc) region of Igs to cellular receptors initiates transport across epithelial cells or intracellular signaling in cells of hematopoieticorigin The membrane-proximal Ig-like domain of FcRn pairs with the Ig-like domain of soluble 1205732-microglobulin (1205732m) The Ig-bindingsubunits of Fc120572RI Fc120574RI Fc120574RII Fc120574RIII and Fc120576RI (shownhere) pair with other protein subunits (not shown) to initiate signaling pathwaysThis figure was compiled using information from [9ndash15]

that includes the IgT-expressing carp and zebrafish The IGHloci of the few extant species of the class Sarcopterygii (lobe-finned bony fishes including coelacanths and lungfishes)differ from those ofmost of the Actinopterygii (Figure 1)TheAfrican coelacanth (Latimeria chalumnae) one of only twospecies of an ancient class of lobe-finned fishes lacks IgM andhas a single Ig heavy chain gene that resembles the IgWDgene of cartilaginous fishes [40] By contrast the Africanlungfish (Protopterus aethiopicus) expresses both IgM and anisotype resembling IgWD [41] No ortholog of IgT has beenidentified in lobe-finned bony fishes Given the diversity of Iggenes in bony fishes the evolutionary origin of IgT remainsobscure Furthermore while IgT shares many functionalsimilarities with IgA in higher vertebrates the structuralgenes for IgT and IgA are not orthologous [23] Thus thegene encoding IgT appears to be an evolutionary dead-endthat emerged in some lineages of bony fishes in response topressures for immunological protection of mucosal surfaceslikely driven by the resident microbiota as well as mucosalpathogens

23 Amphibians Duplication and diversification of genesegments within the IGH locus in a common ancestor of theTetrapoda (four-limbed vertebrates) led to the appearanceof additional heavy chain Ig isotypes (reviewed in [42])(Figure 1) Most extant species of tetrapods have a single IGHlocus the location of which is syntenic with the human IGHlocus Ectothermic vertebrates of the class Amphibia are themost primitive tetrapods having diverged about 370 millionyears ago from a common ancestor with reptiles birds andmammals Early studies of the structural and immunologicalproperties of Igs from several species of clawed frogs (Xeno-pus) suggested the emergence of two novel Ig isotypes IgXand IgY [43ndash47] (Figure 1) B cells expressing IgX but not IgYwere found abundantly in the intestinal epithelium whereasIgX-positive cells were rarely detected in the spleen and IgXlevels were very low in serum [47] Interestingly thymectomyabolished expression of IgY but not IgM or IgX consistentwith a T-independent role for IgX in the mucosal immunesystem of amphibians Genes encoding IgX and IgY weresubsequently identified in 2 species of salamanders [48 49]

ISRN Immunology 5

suggesting that these Ig isotypes may have emerged in acommon ancestor of amphibians To date no studies havebeen reported on IGH loci in caecilians A recent study inXenopus laevis established the position of amphibian IgX asthe evolutionary precursor of IgA in birds and mammals[50] These investigators found that larval thymectomy didnot affect levels of IgX and did not alter the compositionof the gut microbiota confirming the T-independence ofthe IgX response in Xenopus Phylogenetic comparisons ofIgT in bony fishes and IgX in amphibians suggest that theseIg isotypes evolved independently [23] likely responding tosimilar pressures from the resident microbiota and mucosalpathogens

24 Reptiles and Birds The clade Amniota within the super-class Tetrapoda can be subdivided into the sauropsids (rep-tiles and birds) and synapsids (mammals and their closerelatives) (Figure 1) The distinction between reptiles andbirds is based largely on physical characteristics rather thanphylogeny distinguishing the cold-blooded reptiles withscales from the warm-blooded birds with feathers Earlystudies of Igs in turtles lizards and snakes were basedlargely on their physicochemical and antigenic propertiesrevealing a predominance of IgM and lesser amounts of IgYin bile and gut secretions [51ndash53] Subsequent analyses usingantibodies to chicken IgA failed to detect a cross-reactive Igisotype in reptiles [54 55] The recent availability of wholegenome sequences for 2 species of turtles (Chrysemys pictaand Pelodiscus sinensis) [36 56] and the green anole lizard(Anolis carolinensis) [57] demonstrated the presence of genesegments encoding IgM IgD and multiple subclasses ofIgY but no ortholog of IgX in amphibians or IgA in birdsand mammals The leopard gecko (Eublepharis macularius)expresses IgM IgD and a third Ig isotype that is intermediatein homology between IgA and IgY [50 58] (designatedIgldquoArdquo for the purposes of this review) The recent availabilityof whole genome sequences for 4 crocodilians (Alligatorsinensis Alligator mississippiensis Crocodylus siamensis andCrocodylus porosus) revealed significant differences in theIGH loci compared to other reptiles including multiple sub-classes of IgM IgD and IgA (orthologous to the IgA genes ofbirds and mammals) but no IgY [59 60] Early studies of theimmune systems of birds (class Aves) revealed the presenceof an ortholog of mammalian IgA in mucosal secretionsand an ortholog of IgG (designated IgY) in serum [61ndash69]Mapping of the IGH locus in chickens and ducks revealed aninverted gene segment encoding IgA downstream of the IgMgene segment and upstream of the IgY gene segment andloss of the gene segment encoding IgD [70 71] Availabilityof whole genome sequences for a variety of bird species inthe National Center for Biotechnology Information (NCBI)database demonstrates the consistent presence of IgM IgAand IgY and the absence of IgD A recent analysis of Iggene transcripts in the ostrich (Struthio camelus) revealedsimilarities with chickens ducks and other birds includingthe expression of IgM IgA and IgY and the absence of IgD[72] Because the ostrich is one of the most primitive extantspecies of birds it appears that the distinctive organization

of the IGH locus evolved very early during the divergence ofthe avian lineage Furthermore a phylogenetic comparisonof Ig heavy chain sequences from amphibians with those ofhigher vertebrates demonstrated with high statistical supportthat IgX from amphibians and IgA from birds share arecent common ancestor [50] Taken together the evidenceis consistent with an IGH locus in a common ancestor ofreptiles and birds that included gene segments encoding IgMIgD IgA and IgY Instability in the IGH locus in individuallineages apparently resulted in the selective loss of IgA inmostturtles lizards and snakes IgY in crocodilians and IgD inbirds

25 Mammals The structure of Ig genes and their encodedproteins has been studied extensively in extant species of theclass Mammalia including the egg-laying monotremes thepouch-bearing marsupials and the placentals (eutherians)(reviewed in [8]) The IGH locus in all known mammalsis organized as a translocon with gene segments encodingIgM IgD 2 or more subclasses of IgG 1 or more subclassesof IgA and IgE an isotype unique to mammals (Figure 1)A recent phylogenetic analysis of Ig heavy chain classes intetrapods indicated with high statistical probability that theIgA gene(s) in mammals evolved from an IgX gene in acommon ancestor of all tetrapods while the IgG and IgEgenes evolved more recently from IgY in a common ancestorof amniotes [50] Continuing diversification in the IGH locusinmammals is evidenced by differences in the number of IgGand IgA subclasses and in the structure of Ig heavy chainsUnlike all Ig heavy chains in lower vertebrates comprising 1variable Ig-like domain (VH) and 4 constant Ig-like domains(CH1ndashCH4) the CH2 domain in mammalian IgA IgD andIgG was replaced with a short flexible hinge region richin cysteine and proline residues [73] The heavy chain ofmammalian IgE has retained the prototypic 4 constant Ig-likedomains (as has IgM) suggesting that the evolution of thehinge region in mammalian IgG occurred after the evolutionof IgG and IgE from an ancestral IgY gene (Figure 1)

Determination of the structure of the IGH locus in themonotreme duck-billed platypus (Ornithorhynchus anatinus)revealed the presence of 8 CH genes (including 2 subclassesof IgG and 2 subclasses of IgG) arranged in the order C

120583-

C120575-Co-C1205742-C1205741-C1205721-C120576-C1205722 [74 75] Interestingly the gene

encoding platypus IgD lacks a hinge region and is moresimilar in structure to IgD in lower vertebrates than the IgDof eutherian mammals Downstream of the C

120575gene in the

platypus is a novel Co gene (omicron for Ornithorhynchus)which appears to have evolved from an ancestral IgY geneIn contrast to the platypus only one IgA gene was identifiedin another monotreme the echidna (Tachyglossus aculeatus)and in several species of marsupials [76ndash80] Similarly asingle structural gene for IgA has been identified in 3 speciesof the eutherian order Rodentia mouse (Mus musculus)[81] rat (Rattus norvegicus) (unpublishedGenbank accessionnumber AJ510151) and gerbil (Meriones unguiculatus) [82]By contrast the IGH locus in the European rabbit (Orycto-lagus cuniculus order Lagomorpha) is unique among mam-mals apparently having evolved from a common ancestor

6 ISRN Immunology

prior to the divergence of marsupials and monotremes fromeutherians Distinctive features include a single IgG subclass13 functional IgA subclasses and absence of IgD [83ndash85] Amore typical organization of the IGH locus including singlesubclasses of IgM IgD IgA and IgE and 2 subclasses ofIgG has been reported in mammals of the orders Carnivora[86 87] Cetartiodactyla (even-toed ungulates whales anddolphins) [88ndash91] and Perissodactyla (odd-toed ungulates)[92]

Mammals of the order Primates including humanshave the greatest number and diversity of Ig classes andsubclasses among all of the tetrapods Mapping of IGH locihas now been completed for a number of primate speciesincluding human (Homo sapiens) gorilla (Gorilla gorilla)chimpanzee (Pan troglodytes) orangutan (Pongo pygmaeus)gibbon (Hylobates lar) baboon (Papio anubis) mangabey(Cercocebus torquatus atys) and three species of macaquesthe crab-eating monkey (Macaca fascicularis) pig-tailedmonkey (Macaca nemestrina) and rhesus monkey (Macacamulatta) [93ndash97] A distinguishing feature of primates in thefamily Hominidae (great apes including humans gorillaschimpanzees and orangutans) and the family Hylobatidae(gibbons) is the presence of two IgA subclasses Althoughthe orangutan is a member of the family Hominidae its IGHlocus contains only one IgA subclass gene homologous to theIgA1 gene of other hominoids [95] By contrast primates inthe family Cercopithecidae (Old World monkeys includingbaboons mangabeys and macaques) have a single IgA geneGenetic analysis of the IGH locus of primates suggested thatduplication and diversification of the primordial C

1205741-C1205742-

C120576-C120572region occurred in a common ancestor of the great

apes after the divergence from Old World monkeys [98 99]These events resulted in the current organization of the IGHlocus in extant species of great apes with four IgG subclassesand two IgA subclasses (the duplicated C

120576gene became a

nonfunctional pseudogene hence only one class of IgE isexpressed) The close phylogenetic relationship among theC120572genes in the hominoids and Hylobatidae suggests that

the C1205721

and C1205722

genes evolved from a single C120572gene in a

common ancestor of the great apes and that the C1205722gene was

subsequently lost in the orangutan Evidence of continuingevolution in the IGH locus of humans was demonstrated bythe finding of triplication of the C

1205741-C1205742-C120576-C120572region in

several families [100] Subsequent genetic analyses inmultipleethnic groups revealed that gene duplications and deletionsin the human IGH locus are surprisingly common withfrequencies up to 22 in Japanese and Chinese populations[101]

3 Emergence of the IGJ Gene andEvolution of Polymeric Igs

The ability to produce Igs as both monomers (ie one unitcomprising 2 identical heavy chains and 2 identical lightchains) and polymers (covalently linked aggregates of 2 ormore Ig units) dates to the emergence of primitive Igs incartilaginous fish [23 42 50] Whereas pentameric IgM istypically found in serum as well as secretions the polymeric

forms of IgT IgX and IgA are generally restricted to mucosalsecretions The discovery of a low molecular weight ldquoJrdquo orldquojoiningrdquo chain as a component of polymeric Igs suggesteda potential mechanism for polymerization of individual Igmolecules into highermolecular weight complexes [102ndash104]The most primitive extant vertebrates in which the IGJ genehas been identified are the cartilaginous fish concurrent withthe presence of polymeric IgM Although the IGJ gene hasbeen identified in almost all lineages of jawed vertebratesit is surprisingly absent in some lineages of Osteichthyes(bony fishes) No ortholog of the IGJ gene has been identifiedin any species of the class Actinopterygii (ray-finned bonyfishes) for which the genome has been sequenced and anno-tated including Atlantic cod (Gadus morhua) common carp(Cyprinus carpio) tilapia (Oreochromis niloticus) zebrafish(Danio rerio) medaka (Oryzias latipes) and three-spinedstickleback (Gasterosteus aculeatus) In contrast to the ray-finned bony fishes IGJ genes and functional J chain proteinswere recently identified in two species of the class Sar-copterygii (lobe-finned bony fishes the West Indian Oceancoelacanth (Latimeria chalumnae) and the African lungfish(Protopterus dolloi) [105]) These findings suggest that theIGJ gene was lost during the evolution of the Actinopterygiiafter their divergence from a common ancestor with theSarcopterygii Despite the absence of J chain ray-finned bonyfishes are capable of forming polymeric IgM and IgT that canbe transported into mucosal secretions [38]

4 Evolution of Cellular Receptors for Igs

Theunique structure of vertebrate Igs allows for simultaneousbinding of antigen via the N-terminal variable regions ofthe Ig heavy and light chains and execution of effectorfunctions via the C-terminal constant (Fc) region of the Igheavy chains Evolution of multiple Ig heavy chain isotypesin higher vertebrates expanded the repertoire of Ig-mediatedeffector functions including specialized functions atmucosalsurfaces The simplest effector functions involve neutral-ization of microbes and their toxic byproducts whereaskilling of microbes can be affected by interaction of Igs withsoluble factors found in serumand secretionsThe concurrentemergence of Igs and proteins of the classical complementpathway in cartilaginous fishes is the earliest example of aspecific immune effector function mediated by the Fc regionof Ig heavy chains [106] As the immune system diversifiedduring vertebrate evolution cellular receptors for Ig heavychains (Fc receptors) allowed host cells to bind Igs forthe purpose of internalization transport andor activationof intracellular signaling pathways The most evolutionarilyancient of the vertebrate Fc receptors is the polymeric Igreceptor (pIgR) which first emerged in bony fishes (reviewedin [8]) (Figure 3)Theprimary function of pIgR is to transportpolymeric Igs (IgM IgT IgX and IgA) across glandular andmucosal epithelial cells into external secretions (see below)The fact that the extracellular Ig-binding region of pIgR iscomposed of multiple Ig-like domains suggests that the PIGR

ISRN Immunology 7

gene evolved by duplication of a primordial Ig gene is drivenby the need for an efficient mechanism for transport ofmucosal Igs into external secretions Similar forces may havedriven the evolution of FcRY a receptor first described forits function of transporting IgY from maternal blood tothe embryo yolk sac in chicken [9 107ndash109] FcRY is notstructurally homologous to pIgR or mammalian Fc receptorsbut is instead homologous to mammalian receptors formannose and phospholipase A2 with lectin-like extracellulardomains (Figure 3) A BLAST search of the National Centerfor Biotechnology Information (NCBI) nucleotide databasefor homologs of the gene encoding chicken FcRY (designatedPLA2R1 based on its homology to phospholipase A2 receptor1) revealed homologous genes in many bird species as wellas turtles lizards alligators and mammals However thefunctional significance of FcRYPLA2R1 in the transport ofIgY in reptiles (and possibly IgG in mammals) has not beenexplored A functional equivalent of FcRY in mammals isFcRn which mediates transport of IgG across endothelialand epithelial cells in such tissues as placenta and mucosalepithelia (reviewed in [110 111]) FcRn is homologous in struc-ture to major histocompatibility class (MHC) I moleculescomprising a ligand-binding alpha chain associated withsoluble 1205732-microglobulin (Figure 3)

A unique feature of the mammalian immune system isthe expression of Fc receptors for various Ig isotypes bycells of hematopoietic origin (Figure 3) (reviewed in [10])Engagement of these Fc receptors by Ig (in the presenceor absence of bound antigen depending on the particularFc receptor) initiates intracellular signaling pathways thatcan either augment or inhibit immune responses Withthe exception of Fc120576RII which has a single C-type lectin-like domain the extracellular Ig-binding regions of thesehematopoietic Fc receptors comprise 1 2 or 3 Ig-like domains[10] Genes encoding Fc120572120583R Fc120574RI Fc120574RIII Fc120576RI andFc120576RII are widely distributed among mammalian specieswhereas genes encoding Fc120572RI and Fc120574RII are restricted tothe primate lineage suggesting recent evolutionary originsThe genes encoding the120572120573 andor 120574 chains of Fc120576RI Fc120574RIIand Fc120574RIII are linked in a cluster on the long arm of humanchromosome 1 (1q23) not far removed from the gene for the120572 chain of Fc120574RI at 1q21 This tight linkage is consistent withduplication and diversification of a primordial FcR gene ina common ancestor of mammals The primate-specific genesencoding the 120572 and 120573 chains of Fc120574RII appear to have evolvedmore recently Another cluster of immune-related genes onthe long arm of chromosome 1 includes the genes for pIgR(1q31) and Fc120572120583R (1q32) Although the overall homologybetween pIgR and Fc120572120583R is relatively low they share aconserved binding site for IgA and IgM in the N-terminalIg-like domain Interestingly the genes encoding FcRn andFc120572RI are closely linked on the long arm of chromosome19 (19q133 and 19q1342 resp) although they bear littlehomology beyond the presence of a single Ig-like domain inthe extracellular region Finally the gene for the lectin-likereceptor Fc120576RII is located in an unrelated locus on the shortarm of chromosome 19 (19p133)

PIGR

dIgA

pIgR

Ag

SIgA

Free SC

Figure 4 Transcytosis of pIgR through a polarized epithelial celland formation of secretory Igs A polarized columnar epithelial cellis illustrated with the apical surface at the top and the basolateralsurface at the bottom Newly synthesized pIgR is targeted to thebasolateral surface where it binds polymeric Ig (pIg illustrated hereas dimeric (d)IgA) with or without bound antigen (Ag) Followingreceptor-mediated endocytosis pIg-bound and unoccupied pIgRmolecules are transported through a series of intracellular vesiclesto the apical surface Proteolytic cleavage of pIgR at the extracellularface of the plasma membrane releases free secretory component(SC) and secretory SIg (illustrated here as SIgA) Modified from [13]with permission from John Wiley and sons

5 Unique Biological Functions of pIgR

ThepIgR is expressed on the surface of glandular andmucosalepithelial binds where it binds selectively to polymericIg (pIg) and mediates its transport across epithelial cellsinto external secretions (reviewed in [17 111 112]) Most of

8 ISRN Immunology

02

100

Human IgA1Gorilla IgA1

Gorilla IgA281

6164

Human IgA2

Chimpanzee IgA2Chimpanzee IgA1

Gibbon IgA1Gibbon IgA2

Orangutan IgABaboon IgA

Rhesus macaque IgA53 100

98 69Dog IgA

Pig IgA100 Cattle IgA

52

Horse IgARabbit IgA (13 subclasses)

Mouse IgA57

99

Possum IgA

93

Chicken IgAPlatypus IgA1100

5095

Platypus IgA2

Trout IgTFrog IgX

Gecko IgldquoArdquo

(a)

02

Human pIgR

100Chimpanzee pIgRGorilla pIgR

55Gibbon pIgROrangutan pIgR100

100

100 Baboon pIgRRhesus macaque pIgR

Mouse pIgR

66

96

100 Pig pIgRCattle pIgR

85Horse pIgR

Dog pIgR

74

Rabbit pIgRPossum pIgR

Platypus pIgR

Chicken pIgR

10075

5979

Trout pIgRFrog pIgR

Anole pIgR

71

(b)

Figure 5 Coevolution of mucosal Igs and pIgR Simplified neighbor-joining phylogenetic trees of vertebrate (a) Ig and (b) pIgR proteinsequences with human IgA1 and pIgR denoted as outgroups Horizontal distances are proportional to the degree of divergence followinga multiple alignment of amino acid sequences Numbers at nodes denote bootstrap support for each bifurcation after 100 replicationsAccession numbers for mucosal Ig sequences human (Homo sapiens) IgA1 J00220 IgA2 (allotype m1) J00221 gorilla (Gorilla gorilla) IgA1X53703 IgA2 X53707 chimpanzee (Pan troglodytes) IgA1 X53702 IgA2 X53706 gibbon (Hylobates lar) IgA1 X53708 IgA2 X53709 Borneanorangutan (Pongo pygmaeus) IgA X53704 baboon (Papio anubis) IgA DQ868435 rhesus macaque (Macaca mulatta) AY039245 pig (Susscrofa) IgA U12594 cattle (Bos taurus) IgA AF109167 dog (Canis lupus familiaris) IgA L36871 horse (Equus caballus) IgA AY247966mouse (Mus musculus) IgA D11468 rabbit (Oryctolagus cuniculus) IgA1 X51647 brushtail possum (Trichosurus vulpecula) IgA AF027382duck-billed platypus (Ornithorhynchus anatinus) IgA1 AY055778 IgA2 AY055779 chicken (Gallus gallus) IgA AAB226142 leopard gecko(Eublepharis macularius) IgldquoArdquo (so designated because of its uncertain phylogeny with homology to both IgA and IgY) ABG726841African clawed frog (Xenopus laevis) IgX S03186 rainbow trout (Oncorhynchus mykiss) IgT AAW669811 Accession numbers for pIgRsequences with species that vary from those used for the mucosal Ig alignment in panel A noted in parentheses human NM 002644chimpanzee XM 003308710 gorilla XM 004028295 gibbon XM 003272974 Sumatran orangutan (Pongo abelii) NM 001131626 baboonXM 003893189 rhesus macaque XM 001083307 pig NM 214159 cattle NM 174143 dog XM 537133 horse XM 001492298 mouseNM 011082 rabbit NM 001171045 brushtail possum AF091137 duck-billed platypus XM 001508602 chicken NM 001044644 green anole(Anolis carolinensis) XM 003224013 African clawed frog EF079076 rainbow trout FJ940682

ISRN Immunology 9

our knowledge of pIgR-mediated transcytosis of mucosalIgs is derived from studies of mammalian secretory IgA(SIgA) as illustrated in Figure 4 Transcription of the PIGRgene and translation of pIgR mRNA is accompanied byinsertion of the nascent protein into the endoplasmic retic-ulum The pIgR undergoes substantial glycosylation duringtransport through the ER and Golgi apparatus and is thentargeted to the basolateral surface of polarized epithelialcells Membrane-bound pIgR binds pIg and pIg-containingimmune complexes which are internalized along with unoc-cupied pIgR via receptor-mediated endocytosis and thentranscytosed through a series of intracellular vesicles to theapical surface During transcytosis intracellular pIg antibod-ies can neutralize bacteria viruses and other antigens thathave gained access to the interior of the epithelial cell Atthe apical surface proteolytic cleavage of the membrane-spanning region of pIgR leads to the release of its extracellulardomain known as secretory component (SC) either in freeform or covalently bound to pIg Secretory Igs can neutralizepathogens and antigens within the mucosal lumen andfacilitate excretion of antigens that were transported throughthe epithelial cell as IgA immune complexes The SC moietyof SIgA has been shown to protect IgA from degradationby host and bacterial proteases and along with free SCconfers additional innate immune functions that protectthe epithelial surface from microbial invasion and limitpotentially damaging host inflammatory responses (reviewedin [113]) The finding of an SC-like polypeptide associatedwith polymeric IgT in rainbow trout [38] polymeric IgXin Xenopus [50] and polymeric IgA in birds [114] suggeststhat all vertebrate pIgRs share the function of transportingpolymeric Igs into external secretions In many mammalianspecies pIgR mediates epithelial transcytosis of both poly-meric IgM and IgA (reviewed in [111]) Although directevidence is not yet available it is reasonable to assume thatpIgR transports IgM in lower vertebrates It will be interestingto investigate whether the SCmoiety of secretory Igs in lowervertebrates mediates additional innate immune functions ashas been demonstrated for mammalian SC

6 Coevolution of pIgR and Mucosal Igs

Molecular cloning of the PIGR gene was first reportedfor mammalian species including eutherians marsupialsand monotremes [115ndash127] Subsequent elucidation of PIGRsequences from diverse species of jawed vertebrates hasallowed a comprehensive analysis of the evolutionary originsof the PIGR gene [38 128 128ndash132] and additional sequencesavailable in the Genbank database Whereas no ortholog ofthe PIGR gene has been found in any species of cartilaginousfish the PIGR gene has been annotated in all species of teleostfish for which the genome has been sequenced No orthologof the PIGR gene has been reported in lobe-finned bonyfishes but further analyses of whole genome sequences willbe required to determine whether the PIGR gene was lostfollowing the split of the Sarcopterygii It thus appears thatthe PIGR gene emerged in a common ancestor of highervertebrates after the split of cartilaginous fish and prior

to the evolution of modern teleosts likely driven by theselective pressure to provide a mechanism for transport ofpolymeric Igs such as IgM and IgT into mucosal secretionsThis hypothesis is supported by a comparison of phylogenetictrees based on amino acid sequences for IgT IgX and IgAheavy chains and pIgR (Figure 5)The predicted evolutionarydistance between trout IgT and frog IgX is similar to thedistance between trout and frog pIgR suggesting that thetransition from IgT to IgX as the dominantmucosal Ig isotypewas accompanied by adaptations in pIgR structure Similarparallels can be seen in the transition from IgX to IgA inreptiles birds and mammals and the concurrent evolutionof pIgR

Alignments of the amino acid sequences of mucosal Igheavy chains and pIgR from 10 representative vertebratespecies provide further support for the theory of coevolutionof mucosal IGH and PIGR genes (Figure 6) A commonfeature of Ig and pIgR proteins is the presence of repeatingIg-like domains (see Figure 2 for the basic structure of thesedomains) The structure of IgT IgX and IgA heavy chainsfrom fish amphibians reptiles and birds is similar to thatof IgM with 4 constant Ig-like domains In mammalianIgA (and IgG) the exon for the 2nd constant region wastruncated to encode a short ldquohingerdquo region which confersgreater mobility to the antigen-binding region at the N-terminusThus the CH3 domain of IgT IgX and IgA in lowervertebrates is structurally and functionally homologous tothe CH2 domain of mammalian IgA The heavy chains ofIgT IgX and IgA have retained a characteristic feature ofthe IgM heavy chain that is the presence of a conservedcysteine residue in the tailpiece that allows disulfide bondingbetween heavy chains of individual Ig proteins to formhigher molecular weight polymers These large Ig structurescontaining multiple antigen-binding sites are particularlywell suited for immune clearance of large antigens found atmucosal surfaces such as intact microbes and food particlesIn mucosal Igs from most vertebrate orders the J chainprotein initiates this polymerization process by disulfidebonding with 2 Ig heavy chains remaining associated withthe polymeric Ig at a stoichiometric ratio of 1 J chain subunitper 2 3 4 or 5 Ig units Despite the absence of J chainthe predominant form of IgM and IgT in mucus secretionsin rainbow trout was found to be polymeric in contrastto monomeric forms of IgM and IgT in the blood [38] Inmammals IgM is mainly found as a pentamer whereas theshorter heavy chain ofmammalian IgA restricts its polymericforms to dimers trimers and tetramers Further studies willbe required to characterize the polymeric structures of IgMIgT IgX and IgA in lower vertebrates

Alignment of pIgR amino acid sequences from 10 rep-resentative vertebrate species reveals structural changes thatwere evolved in parallel with structural changes in mucosalIgs (Figure 6(b)) All pIgR proteins have an N-terminalhydrophobic leader peptide required for targeting of thenascent protein into the ER The extracellular region ofpIgR protein is characterized by repeating ldquoIg-likerdquo domainssimilar to Ig heavy chains [115 133] Interestingly the num-ber of extracellular Ig-like domains has increased duringvertebrate evolution culminating with a total of 5 domains

10 ISRN Immunology

TailpieceHinge

Tailpiece

Mammalian IgA

VVVVVVVVVV

200121 300 400 4721

Human IgA1Rhesus IgA

Cattle IgAMouse IgA

Possum IgAPlatypus IgAChicken IgA

Frog IgXTrout IgT

Premammalian IgTXA

Gecko IgldquoArdquo

CH1

CH1

CH2

CH2

CH3

CH3

CH4

(a)

Leader 1 2 3 4 5

Ig homology extracellular domains

Linker CytoplasmicTM

1001 200 300 400 500 600 700 764

HumanRhesus

CattleMouse

PossumPlatypusChicken

AnoleFrog

Trout

(b)

Figure 6 Interspecies similarity in mucosal Ig and pIgR protein sequences from 10 representative vertebrate species Alignments in aminoacid sequences correspond to the phylogenetic trees shown in Figure 5 (a) Numbering ofmucosal Ig amino acids corresponds to the sequenceof human IgA1 beginning with the first residue of the variable domain CH heavy chain constant region domain (b) Numbering of pIgRamino acids corresponds to the sequence of human pIgR beginning with the first residue of the leader peptide TM transmembrane Forboth alignments the intensity of shading at each position signifies the degree of similarity amongmucosal Ig or pIgR sequences from differentspecies Gaps in sequence alignments signify regions of limited interspecies homology Approximate boundaries are noted of key structuralelements in mucosal Ig and pIgR proteins

in mammalian pIgR By contrast pIgR from amphibiansreptiles and birds contains 4 extracellular domains lackinga homolog of domain 2 of mammalian pIgR The mostprimitive form of pIgR found in teleost fish contains only2 extracellular domains homologous to domains 1 and 5of mammalian pIgR Interspecies homology is greatest indomain 1 which has been shown to be critical for binding ofmammalian pIgR to polymeric Igs (reviewed in [111]) Highlyconserved internal disulfide bonds are found in all the Ig-like domains of pIgR characteristic of the immunoglobulinfold An additional disulfide bond is found in domain 5 ofpIgR frommammals birds reptiles and amphibians but notfish In human SIgA this ldquoextrardquo disulfide bond in domain 5has been shown to rearrange to form a disulfide bond with

cysteine residues in one of the heavy chains of polymericIgA [134] Although the structure of SIgA has not beenfully characterized for lower vertebrates it is reasonable toassume that similar disulfide bonds form between domain 5of pIgR and polymeric IgA or IgX from birds reptiles andamphibians The linker region connecting domain 5 of pIgRto the transmembrane domain has a random structure that ispoorly conserved across species Proteolytic cleavage of pIgRwithin this domain leads to the release of SC from the apicalsurface of epithelial cells either free or bound to polymericIg The cytoplasmic domain of mammalian pIgR containsa number of intracellular sorting motifs that interact withcytoplasmic proteins to direct pIgR through the transcytoticpathway (reviewed in [111]) These motifs are reasonably

ISRN Immunology 11

Linker

TMCytoplasmic

J chain

Hinge 1

2

34

5

CL

VLVH

C1205721C1205722 C1205723

(a)

Linker

TMCytoplasmic

J chain

1

3 4

5

CL

VL

VH

C1205941205721

C1205941205722C1205941205723 C1205941205724

(b)

11

5

LinkerTM

Cytoplasmic

5

CL

VL

VH

C1205911C1205912

C1205913 C1205914

pIgR Ig-like domain

H chain Ig-like domain

L chain Ig-like domain

J chain

Disulfide bond

(c)

Figure 7 Theoretical model for changes in the structure of secretory Igs during evolution (a) The structure for mammalian SIgA is adaptedfrom the model of Woof and Russell [16] for human SIgA1 with permission from Nature Publishing Group (b) and (c) Theoretical modelsfor the structure of IgXA from amphibians and birds and SIgT from teleost fish respectively are predicted from alignment of Ig heavy chainand pIgR sequences with mammalian homologs

well conserved in pIgR from birds and reptiles but not inpIgR from amphibians and fish suggesting that complexmechanisms of intracellular trafficking of pIgR coevolvedwith the increasing complexity of the mucosal immunesystem

7 Hypothetical Models for Changes inSecretory Ig Structure during Coevolutionof Mucosal Igs and pIgR

A large number of structural and functional analyses overthe past 30 years allowed the development of detailed modelsfor the structure of mammalian SIgA (reviewed in [111 135])(Figure 7(a)) Domains 1 and 5 of pIgR the most highlyconserved Ig-like domains associate with theC1205722 subunits oftwo adjacent IgA heavy chains in a near-planar structure [136137] During transcytosis a disulfide bond forms betweenhighly conserved cysteine residues in domain 5 of pIgRand the C1205722 domain of one of the IgA heavy chains [134]Domains 2 3 and 4 allow mammalian pIgR to assume aflexible extended structure which is thought to wrap aroundthe IgA heavy chains and protect against degradation fromhost and microbial proteases Binding of mammalian pIgRto polymeric IgA or IgM requires the presence of J chain

connecting the Ig subunits (reviewed in [138]) and J chain-deficient mice fail to transport IgA and IgM into externalsecretions [139ndash141] Structure-function studies usingmutantforms of human J chain suggested that J chain binds directlyto pIgR and also maintains polymeric Ig in an optimalconformation for pIgR binding and transcytosis [142] Theunstructured linker region connecting domain 5 of pIgRto the transmembrane (TM) region gives membrane-boundpIgR the flexibility to bind large polymeric Igs (with orwithout associated antigens) and provides an exposed site forproteolytic cleavage of pIgR to SC The C-terminal region ofpIgR extends past the cytoplasmic face of the plasma mem-brane allowing association with cytoplasmic factors thatregulate trafficking of pIgR with or without bound polymericIg

Although detailed structural studies have not yet beenperformed on secretory Igs from lower vertebrates hypo-thetical models can be constructed based on alignmentswith their mammalian homologs A model for secretoryIgXA in birds reptiles and amphibians is illustrated inFigure 7(b) showing the C

1205941205722 domain in place of the hinge

region ofmammalian IgAThenumbering of the extracellulardomains of pIgR corresponds to the homologous domainsin mammalian pIgR noting the absence of domain 2 In

12 ISRN Immunology

this model the C120594120572

3 domains of two adjacent IgXA heavychains (homologous to the C

1205722 domain of mammalian IgA)

bind to the highly conserved domains 1 and 5 of pIgRGiven the conservation of the analogous cysteine residuesin domain 5 of pIgR and the C

1205941205723 domain of IgXA it

is assumed that a disulfide bond forms between pIgR andpolymeric Ig during epithelial transcytosis in birds reptilesand amphibiansThe absence of domain 2 in pIgR from thesevertebrate orders necessitates a more rigid structure thanthat of mammalian pIgR with a corresponding decrease inits ability to wrap around the IgXA heavy chains and pro-vide protection against proteoltyic degradation Despite theshorter length of pIgR in birds reptiles and amphibians theassociation with the J chain subunit of polymeric IgXA stillappears to be required Recombinant pIgR from the Africanfrog (Xenopus laevis) was shown to bind with moderatelyhigh affinity to human polymeric IgA containing J chain butnot to monomeric IgA [125] The affinity of Xenopus pIgRfor human pIgA was improved when Xenopus J chain wassubstituted for human J chain in a chimeric polymeric IgAmolecule The lack of sequence conservation across speciesin the linker region connecting domain 5 of pIgR to the TMregion suggests that it acts as a nonspecific ldquospacerrdquo As statedabove the cytoplasmic region of pIgR appears to have evolvedover time to provide enhanced regulation of pIgR trafficking

The hypothetical structure of secretory IgT from teleostfish in Figure 7(c) illustrates how the most primitive form ofpIgR comprising only extracellular domains 1 and 5 couldassociate with polymeric Ig and mediate epithelial transcy-tosis Association of pIgR domain 1 with the C

1205913 domain of

IgT would preserve the functional homology with secretoryIgs in higher vertebrates The short length of teleost pIgRwould necessitate the association of domain 5 with a C

1205913

domain on one of the heavy chains of the same IgT ratherthan spanning across to the adjaent IgT subunit While thismodel preserves the highly conserved association of pIgRdomain 1 with the orthologous domain of the IgT heavychain it does not explain the selectivity of teleost pIgR forpolymeric rather than monomeric IgT Although there is noexperimental evidence to support this model it could behypothesized that dimerization of two pIgR molecules in theplasmamembrane is required for high affinity binding of IgTas illustrated in the model in Figure 7(c) This hypotheticalmodel would also explain the lack of a necessity for J chainin polymeric IgT since each subunit in the pIgR dimer wouldonly be in contact with one IgT subunit The unstructuredlinker region connecting domain 5 of pIgR to the TM regionwould provide flexibility for association of 2 membrane-bound pIgR molecules with a large polymeric IgT molecule

Taken together the structural models for secretory Igsshown in Figure 7 are consistent with the selection of a morefunctional pIgR molecule over evolutionary time Duplica-tion and diversification of the extracellular Ig-like domainsof pIgR would provide a longer more flexible surface forbinding to polymeric Igs with higher affinity and protectingthe Ig heavy chains against proteolytic attack Expansion ofthe cytoplasmic domain of pIgR and incorporation of motifsfor binding cytoplasmic proteins would allow regulated

trafficking of pIgR and polymeric Igs across mucosal andglandular epithelial cells Importantly these models illustratea potential path for coevolution of IGH and PIGR genesdriven by the common selective pressure to provide antigen-specific humoral immune responses at mucosal surfaces

8 Evidence that the CommensalMicrobiota Provided the Driving Force forCoevolution of Mucosal Igs and pIgR

From the earliest evolution of vertebrate animals mucosal Igshave been an integral part of the emerging adaptive immunesystem Clearly many environmental factors served as driv-ing forces for the evolution of the adaptive immune systemin vertebrates including a longer lifespan thanmany (but notall) invertebrates and amore diverse diet that could introducea broader range of potential gut pathogens However it hasbeen proposed that the most significant force may havebeen the dramatic increase in the numbers and complexityof the resident microbiota in the evolution of vertebratesfrom their invertebrate ancestors [1 143 144] Antibodiesin mucosal secretions contribute to immune homeostasis bylimiting access of microbes and their products to the bodyproper maintaining the integrity of the epithelial barrier andshaping the composition of the commensal microbiota infavor of metabolically beneficial microorganisms [145] Thepredominance of polymeric Igs in these secretions promotesthese functions by providing multiple antigen-binding sitesper Ig complex thus increasing the overall avidity of antigen-antibody interactions Structural and functional refinementsin mucosal Igs culminating with the multifunctional secre-tory IgA molecule in mammals have further enhanced theirability to enhance immune homeostasis

The early emergence of pIgR in vertebrate evolutionprovided a mechanism for efficient transport of mucosal Igsinto external secretions It is well documented that crosstalkbetween mucosal epithelial cells and the resident microbiotamodulates expression of pIgR (reviewed in [17 111 112]) andit is reasonable to assume that these host-microbe interac-tions provided a driving force for evolution of the PIGR genein vertebrates The first demonstration that gut bacteria maymodulate pIgR expression in epithelial cells was the findingthat butyrate a bacterial fermentation product and importantenergy source in the colon upregulated expression of pIgRin the human colonic epithelial cell line HT-29 [146] A rolefor commensal bacteria in pIgR regulation was subsequentlydemonstrated by the observation that pIgR expression wasincreased when germ-free mice were colonized with Bacteri-oides thetaiotaomicron a prominent organism of the normalmouse and human intestinal microbiota [147] Amore recentstudy using a model of reversible colonization of germ-free mice with a nondividing mutant of Escherichia colidemonstrated that a long-lived SIgA response could besustained that specifically recognized the inducing bacteria[148] However exposure of E coli-colonized mice to otherbacteria limited the duration of the SIgA response against theoriginal colonizer suggesting a dynamic equilibriumbetweenmembers of the gut microbial community and host SIgA A

ISRN Immunology 13

study from the laboratory of Finn-Eirik Johansen demon-strated that diversity of the bacterial community in the cecallumen was reduced in pIgR-knockoutmice supporting a rolefor SIgA in limiting overgrowth of selected species [149] Incontrast the community of bacteria adherent to the epithelialsurface was more diverse in pIgR-knockout mice than inwild-typemice and these adherent bacteria caused enhancedexpression of several epithelial antimicrobial peptides Thesefindings suggest that bacteria-specific SIgA anchored in themucus layer restricts adhesion of bacteria to the epithelialsurface and limits bacterial stimulation of host epithelial cellsA recent study from the authorrsquos laboratory employing abreeding scheme in which119875119894119892119903minusminus damswere bred to119875119894119892119903+minusmales and vice versa demonstrated that SIgA antibodiesin breast milk promote long-term intestinal homeostasis byregulating the gut microbiota and gene expression in colonicepithelial cells [150]

A direct role for commensal andor pathogenic bacteriain the regulation of pIgR expression suggests that the innateimmune system may ldquoprimerdquo epithelial cells for transportof polymeric Ig produced during the adaptive immuneresponse Host cells mediate innate immune responses tomicrobial components through toll-like receptor (TLR) sig-naling (reviewed in [151 152]) Intestinal epithelial cells havebeen shown to express a wide variety of TLRs the expressionof which is upregulated during intestinal inflammation [153ndash155] Significantly expression of pIgR was shown to beupregulated in the HT-29 human intestinal epithelial cellline by bacterial LPS a ligand for TLR4 [156 157] Similarinduction of PIGR gene transcription was seen followingdirect binding of bacteria of the family Enterobacteriaceaewhich express a form of LPS that stimulates TLR4 [158]A recent study from the authorrsquos laboratory demonstratedthat shRNA-mediated knockdown of myeloid differentiationprimary response protein 88 (MyD88) a cytoplasmic adapterprotein that transduces signals from cell surface TLR4blocked the induction of PIGR gene transcription by LPS inHT-29 cells [159] The in vivo significance was confirmed bythe finding that mice with a targeted deletion of the Myd88gene only in intestinal epithelial cells had reduced expressionof pIgR compared to wild-type littermates [159] Mice withtargeted depletion of MyD88 in intestinal epithelial cells alsoexhibited reduced expression of mucin-2 the major compo-nent of the intestinal mucus layer and several antimicrobialpeptides and decreased transmucosal electrical resistanceThese alterations in epithelial barrier function were accom-panied by significant changes in the composition of the fecalmicrobiota increased numbers of bacteria adherent to theintestinal mucus layer and a dramatic increase in transloca-tion of gut bacteria into the drainingmesenteric lymphnodesincluding the opportunistic pathogen Klebsiella pneumoniaeThese findings demonstrate that MyD88-mediated crosstalkbetween the gut microbiota and intestinal epithelial cells iscrucial for optimal expression of pIgR production of SIgAdevelopment of a healthy gut microbiota and maintenanceof intestinal homeostasis

A model can be proposed in which continuous stimu-lation of intestinal epithelial cells by gut bacteria regulates

Lumen

Mucus

Epithelium

Lamina

PIGR

TLRs

MyD88

Bacteria

Plasma cells

propria

Polymeric Ig

Polymeric Ig receptor

Secretory component

Figure 8 Crosstalk between the polymeric immunoglobulin recep-tor secretory immunoglobulins and the gut microbiotaThe single-layered epithelium that lines the gastrointestinal tract is coveredwith a thick mucus layer which physically excludes members ofthe resident microbiota but allows diffusion of shed components ofmicrobial cells Stimulation of epithelial toll-like receptors (TLRs)with microbial products engages the cytoplasmic adaptor proteinMyD88 and initiates NF120581B-dependent signaling pathways Translo-cation of activated NF120581B and other transcription factors to thenucleus enhances transcription of thePIGR gene Activation of TLRsmay also stimulate pIgR transcytosis Polymeric Igs secreted bylamina propria plasma cells bind to pIgRon the basolateral surface ofepithelial cells and are transcytosed to the apical surface along withunoccupied pIgR Proteolytic cleavage of pIgR at the apical surfacereleases secretory SIg and free secretory component (SC) Binding ofSIg and SC to luminal bacteria promotes association with themucuslayer and prevents direct access of bacteria to the epithelial surfaceOver time the continuous crosstalk with SIg shapes the compositionof the gut microbiota Modified from [17] under terms of authorrsquoscopyright with Nature Publishing Group

pIgR expression and transport of SIgA and promotes immuneexclusion of resident and pathogenic bacteria (Figure 8) Adense layer of mucus which increases in thickness fromthe proximal to the distal colon serves to separate bacteriafrom direct contact with the epithelial surface Secretionof microbial-associated molecular patterns (MAMPs) bycommensal bacteria stimulates MyD88-dependent TLR sig-naling leading to enhanced expression of pIgR and antimi-crobial peptides and increased mucus production Bindingof pIgA to pIgR and possibly also signaling via MAMPs

14 ISRN Immunology

enhances transcytosis of pIgA pIgA-containing immunecomplexes and unoccupied pIgR which promotes clearanceof antigens and pathogens from the lamina propria intra-cellular neutralization and release of SIgA and SC at theluminal surface SIgA and SC serve to trap bacteria in themucus layer limiting their access to the epithelial surface Inmice with a targeted deletion of the Muc2 gene which havea severely depleted mucus layer in the colon SIgA and SCfail to associate with the surface of colonic epithelial cells[160] The presence of SIgA in the intestinal lumen whetherderived passively frommaternalmilk or actively via epithelialtranscytosis shapes the composition of the gut microbiotaand modulates intestinal epithelial gene expression

9 Concluding Remarks

The first microbes that emerged on Earth almost 4 billionyears ago encountered a hostile world where nutrients werescarce hazards were everywhere and life was short Withthe evolution of multicellular organisms about 3 billion yearslater a select group ofmicrobes chose to sacrifice an indepen-dent existence for the benefits of a mutualistic relationshipwith eukaryotic hosts Prokaryotic-eukaryotic mutualismreached its apex some 500 million years ago with theemergence of primitive vertebrates whose gastrointestinaltracts were populated by an abundant and diverse commensalmicrobiota In humans the large intestine is home to some100 trillion microorganisms 10 times more than the totalnumber of eukaryotic cells in the entire body The microbesthat inhabit the vertebrate GI tract provide many benefitsto the eukaryotic host including digestion of complex foodmolecules synthesis of vitamins and production of solublefactors that enhance the development of the host immunesystem In return the eukaryotic host provides the microbeswith a warm moist place to live abundant food low oxygentension and a soft bed of mucus on which to form biofilmsWhen this mutually beneficial arrangement is challenged bypathogenicmicrobes the eukaryotic host and the commensalmicrobiota join forces to battle the pathogens and protectthe body from invasion The vertebrate immune system isequipped with a well-trained army of immune cells and asophisticated arsenal of weapons (cell surface molecules andsecreted factors) that protect the host from all but the mostvirulent pathogens This immune ldquoarmyrdquo also serves as aconstant reminder to the commensal microbes that whilethey are free to enjoy the amenities of the mucosal surfacesthey are not welcome in the body proper The emergence ofantigen-specific Igs and T-cell receptors in jawed vertebratesbegan a process of immunological diversification that led tothe development of a specialized mucosal immune systemin higher vertebrates in which secretory Igs play a centralrole The relationship between host and microbiota is clearlyreciprocal the mucosal Igs that evolved in response toselective pressure from the commensal microbiota play acentral role throughout life in shaping the compositiongenetics andmetabolic activity of themicrobiota [1 161 162]

The epithelial layer lining mucosal surfaces provides aphysical and innate immune barrier against penetration of

the body proper by microbes undigested food antigens andpotentially noxious environmental substances The evolu-tionary challenge of transporting mucosal Igs into externalsecretions without compromising the epithelial barrier wasmet by the emergence of the PIGR gene in an ancestor ofbony fishes encoding an epithelial-specific transmembraneprotein that actively transports polymeric Igs across mucosaland glandular epithelia (Figure 4) Structural similaritiesbetween Igs and the extracellular Ig-binding domains of pIgR(Figure 6) suggest that duplication and diversification of agene encoding primordial Ig-like domain may have givenrise to the PIGR gene in a primitive vertebrate ancestorParallel refinement of the structures of mucosal Igs andpIgR during tetrapod evolution (Figures 6 and 7) culminatedin the evolution of the multifunctional SIgA molecule inmammals in which the pIgR-derived SC subunit providesinnate immune functions and protects the antigen-bindingIgA polymer from proteolytic degradation In addition toacting as a powerful force during vertebrate evolution thereciprocal relationship between pIgR mucosal Igs and thecommensal microbiota provides benefits throughout thelife of the individual Microbial colonization of newbornvertebrates stimulates development of mucosal B cells andclass switching to mucosal Ig isotypes [1 163] Microbialfactors upregulate expression of pIgR enhancing transportof mucosal Igs into external secretions where they in turnregulate the microbiotaThis beautifully orchestrated processallows us to maintain a healthy relationship with our resi-dent microbiota while providing mutual protection againstpathogens

Conflict of Interests

The author declares that there is no conflict of interestsregarding the publication of this paper

Acknowledgments

This work was supported by Grant no AI069027 from theNational Institutes of Health of the United States of America(and an associatedAmerican Recovery andReinvestmentActsupplement) and a Senior Research Award from the Crohnrsquosand Colitis Foundation of America

References

[1] C L Maynard C O Elson R D Hatton and C T WeaverldquoReciprocal interactions of the intestinal microbiota andimmune systemrdquo Nature vol 489 no 7415 pp 231ndash241 2012

[2] M F Flajnik and M Kasahara ldquoOrigin and evolution of theadaptive immune system genetic events and selective pres-suresrdquo Nature Reviews Genetics vol 11 no 1 pp 47ndash59 2010

[3] M F Flajnik and L du Pasquier ldquoEvolution of the immunesystemrdquo in Fundamental Immunology W E Paul Ed chapter4 pp 67ndash128 Lippincott Williams ampWilkins Philadelphia PaUSA 2012

[4] M Hirano S Das P Guo and M D Cooper ldquoThe evolutionof adaptive immunity in vertebratesrdquo Advances in Immunologyvol 109 pp 125ndash157 2011

ISRN Immunology 15

[5] T BoehmNMcCurley Y SutohM SchorppMKasahara andM D Cooper ldquoVLR-based adaptive immunityrdquo Annual Reviewof Immunology vol 30 pp 203ndash220 2012

[6] T Hunkapiller and L Hood ldquoImmunology the growing immu-noglobulin gene superfamilyrdquoNature vol 323 no 6083 pp 15ndash16 1986

[7] P Bork L Holm and C Sander ldquoThe immunoglobulin foldstructural classification sequence patterns and common corerdquoJournal of Molecular Biology vol 242 no 4 pp 309ndash320 1994

[8] C S Kaetzel and M W Russell ldquoPhylogeny and comparativephysiology of IgArdquo in Mucosal Immunology J Mestecky WStrober H Cheroutre B Kelsall B N Lambrecht and M WRussell Eds chapter 19 Academic PressElsevier WalthamMass USA 2014

[9] Y He and P J Bjorkman ldquoStructure of FcRY an avian immu-noglobulin receptor related to mammalian mannose receptorsand its complex with IgYrdquo Proceedings of the National Academyof Sciences of the United States of America vol 108 no 30 pp12431ndash12436 2011

[10] J M Woof and D R Burton ldquoHuman antibody-Fc receptorinteractions illuminated by crystal structuresrdquo Nature ReviewsImmunology vol 4 no 2 pp 89ndash99 2004

[11] W L Martin A P West Jr L Gan and P J Bjorkman ldquoCrystalstructure at 28 A of an FcRnheterodimeric Fc complexmechanism of pH-dependent bindingrdquo Molecular Cell vol 7no 4 pp 867ndash877 2001

[12] E S Ward ldquoAcquiring maternal immunoglobulin differentreceptors similar functionsrdquo Immunity vol 20 no 5 pp 507ndash508 2004

[13] C S Kaetzel ldquoThe polymeric immunoglobulin receptor bridg-ing innate and adaptive immune responses atmucosal surfacesrdquoImmunological Reviews vol 206 no 1 pp 83ndash99 2005

[14] M Acharya G Borland A L Edkins et al ldquoCD23Fc120576RIImolecular multi-taskingrdquo Clinical and Experimental Immunol-ogy vol 162 no 1 pp 12ndash23 2010

[15] V B Klimovich ldquoIgM and its receptors structural and func-tional aspectsrdquo Biochemistry vol 76 no 5 pp 534ndash549 2011

[16] J MWoof andMW Russell ldquoStructure and function relation-ships in IgArdquo Mucosal Immunology vol 4 no 6 pp 590ndash5972011

[17] F-E Johansen and C S Kaetzel ldquoRegulation of the polymericimmunoglobulin receptor and IgA transport new advances inenvironmental factors that stimulate pIgR expression and itsrole in mucosal immunityrdquo Mucosal Immunology vol 4 no 6pp 598ndash602 2011

[18] F Kokubu K Hinds R Litman M J Shamblott and G WLitman ldquoExtensive families of constant region genes in a phy-logenetically primitive vertebrate indicate an additional levelof immunoglobulin complexityrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 84 no16 pp 5868ndash5872 1987

[19] A S Greenberg A L Hughes J Guo D Avila E CMcKinneyand M F Flajnik ldquoA novel ldquochimericrdquo antibody class in carti-laginous fish IgMmay not be the primordial immunoglobulinrdquoEuropean Journal of Immunology vol 26 no 5 pp 1123ndash11291996

[20] H Dooley and M F Flajnik ldquoShark immunity bites back affin-ity maturation and memory response in the nurse shark Ging-lymostoma cirratumrdquo European Journal of Immunology vol 35no 3 pp 936ndash945 2005

[21] S F Schluter R M Bernstein and J J Marchalonis ldquoMolecularorigins and evolution of immunoglobulin heavy-chain genes ofjawed vertebratesrdquo Immunology Today vol 18 no 11 pp 543ndash549 1997

[22] Y Ohta and M Flajnik ldquoIgD like IgM is a primordial immu-noglobulin class perpetuated in most jawed vertebratesrdquo Pro-ceedings of the National Academy of Sciences of the United Statesof America vol 103 no 28 pp 10723ndash10728 2006

[23] S Fillatreau A Six S Magadan R Castro J O Sunyer andP Boudinot ldquoThe astonishing diversity of Ig classes and B cellrepertoires in teleost fishrdquo Frontiers in Immunology vol 4 no28 2013

[24] W Harriman H Volk N Defranoux and M Wabl ldquoImmu-noglobulin class switch recombinationrdquo Annual Review ofImmunology vol 11 pp 361ndash384 1993

[25] J Stavnezer and C T Amemiya ldquoEvolution of isotype switch-ingrdquo Seminars in Immunology vol 16 no 4 pp 257ndash275 2004

[26] V M Barreto Q Pan-Hammarstrom Y Zhao L Ham-marstrom Z Misulovin and M C Nussenzweig ldquoAID frombony fish catalyzes class switch recombinationrdquo Journal ofExperimental Medicine vol 202 no 6 pp 733ndash738 2005

[27] T C Fletcher and AWhite ldquoAntibody production in the plaice(Pleuronectes platessa L) after oral and parenteral immuniza-tion with Vibrio anguillarum antigensrdquo Aquaculture vol 1 pp417ndash428 1972

[28] J W H M Rombout L J Blok C H J Lamers and E EgbertsldquoImmunization of carp (Cyprinus carpio) with a Vibrio anguil-larum bacterin indications for a common mucosal immunesystemrdquo Developmental and Comparative Immunology vol 10no 3 pp 341ndash351 1986

[29] U Georgopoulou and J-M Vernier ldquoLocal immunologicalresponse in the posterior intestinal segment of the rainbowtrout after oral administration of macromoleculesrdquo Develop-mental andComparative Immunology vol 10 no 4 pp 529ndash5371986

[30] C J Lobb ldquoSecretory immunity induced in catfish Ictaluruspunctatus following bath immunizationrdquo Developmental andComparative Immunology vol 11 no 4 pp 727ndash738 1987

[31] J D Hansen E D Landis and R B Phillips ldquoDiscovery ofa unique Ig heavy-chain (IgT) in rainbow trout implicationsfor a distinctive B cell developmental pathway in teleost fishrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 102 no 19 pp 6919ndash6924 2005

[32] N Danilova J Bussmann K Jekosch and L A Steiner ldquoTheimmunoglobulin heavy-chain locus in zebrafish identificationand expression of a previously unknown isotype immunoglob-ulin Zrdquo Nature Immunology vol 6 no 3 pp 295ndash302 2005

[33] R Savan A Aman K Sato R Yamaguchi and M Sakai ldquoDis-covery of a new class of immunoglobulin heavy chain fromfugurdquo European Journal of Immunology vol 35 no 11 pp 3320ndash3331 2005

[34] R Savan A AmanMNakao HWatanuki andM Sakai ldquoDis-covery of a novel immunoglobulin heavy chain gene chimerafrom common carp (Cyprinus carpio L)rdquo Immunogenetics vol57 no 6 pp 458ndash463 2005

[35] F Gambon-Deza C Sanchez-Espinel and S Magadan-Mompo ldquoPresence of an unique IgT on the IGH locus in three-spined stickleback fish (Gasterosteus aculeatus) and the veryrecent generation of a repertoire of VH genesrdquo Developmentaland Comparative Immunology vol 34 no 2 pp 114ndash122 2010

[36] T M Tadiso K K Lie and I Hordvik ldquoMolecular cloning ofIgT fromAtlantic salmon and analysis of the relative expression

16 ISRN Immunology

of 120591 120583 and 120575 in different tissuesrdquo Veterinary Immunology andImmunopathology vol 139 no 1 pp 17ndash26 2011

[37] S Mashoof C Pohlenz P L Chen et al ldquoExpressed IgH 120583and 120591 transcripts share diversity segment in ranched Thunnusorientalisrdquo Developmental and Comparative Immunology vol43 no 1 pp 76ndash86 2014

[38] Y-A Zhang I Salinas J Li et al ldquoIgT a primitive immunoglob-ulin class specialized in mucosal immunityrdquo Nature Immunol-ogy vol 11 no 9 pp 827ndash835 2010

[39] S Magadan-Mompo C Sanchez-Espinel and F Gambon-Deza ldquoImmunoglobulin heavy chains in medaka (Oryziaslatipes)rdquo BMC Evolutionary Biology vol 11 no 1 article 1652011

[40] C T Amemiya J Alfoldi A P Lee et al ldquoThe African coela-canth genome provides insights into tetrapod evolutionrdquoNature vol 496 no 7445 pp 311ndash316 2013

[41] T Ota J P Rast G W Litman and C T Amemiya ldquoLineage-restricted retention of a primitive immunoglobulin heavy chainisotype within the Dipnoi reveals an evolutionary paradoxrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 100 no 5 pp 2501ndash2506 2003

[42] Y Sun Z Wei N Li and Y Zhao ldquoA comparative overview ofimmunoglobulin genes and the generation of their diversity intetrapodsrdquo Developmental and Comparative Immunology vol39 no 1-2 pp 103ndash109 2013

[43] I Hadji-Azimi ldquoAnuran immunoglobulins a reviewrdquo Develop-mental and Comparative Immunology vol 3 no 2 pp 223ndash2431979

[44] E Hsu M F Flajnik and L du Pasquier ldquoA third immunoglob-ulin class in amphibiansrdquo The Journal of Immunology vol 135no 3 pp 1998ndash2004 1985

[45] C T Amemiya R N Haire and G W Litman ldquoNucleotidesequence of a cDNA encoding a third distinct Xenopusimmunoglobulin heavy chain isotyperdquo Nucleic Acids Researchvol 17 no 13 p 5388 1989

[46] R Muszligmann M Wilson A Marcuz M Courtet and L duPasquier ldquoMembrane exon sequences of the three Xenopus Igclasses explain the evolutionary origin of mammalian isotypesrdquoEuropean Journal of Immunology vol 26 no 2 pp 409ndash4141996

[47] R Muszligmann L du Pasquier and E Hsu ldquoIs Xenopus IgX ananalog of IgArdquo European Journal of Immunology vol 26 no12 pp 2823ndash2830 1996

[48] B Schaerlinger and J-P Frippiat ldquoIgX antibodies in the urodeleamphibian Ambystoma mexicanumrdquo Developmental and Com-parative Immunology vol 32 no 8 pp 908ndash915 2008

[49] B Schaerlinger M Bascove and J-P Frippiat ldquoA new isotypeof immunoglobulin heavy chain in the urodele amphibianPleurodeles waltl predominantly expressed in larvaerdquoMolecularImmunology vol 45 no 3 pp 776ndash786 2008

[50] S Mashoof A Goodroe C C Du et al ldquoAncient T-independence of mucosal IgXA gut microbiota unaffected bylarval thymectomy in Xenopus laevisrdquo Mucosal Immunologyvol 6 no 2 pp 358ndash368 2013

[51] J P Vaerman J Picard and J F Heremans ldquoStructural dataon chicken IgA and failure to identify the IgA of the tortoiserdquoin Immunologic Phylogeny vol 64 of Advances in ExperimentalMedicine and Biology pp 185ndash195 Springer New York NYUSA 1975

[52] J L Portis and J E Coe ldquoIgM the secretory immunoglobulinof reptiles and amphibiansrdquo Nature vol 258 no 5535 pp 547ndash548 1975

[53] J E Coe D Leong J L Portis and L A Thomas ldquoImmuneresponse in the garter snake (Thamnophis ordinoides)rdquo Immu-nology vol 31 no 3 pp 417ndash424 1976

[54] D Hadge and H Ambrosius ldquoEvolution of low molecularweight immunoglobulinsmdashIV IgY-like immunoglobulins ofbirds reptiles and amphibians precursors of mammalian IgArdquoMolecular Immunology vol 21 no 8 pp 699ndash707 1984

[55] D Hadge and H Ambrosius ldquoEvolution of low molecularweight immunoglobulins V Degree of antigenic relationshipbetween the 7S immunoglobulins ofmammals birds and lowervertebrates to the turkey IgYrdquo Developmental and ComparativeImmunology vol 10 no 3 pp 377ndash385 1986

[56] S Magadan-Mompo C Sanchez-Espinel and F Gambon-Deza ldquoImmunoglobulin genes of the turtlesrdquo Immunogeneticsvol 65 no 3 pp 227ndash237 2013

[57] Z Wei Q Wu L Ren et al ldquoExpression of IgM IgD and IgYin a reptile Anolis carolinensisrdquoThe Journal of Immunology vol183 no 6 pp 3858ndash3864 2009

[58] F Gambon-Deza C Sanchez-Espinel and J V Beneitez ldquoAnovel IgA-like immunoglobulin in the reptile Eublepharis mac-ulariusrdquo Developmental and Comparative Immunology vol 31no 6 pp 596ndash605 2007

[59] G Cheng Y Gao T Wang et al ldquoExtensive diversification ofIgH subclass-encoding genes and IgM subclass switching incrocodiliansrdquo Nature Communications vol 4 article 1337 2013

[60] S Magadan-Mompo C Sanchez-Espinel and F Gambon-Deza ldquoIgH loci of American alligator and saltwater crocodileshed light on IgA evolutionrdquo Immunogenetics vol 65 no 7 pp531ndash541 2013

[61] E Orlans and M E Rose ldquoAn IgA-like immunoglobulin in thefowlrdquo Immunochemistry vol 9 no 8 pp 833ndash838 1972

[62] G A Leslie and L N Martin ldquoStudies on the secretory immu-nologic system of fowl 3 Serum and secretory IgA of thechickenrdquoThe Journal of Immunology vol 110 no 1 pp 1ndash9 1973

[63] J Bienenstock D Y Perey J Gauldie and B J UnderdownldquoChicken 120574A physicochemical and immunochemical charac-teristicsrdquoThe Journal of Immunology vol 110 no 2 pp 524ndash5331973

[64] A M Lebacq-Verheyden J P Vaerman and J F HeremansldquoQuantification and distribution of chicken immunoglobulinsIgA IgM and IgG in serum and secretionsrdquo Immunology vol27 no 4 pp 683ndash692 1974

[65] J Goudswaard A Noordzij R H van Dam J A vanderDonk and J P Vaerman ldquoThe immunoglobulins of the turkey(Meleagris gallopavo) Isolation and characterization of IgGIgM and IgA in body fluids eggs and intraocular tissuesrdquoPoultry science vol 56 no 6 pp 1847ndash1851 1977

[66] D Hadge and H Ambrosius ldquoComparative studies on thestructure of biliary immunoglobulins of some avian speciesII Antigenic properties of the biliary immunoglobulins ofchicken turkey duck and gooserdquo Developmental and Compar-ative Immunology vol 12 no 2 pp 319ndash329 1988

[67] J Goudswaard J P Vaerman and J F Heremans ldquoThreeimmunoglobulin classes in the pigeon (Columbia livia)rdquo Inter-national Archives of Allergy andApplied Immunology vol 53 no5 pp 409ndash419 1977

[68] P L K Ng and D A Higgins ldquoBile immunoglobulin of theduck (Anas platyrhynchos) I Preliminary characterization andontogenyrdquo Immunology vol 58 no 2 pp 323ndash327 1986

[69] K E Magor G W Warr Y Bando D L Middleton and DA Higgins ldquoSecretory immune system of the duck (Anas

ISRN Immunology 17

platyrhynchos) Identification and expression of the genesencoding IgA and IgM heavy chainsrdquo European Journal ofImmunology vol 28 no 3 pp 1063ndash1068 1998

[70] Y Zhao H Rabbani A Shimizu and L Hammarstrom ldquoMap-ping of the chicken immunoglobulin heavy-chain constantregion gene locus reveals an inverted 120572 gene upstream of acondensed 120592 generdquo Immunology vol 101 no 3 pp 348ndash3532000

[71] M L Lundqvist D L Middleton S Hazard and G W WarrldquoThe immunoglobulin heavy chain locus of the duck genomicorganization and expression of D J and C region genesrdquo TheJournal of Biological Chemistry vol 276 no 50 pp 46729ndash46736 2001

[72] T HuangM Zhang ZWei et al ldquoAnalysis of immunoglobulintranscripts in the ostrich Struthio camelus a primitive avianspeciesrdquo PLoS ONE vol 7 no 3 Article ID e34346 2012

[73] K H Roux ldquoImmunoglobulin structure and function asrevealed by electron microscopyrdquo International Archives ofAllergy and Immunology vol 120 no 2 pp 85ndash99 1999

[74] F Gambon-Deza C Sanchez-Espinel and S Magadan-Mompo ldquoThe immunoglobulin heavy chain locus in the platy-pus (Ornithorhynchus anatinus)rdquo Molecular Immunology vol46 no 13 pp 2515ndash2523 2009

[75] Y Zhao H Cui C M Whittington et al ldquoOrnithorhynchusanatinus (platypus) links the evolution of immunoglobulingenes in eutherian mammals and nonmammalian tetrapodsrdquoThe Journal of Immunology vol 183 no 5 pp 3285ndash3293 2009

[76] M Aveskogh and L Hellman ldquoEvidence for an early appear-ance of modern post-switch isotypes in mammalian evolutioncloning of IgE IgG and IgA from the marsupial Monodelphisdomesticardquo European Journal of Immunology vol 28 no 9 pp2738ndash2750 1998

[77] K Belov G A Harrison and DW Cooper ldquoMolecular cloningof the cDNA encoding the constant region of the immunoglob-ulin a heavy chain (C120572) from amarsupialTrichosurus vulpecula(common brushtail possum)rdquo Immunology Letters vol 60 no2-3 pp 165ndash170 1998

[78] K Belov K R Zenger L Hellman and DW Cooper ldquoEchidnaIgA supports mammalian unity and traditional Therian rela-tionshiprdquo Mammalian Genome vol 13 no 11 pp 656ndash6632002

[79] K Belov and L Hellman ldquoImmunoglobulin genetics of Orni-thorhynchus anatinus (platypus) and Tachyglossus aculeatus(short-beaked echidna)rdquo Comparative Biochemistry and Phys-iology vol 136 no 4 pp 811ndash819 2003

[80] M VernerssonM Aveskogh BMunday and L Hellman ldquoEvi-dence for an early appearance of modern post-switch immu-noglobulin isotypes in mammalian evolution (II) cloning ofIgE IgG1 and IgG2 fromamonotreme the duck-billed platypusOrnithorhynchus anatinusrdquo European Journal of Immunologyvol 32 no 8 pp 2145ndash2155 2002

[81] C Auffray R Nageotte and J L Sikorav ldquoMouse immunoglob-ulin A nucleotide sequence of the structural gene for the 120572heavy chain derived from cloned cDNAsrdquo Gene vol 13 no 4pp 365ndash374 1981

[82] T Ukaji D Sumiyama and O Kai ldquoSequence determinationof the heavy-chain constant region in four immunoglobulinclasses of Mongolian gerbils (Meriones unguiculatus)rdquo Experi-mental Animals vol 61 no 2 pp 99ndash107 2012

[83] R C Burnett W C Hanly S K Zhai and K L Knight ldquoTheIgA heavy chain gene family in rabbit cloning and sequence

analysis of 13 C120572 genesrdquo The EMBO Journal vol 8 no 13 pp4041ndash4047 1989

[84] D K Lanning S-K Zhai and K L Knight ldquoAnalysis of the 31015840C120583 region of the rabbit Ig heavy chain locusrdquoGene vol 309 no2 pp 135ndash144 2003

[85] F Ros J Puels N Reichenberger W van Schooten R Buelowand J Platzer ldquoSequence analysis of 05Mb of the rabbitgermline immunoglobulin heavy chain locusrdquo Gene vol 330no 1-2 pp 49ndash59 2004

[86] M Patel D Selinger G E Mark G J Hickey and G FHollis ldquoSequence of the dog immunoglobulin alpha and epsilonconstant region genesrdquo Immunogenetics vol 41 no 5 pp 282ndash286 1995

[87] Z Zhao Y Zhao Q Pan-Hammarstrom et al ldquoPhysical map-ping of the giant panda immunoglobulin heavy chain constantregion genesrdquo Developmental and Comparative Immunologyvol 31 no 10 pp 1034ndash1049 2007

[88] W R Brown and J E Butler ldquoCharacterization of a C120572 gene ofswinerdquoMolecular Immunology vol 31 no 8 pp 633ndash642 1994

[89] W R Brown H Rabbani J E Butler and L HammarstromldquoCharacterization of the bovine C120572 generdquo Immunology vol 91no 1 pp 1ndash6 1997

[90] G PWhite P Roche M R Brandon S E Newton and E N TMeeusen ldquoCloning and characterization of sheep (Ovis aries)immunoglobulin 120572 chainrdquo Immunogenetics vol 48 no 5 pp359ndash362 1998

[91] AMancia T A Romano H A Gefroh et al ldquoCharacterizationof the immunoglobulin A heavy chain gene of the Atlantic bot-tlenose dolphin (Tursiops truncatus)rdquo Veterinary Immunologyand Immunopathology vol 118 no 3-4 pp 304ndash309 2007

[92] B Wagner I Greiser-Wilke and D F Antczak ldquoCharacteriza-tion of the horse [Equus caballus] IGHA generdquo Immunogeneticsvol 55 no 8 pp 552ndash560 2003

[93] N Takahashi S Ueda and M Obata ldquoStructure of humanimmunoglobulin gamma genes implications for evolution of agene familyrdquo Cell vol 29 no 2 pp 671ndash679 1982

[94] J G Flanagan M-P Lefranc and T H Rabbitts ldquoMechanismsof divergence and convergence of the human immunoglobulin1205721 and 1205722 constant region gene sequencesrdquo Cell vol 36 no 3pp 681ndash688 1984

[95] S Kawamura K Omoto and S Ueda ldquoEvolutionary hypervari-ability in the hinge region of the immunoglobulin alpha generdquoJournal of Molecular Biology vol 215 no 2 pp 201ndash206 1990

[96] F Scinicariello F Masseoud L Jayashankar and R AttanasioldquoSooty mangabey (Cercocebus torquatus atys) IGHG and IGHAgenesrdquo Immunogenetics vol 58 no 12 pp 955ndash965 2006

[97] K A Rogers L Jayashankar F Scinicariello and R AttanasioldquoNonhuman primate IgA genetic heterogeneity and interac-tions with CD89rdquoThe Journal of Immunology vol 180 no 7 pp4816ndash4824 2008

[98] S Kawamura N Saitou and S Ueda ldquoConcerted evolution ofthe primate immunoglobulin 120572-gene through gene conversionrdquoThe Journal of Biological Chemistry vol 267 no 11 pp 7359ndash7367 1992

[99] S Kawamura and S Ueda ldquoImmunoglobulin C119867gene family in

hominoids and its evolutionary historyrdquo Genomics vol 13 no1 pp 194ndash200 1992

[100] A Brusco U Cariota A Bottaro et al ldquoStructural andimmunologic analysis of gene triplications in the Ig heavy chainconstant region locusrdquoThe Journal of Immunology vol 152 no1 pp 129ndash135 1994

18 ISRN Immunology

[101] H Rabbani Q Pan N Kondo C I E Smith and L Ham-marstrom ldquoDuplications and deletions of the human IGHClocus evolutionary implicationsrdquo Immunogenetics vol 45 no2 pp 136ndash141 1996

[102] P F Weinheimer J Mestecky and R T Acton ldquoSpecies distri-bution of J chainrdquoThe Journal of Immunology vol 107 no 4 pp1211ndash1212 1971

[103] F P Inman and J Mestecky ldquoThe J chain of polymeric immu-noglobulinsrdquo inContemporary Topics inMolecular Immunologyvol 3 pp 111ndash141 Springer New York NY USA 1974

[104] P Brandtzaeg ldquoPresence of J chain in human immunocytescontaining various immunoglobulin classesrdquo Nature vol 252no 5482 pp 418ndash420 1974

[105] L Tacchi E Larragoite and I Salinas ldquoDiscovery of J chain inAfrican lungfish (Protopterus dolloi Sarcopterygii) using highthroughput transcriptome sequencing implications in mucosalimmunityrdquo PLoS ONE vol 8 no 8 Article ID e70650 2013

[106] I K Zarkadis D Mastellos and J D Lambris ldquoPhylogeneticaspects of the complement systemrdquo Developmental and Com-parative Immunology vol 25 no 8-9 pp 745ndash762 2001

[107] A P West Jr A B Herr and P J Bjorkman ldquoThe chickenyolk sac IgY receptor a functional equivalent of themammalianMHC-related Fc receptor is a phospholipase A

2receptor

homologrdquo Immunity vol 20 no 5 pp 601ndash610 2004[108] D B Tesar E J Cheung and P J Bjorkman ldquoThe chicken

yolk sac IgY receptor a mammalian mannose receptor familymember transcytoses IgY across polarized epithelial cellsrdquoMolecular Biology of the Cell vol 19 no 4 pp 1587ndash1593 2008

[109] A I Taylor R L Beavil B J Sutton and R A Calvert ldquoAmonomeric chicken IgY receptor binds IgY with 21 stoichiom-etryrdquo The Journal of Biological Chemistry vol 284 no 36 pp24168ndash24175 2009

[110] K Baker S-W Qiao T Kuo et al ldquoImmune and non-immunefunctions of the (not so) neonatal Fc receptor FcRnrdquo Seminarsin Immunopathology vol 31 no 2 pp 223ndash236 2009

[111] K Baker R S Blumberg and C S Kaetzel ldquoImmunoglob-ulin transport and immunoglobulin receptorsrdquo in MucosalImmunology J Mestecky W Strober H Cheroutre B KelsallB N Lambrecht andMW Russell Eds chapter 20 AcademicPressElsevier Waltham Mass USA 2014

[112] C S Kaetzel ldquoThepolymeric immunoglobulin receptorrdquo in eLSJohn Wiley amp Sons Chichester UK 2013

[113] N J Mantis N Rol and B Corthesy ldquoSecretory IgArsquos complexroles in immunity andmucosal homeostasis in the gutrdquoMucosalImmunology vol 4 no 6 pp 603ndash611 2011

[114] J V Peppard M E Rose and P Hesketh ldquoA functional homo-logue of mammalian secretory component exists in chickensrdquoEuropean Journal of Immunology vol 13 no 7 pp 566ndash5701983

[115] K E Mostov M Friedlander and G Blobel ldquoThe receptorfor transepithelial transport of IgA and IgM contains multipleimmunoglobulin-like domainsrdquo Nature vol 308 no 5954 pp37ndash43 1984

[116] P Krajci R Solberg M Sandberg O Oyen T Jahnsen and PBrandtzaeg ldquoMolecular cloning of the human transmembranesecretory component (poly-Ig receptor) and its mRNA expres-sion in human tissuesrdquo Biochemical and Biophysical ResearchCommunications vol 158 no 3 pp 783ndash789 1989

[117] P Krajci D Kvale K Tasken and P Brandtzaeg ldquoMolecularcloning and exon-intron mapping of the gene encoding humantransmembrane secretory component (the poly-Ig receptor)rdquo

European Journal of Immunology vol 22 no 9 pp 2309ndash23151992

[118] J F Piskurich J A France C M Tamer C A Willmer CS Kaetzel and D M Kaetzel ldquoInterferon-120574 induces polymericimmunoglobulin receptormRNA in human intestinal epithelialcells by a protein synthesis dependent mechanismrdquo MolecularImmunology vol 30 no 4 pp 413ndash421 1993

[119] J F Piskurich M H Blanchard K R Youngman J A Franceand C S Kaetzel ldquoMolecular cloning of the mouse polymericIg receptor functional regions of the molecule are conservedamong five mammalian speciesrdquo The Journal of Immunologyvol 154 no 4 pp 1735ndash1747 1995

[120] M A Kulseth P Krajci O Myklebost and S RogneldquoCloning and characterization of two forms of bovine polymericimmunoglobulin receptor cDNArdquo DNA and Cell Biology vol14 no 3 pp 251ndash256 1995

[121] K S Koch A S Gleiberman T Aoki et al ldquoDiscordant expres-sion and variable numbers of neighboring GGA- and GAA-richtriplet repeats in the 31015840 untranslated regions of two groups ofmessenger RNAs encoded by the rat polymeric immunoglob-ulin receptor generdquo Nucleic Acids Research vol 23 no 7 pp1098ndash1112 1995

[122] F M Adamski and J Demmer ldquoTwo stages of increased IgAtransfer during lactation in themarsupialTrichosurus vulpecula(brushtail possum)rdquoThe Journal of Immunology vol 162 no 10pp 6009ndash6015 1999

[123] H Kumura T Sone K-I Shimazaki and E KobayashildquoSequence analysis of porcine polymeric immunoglobulinreceptor from mammary epithelial cells present in colostrumrdquoThe Journal of Dairy Research vol 67 no 4 pp 631ndash636 2000

[124] C L Taylor G A Harrison C M Watson and E M DeaneldquocDNA cloning of the polymeric immunoglobulin receptor ofthe marsupial Macropus eugenii (tammar wallaby)rdquo EuropeanJournal of Immunogenetics vol 29 no 2 pp 87ndash93 2002

[125] R Braathen V S Hohman P Brandtzaeg and F-E JohansenldquoSecretory antibody formation conserved binding interactionsbetween J chain and polymeric Ig receptor from humans andamphibiansrdquo The Journal of Immunology vol 178 no 3 pp1589ndash1597 2007

[126] M J Lewis BWagner R M Irvine and J MWoof ldquoIgA in thehorse cloning of equine polymeric Ig receptor and J chain andcharacterization of recombinant forms of equine IgArdquoMucosalImmunology vol 3 no 6 pp 610ndash621 2010

[127] A J Leon D Banner L Xu et al ldquoSequencing annotation andcharacterization of the influenza ferret infectomerdquo Journal ofVirology vol 87 no 4 pp 1957ndash1966 2013

[128] W H Wieland D Orzaez A Lammers H K ParmentierM W A Verstegen and A Schots ldquoA functional polymericimmunoglobulin receptor in chicken (Gallus gallus) indicatesancient role of secretory IgA inmucosal immunityrdquoBiochemicalJournal vol 380 no 3 pp 669ndash676 2004

[129] K Hamuro H Suetake N R Saha K Kikuchi and YSuzuki ldquoA teleost polymeric Ig receptor exhibiting two Ig-likedomains transports tetrameric IgM into the skinrdquo The Journalof Immunology vol 178 no 9 pp 5682ndash5689 2007

[130] J H W M Rombout S J L van der Tuin G Yang et alldquoExpression of the polymeric immunoglobulin receptor (pIgR)in mucosal tissues of common carp (Cyprinus carpio L)rdquo Fishand Shellfish Immunology vol 24 no 5 pp 620ndash628 2008

[131] L-N Feng D-Q Lu J-X Bei et al ldquoMolecular cloning andfunctional analysis of polymeric immunoglobulin receptor gene

ISRN Immunology 19

in orange-spotted grouper (Epinephelus coioides)rdquo ComparativeBiochemistry and Physiology B vol 154 no 3 pp 282ndash289 2009

[132] A E Oslashstergaard S A M Martin T Wang R J M Stet andC J Secombes ldquoRainbow trout (Oncorhynchus mykiss) pos-sessmultiple novel immunoglobulin-like transcripts containingeither an ITAM or ITIMsrdquo Developmental and ComparativeImmunology vol 33 no 4 pp 525ndash532 2009

[133] H Eiffert E Quentin and J Decker ldquoThe primary structureof the human free secretory component and the arrangementof disulfide bondsrdquo Hoppe-Seylerrsquos Zeitschrift fur PhysiologischeChemie vol 365 no 12 pp 1489ndash1495 1984

[134] E Fallgreen-Gebauer W Gebauer A Bastian et al ldquoThe cova-lent linkage of secretory component to IgA Structure of sIgArdquoBiological Chemistry Hoppe-Seyler vol 374 no 11 pp 1023ndash1028 1993

[135] J MWoof ldquoThe structure of IgArdquo inMucosal Immune DefenseImmunoglobulin A C S Kaetzel Ed chapter 1 pp 1ndash24Springer New York NY USA 2007

[136] A Bonner A Almogren P B Furtado M A Kerr and S JPerkins ldquoLocation of secretory component on the Fc edge ofdimeric IgA1 reveals insight into the role of secretory IgA1 inmucosal immunityrdquoMucosal Immunology vol 2 no 1 pp 74ndash84 2009

[137] A Bonner A Almogren P B Furtado M A Kerr and S JPerkins ldquoThe nonplanar secretory IgA2 and near planar secre-tory IgA1 solution structures rationalize their different mucosalimmune responsesrdquo The Journal of Biological Chemistry vol284 no 8 pp 5077ndash5087 2009

[138] J Johansen B Braathen and P Brandtzaeg ldquoRole of J chain insecretory immunoglobulin formationrdquo Scandinavian Journal ofImmunology vol 52 no 3 pp 240ndash248 2000

[139] B A Hendrickson D A Conner D J Ladd et al ldquoAlteredhepatic transport of immunoglobulin A in mice lacking the Jchainrdquo Journal of Experimental Medicine vol 182 no 6 pp1905ndash1911 1995

[140] B A Hendrickson L Rindisbacher B Corthesy et al ldquoLackof association of secretory component with IgA in J chain-deficient micerdquo The Journal of Immunology vol 157 no 2 pp750ndash754 1996

[141] N Lycke L Erlandsson L Ekman K Schon and T Lean-derson ldquoLack of J chain inhibits the transport of gut IgA andabrogates the development of intestinal antitoxic protectionrdquoThe Journal of Immunology vol 163 no 2 pp 913ndash919 1999

[142] F-E Johansen R Braathen and P Brandtzaeg ldquoThe J chainis essential for polymeric Ig receptor-mediated epithelial trans-port of IgArdquoThe Journal of Immunology vol 167 no 9 pp 5185ndash5192 2001

[143] R E Ley D A Peterson and J I Gordon ldquoEcological andevolutionary forces shaping microbial diversity in the humanintestinerdquo Cell vol 124 no 4 pp 837ndash848 2006

[144] M McFall-Ngai ldquoAdaptive immunity care for the communityrdquoNature vol 445 no 7124 p 153 2007

[145] A J Macpherson K D McCoy F-E Johansen and PBrandtzaeg ldquoThe immune geography of IgA induction andfunctionrdquoMucosal Immunology vol 1 no 1 pp 11ndash22 2008

[146] D Kvale and P Brandtzaeg ldquoConstitutive and cytokine inducedexpression of HLA molecules secretory component and inter-cellular adhesion molecule-1 is modulated by butyrate in thecolonic epithelial cell line HT-29rdquo Gut vol 36 no 5 pp 737ndash742 1995

[147] L VHooperMHWong AThelin L Hansson P G Falk andJ I Gordon ldquoMolecular analysis of commensal host-microbialrelationships in the intestinerdquo Science vol 291 no 5505 pp 881ndash884 2001

[148] S Hapfelmeier M A E Lawson E Slack et al ldquoReversiblemicrobial colonization of germ-free mice reveals the dynamicsof IgA immune responsesrdquo Science vol 328 no 5986 pp 1705ndash1709 2010

[149] DH ReikvamMDerrien R Islam et al ldquoEpithelial-microbialcross-talk in polymeric Ig receptor deficient micerdquo EuropeanJournal of Immunology vol 42 no 11 pp 2959ndash2970 2012

[150] EW Rogier A L Frantz M E C Bruno et al ldquoSecretory anti-bodies in breast milk promote long-term intestinal homeostasisby regulating the gut microbiota and host gene expressionrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 111 no 8 pp 3074ndash3079 2014

[151] G M Barton and R Medzhitov ldquoToll-like receptor signalingpathwaysrdquo Science vol 300 no 5625 pp 1524ndash1525 2003

[152] K Takeda and S Akira ldquoToll receptors and pathogen resis-tancerdquo Cellular Microbiology vol 5 no 3 pp 143ndash153 2003

[153] E Cario andD K Podolsky ldquoDifferential alteration in intestinalepithelial cell expression of Toll-like receptor 3 (TLR3) andTLR4 in inflammatory bowel diseaserdquo Infection and Immunityvol 68 no 12 pp 7010ndash7017 2000

[154] M Hausmann S Kiessling S Mestermann et al ldquoToll-likereceptors 2 and 4 are up-regulated during intestinal inflamma-tionrdquo Gastroenterology vol 122 no 7 pp 1987ndash2000 2002

[155] M T Abreu L S Thomas S Y Tesfay et al ldquoRegulation ofTLR4 and MD-2 in the intestinal epithelium evidence for dys-regulated LPS signaling in human inflammatory bowel diseaserdquoin Proceedings of the 90th Annual Meeting of the AmericanAssociation for Immunologists Abstract 3634 Denver ColoUSA 2003

[156] T A Schneeman M E C Bruno H Schjerven F-E JohansenL Chady and C S Kaetzel ldquoRegulation of the polymeric Igreceptor by signaling through TLRs 3 and 4 linking innate andadaptive immune responsesrdquo The Journal of Immunology vol175 no 1 pp 376ndash384 2005

[157] M E C Bruno A L Frantz E W Rogier F-E Johansen andC S Kaetzel ldquoRegulation of the polymeric immunoglobulinreceptor by the classical and alternative NF-120581B pathways inintestinal epithelial cellsrdquoMucosal Immunology vol 4 no 4 pp468ndash478 2011

[158] M E C Bruno E W Rogier A L Frantz A T Stefka SN Thompson and C S Kaetzel ldquoRegulation of the poly-meric immunoglobulin receptor in intestinal epithelial cellsby Enterobacteriaceae implications for mucosal homeostasisrdquoImmunological Investigations vol 39 no 4-5 pp 356ndash382 2010

[159] A L Frantz E W Rogier C R Weber et al ldquoTargeted deletionof MyD88 in intestinal epithelial cells results in compromisedantibacterial immunity associatedwith downregulation of poly-meric immunoglobulin receptor mucin-2 and antibacterialpeptidesrdquoMucosal Immunology vol 5 no 5 pp 501ndash512 2012

[160] E W Rogier A L Frantz M E C Bruno and C S KaetzelldquoSecretory IgA is concentrated in the outer layer of intestinalmucus along with gut bacteriardquo Pathogens In press

[161] M B Geuking K D McCoy and A J Macpherson ldquoThe func-tion of secretory IgA in the context of the intestinal continuumof adaptive immune responses in host-microbial mutualismrdquoSeminars in Immunology vol 24 no 1 pp 36ndash42 2012

20 ISRN Immunology

[162] L VHooper D R Littman andA JMacpherson ldquoInteractionsbetween the microbiota and the immune systemrdquo Science vol336 no 6086 pp 1268ndash1273 2012

[163] A J Macpherson M B Geuking E Slack S Hapfelmeierand K D McCoy ldquoThe habitat double life citizenship andforgetfulness of IgArdquo Immunological Reviews vol 245 no 1 pp132ndash146 2012

Submit your manuscripts athttpwwwhindawicom

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

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BioMed Research International

OncologyJournal of

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Oxidative Medicine and Cellular Longevity

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PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

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Research and TreatmentAIDS

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Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

ISRN Immunology 5

suggesting that these Ig isotypes may have emerged in acommon ancestor of amphibians To date no studies havebeen reported on IGH loci in caecilians A recent study inXenopus laevis established the position of amphibian IgX asthe evolutionary precursor of IgA in birds and mammals[50] These investigators found that larval thymectomy didnot affect levels of IgX and did not alter the compositionof the gut microbiota confirming the T-independence ofthe IgX response in Xenopus Phylogenetic comparisons ofIgT in bony fishes and IgX in amphibians suggest that theseIg isotypes evolved independently [23] likely responding tosimilar pressures from the resident microbiota and mucosalpathogens

24 Reptiles and Birds The clade Amniota within the super-class Tetrapoda can be subdivided into the sauropsids (rep-tiles and birds) and synapsids (mammals and their closerelatives) (Figure 1) The distinction between reptiles andbirds is based largely on physical characteristics rather thanphylogeny distinguishing the cold-blooded reptiles withscales from the warm-blooded birds with feathers Earlystudies of Igs in turtles lizards and snakes were basedlargely on their physicochemical and antigenic propertiesrevealing a predominance of IgM and lesser amounts of IgYin bile and gut secretions [51ndash53] Subsequent analyses usingantibodies to chicken IgA failed to detect a cross-reactive Igisotype in reptiles [54 55] The recent availability of wholegenome sequences for 2 species of turtles (Chrysemys pictaand Pelodiscus sinensis) [36 56] and the green anole lizard(Anolis carolinensis) [57] demonstrated the presence of genesegments encoding IgM IgD and multiple subclasses ofIgY but no ortholog of IgX in amphibians or IgA in birdsand mammals The leopard gecko (Eublepharis macularius)expresses IgM IgD and a third Ig isotype that is intermediatein homology between IgA and IgY [50 58] (designatedIgldquoArdquo for the purposes of this review) The recent availabilityof whole genome sequences for 4 crocodilians (Alligatorsinensis Alligator mississippiensis Crocodylus siamensis andCrocodylus porosus) revealed significant differences in theIGH loci compared to other reptiles including multiple sub-classes of IgM IgD and IgA (orthologous to the IgA genes ofbirds and mammals) but no IgY [59 60] Early studies of theimmune systems of birds (class Aves) revealed the presenceof an ortholog of mammalian IgA in mucosal secretionsand an ortholog of IgG (designated IgY) in serum [61ndash69]Mapping of the IGH locus in chickens and ducks revealed aninverted gene segment encoding IgA downstream of the IgMgene segment and upstream of the IgY gene segment andloss of the gene segment encoding IgD [70 71] Availabilityof whole genome sequences for a variety of bird species inthe National Center for Biotechnology Information (NCBI)database demonstrates the consistent presence of IgM IgAand IgY and the absence of IgD A recent analysis of Iggene transcripts in the ostrich (Struthio camelus) revealedsimilarities with chickens ducks and other birds includingthe expression of IgM IgA and IgY and the absence of IgD[72] Because the ostrich is one of the most primitive extantspecies of birds it appears that the distinctive organization

of the IGH locus evolved very early during the divergence ofthe avian lineage Furthermore a phylogenetic comparisonof Ig heavy chain sequences from amphibians with those ofhigher vertebrates demonstrated with high statistical supportthat IgX from amphibians and IgA from birds share arecent common ancestor [50] Taken together the evidenceis consistent with an IGH locus in a common ancestor ofreptiles and birds that included gene segments encoding IgMIgD IgA and IgY Instability in the IGH locus in individuallineages apparently resulted in the selective loss of IgA inmostturtles lizards and snakes IgY in crocodilians and IgD inbirds

25 Mammals The structure of Ig genes and their encodedproteins has been studied extensively in extant species of theclass Mammalia including the egg-laying monotremes thepouch-bearing marsupials and the placentals (eutherians)(reviewed in [8]) The IGH locus in all known mammalsis organized as a translocon with gene segments encodingIgM IgD 2 or more subclasses of IgG 1 or more subclassesof IgA and IgE an isotype unique to mammals (Figure 1)A recent phylogenetic analysis of Ig heavy chain classes intetrapods indicated with high statistical probability that theIgA gene(s) in mammals evolved from an IgX gene in acommon ancestor of all tetrapods while the IgG and IgEgenes evolved more recently from IgY in a common ancestorof amniotes [50] Continuing diversification in the IGH locusinmammals is evidenced by differences in the number of IgGand IgA subclasses and in the structure of Ig heavy chainsUnlike all Ig heavy chains in lower vertebrates comprising 1variable Ig-like domain (VH) and 4 constant Ig-like domains(CH1ndashCH4) the CH2 domain in mammalian IgA IgD andIgG was replaced with a short flexible hinge region richin cysteine and proline residues [73] The heavy chain ofmammalian IgE has retained the prototypic 4 constant Ig-likedomains (as has IgM) suggesting that the evolution of thehinge region in mammalian IgG occurred after the evolutionof IgG and IgE from an ancestral IgY gene (Figure 1)

Determination of the structure of the IGH locus in themonotreme duck-billed platypus (Ornithorhynchus anatinus)revealed the presence of 8 CH genes (including 2 subclassesof IgG and 2 subclasses of IgG) arranged in the order C

120583-

C120575-Co-C1205742-C1205741-C1205721-C120576-C1205722 [74 75] Interestingly the gene

encoding platypus IgD lacks a hinge region and is moresimilar in structure to IgD in lower vertebrates than the IgDof eutherian mammals Downstream of the C

120575gene in the

platypus is a novel Co gene (omicron for Ornithorhynchus)which appears to have evolved from an ancestral IgY geneIn contrast to the platypus only one IgA gene was identifiedin another monotreme the echidna (Tachyglossus aculeatus)and in several species of marsupials [76ndash80] Similarly asingle structural gene for IgA has been identified in 3 speciesof the eutherian order Rodentia mouse (Mus musculus)[81] rat (Rattus norvegicus) (unpublishedGenbank accessionnumber AJ510151) and gerbil (Meriones unguiculatus) [82]By contrast the IGH locus in the European rabbit (Orycto-lagus cuniculus order Lagomorpha) is unique among mam-mals apparently having evolved from a common ancestor

6 ISRN Immunology

prior to the divergence of marsupials and monotremes fromeutherians Distinctive features include a single IgG subclass13 functional IgA subclasses and absence of IgD [83ndash85] Amore typical organization of the IGH locus including singlesubclasses of IgM IgD IgA and IgE and 2 subclasses ofIgG has been reported in mammals of the orders Carnivora[86 87] Cetartiodactyla (even-toed ungulates whales anddolphins) [88ndash91] and Perissodactyla (odd-toed ungulates)[92]

Mammals of the order Primates including humanshave the greatest number and diversity of Ig classes andsubclasses among all of the tetrapods Mapping of IGH locihas now been completed for a number of primate speciesincluding human (Homo sapiens) gorilla (Gorilla gorilla)chimpanzee (Pan troglodytes) orangutan (Pongo pygmaeus)gibbon (Hylobates lar) baboon (Papio anubis) mangabey(Cercocebus torquatus atys) and three species of macaquesthe crab-eating monkey (Macaca fascicularis) pig-tailedmonkey (Macaca nemestrina) and rhesus monkey (Macacamulatta) [93ndash97] A distinguishing feature of primates in thefamily Hominidae (great apes including humans gorillaschimpanzees and orangutans) and the family Hylobatidae(gibbons) is the presence of two IgA subclasses Althoughthe orangutan is a member of the family Hominidae its IGHlocus contains only one IgA subclass gene homologous to theIgA1 gene of other hominoids [95] By contrast primates inthe family Cercopithecidae (Old World monkeys includingbaboons mangabeys and macaques) have a single IgA geneGenetic analysis of the IGH locus of primates suggested thatduplication and diversification of the primordial C

1205741-C1205742-

C120576-C120572region occurred in a common ancestor of the great

apes after the divergence from Old World monkeys [98 99]These events resulted in the current organization of the IGHlocus in extant species of great apes with four IgG subclassesand two IgA subclasses (the duplicated C

120576gene became a

nonfunctional pseudogene hence only one class of IgE isexpressed) The close phylogenetic relationship among theC120572genes in the hominoids and Hylobatidae suggests that

the C1205721

and C1205722

genes evolved from a single C120572gene in a

common ancestor of the great apes and that the C1205722gene was

subsequently lost in the orangutan Evidence of continuingevolution in the IGH locus of humans was demonstrated bythe finding of triplication of the C

1205741-C1205742-C120576-C120572region in

several families [100] Subsequent genetic analyses inmultipleethnic groups revealed that gene duplications and deletionsin the human IGH locus are surprisingly common withfrequencies up to 22 in Japanese and Chinese populations[101]

3 Emergence of the IGJ Gene andEvolution of Polymeric Igs

The ability to produce Igs as both monomers (ie one unitcomprising 2 identical heavy chains and 2 identical lightchains) and polymers (covalently linked aggregates of 2 ormore Ig units) dates to the emergence of primitive Igs incartilaginous fish [23 42 50] Whereas pentameric IgM istypically found in serum as well as secretions the polymeric

forms of IgT IgX and IgA are generally restricted to mucosalsecretions The discovery of a low molecular weight ldquoJrdquo orldquojoiningrdquo chain as a component of polymeric Igs suggesteda potential mechanism for polymerization of individual Igmolecules into highermolecular weight complexes [102ndash104]The most primitive extant vertebrates in which the IGJ genehas been identified are the cartilaginous fish concurrent withthe presence of polymeric IgM Although the IGJ gene hasbeen identified in almost all lineages of jawed vertebratesit is surprisingly absent in some lineages of Osteichthyes(bony fishes) No ortholog of the IGJ gene has been identifiedin any species of the class Actinopterygii (ray-finned bonyfishes) for which the genome has been sequenced and anno-tated including Atlantic cod (Gadus morhua) common carp(Cyprinus carpio) tilapia (Oreochromis niloticus) zebrafish(Danio rerio) medaka (Oryzias latipes) and three-spinedstickleback (Gasterosteus aculeatus) In contrast to the ray-finned bony fishes IGJ genes and functional J chain proteinswere recently identified in two species of the class Sar-copterygii (lobe-finned bony fishes the West Indian Oceancoelacanth (Latimeria chalumnae) and the African lungfish(Protopterus dolloi) [105]) These findings suggest that theIGJ gene was lost during the evolution of the Actinopterygiiafter their divergence from a common ancestor with theSarcopterygii Despite the absence of J chain ray-finned bonyfishes are capable of forming polymeric IgM and IgT that canbe transported into mucosal secretions [38]

4 Evolution of Cellular Receptors for Igs

Theunique structure of vertebrate Igs allows for simultaneousbinding of antigen via the N-terminal variable regions ofthe Ig heavy and light chains and execution of effectorfunctions via the C-terminal constant (Fc) region of the Igheavy chains Evolution of multiple Ig heavy chain isotypesin higher vertebrates expanded the repertoire of Ig-mediatedeffector functions including specialized functions atmucosalsurfaces The simplest effector functions involve neutral-ization of microbes and their toxic byproducts whereaskilling of microbes can be affected by interaction of Igs withsoluble factors found in serumand secretionsThe concurrentemergence of Igs and proteins of the classical complementpathway in cartilaginous fishes is the earliest example of aspecific immune effector function mediated by the Fc regionof Ig heavy chains [106] As the immune system diversifiedduring vertebrate evolution cellular receptors for Ig heavychains (Fc receptors) allowed host cells to bind Igs forthe purpose of internalization transport andor activationof intracellular signaling pathways The most evolutionarilyancient of the vertebrate Fc receptors is the polymeric Igreceptor (pIgR) which first emerged in bony fishes (reviewedin [8]) (Figure 3)Theprimary function of pIgR is to transportpolymeric Igs (IgM IgT IgX and IgA) across glandular andmucosal epithelial cells into external secretions (see below)The fact that the extracellular Ig-binding region of pIgR iscomposed of multiple Ig-like domains suggests that the PIGR

ISRN Immunology 7

gene evolved by duplication of a primordial Ig gene is drivenby the need for an efficient mechanism for transport ofmucosal Igs into external secretions Similar forces may havedriven the evolution of FcRY a receptor first described forits function of transporting IgY from maternal blood tothe embryo yolk sac in chicken [9 107ndash109] FcRY is notstructurally homologous to pIgR or mammalian Fc receptorsbut is instead homologous to mammalian receptors formannose and phospholipase A2 with lectin-like extracellulardomains (Figure 3) A BLAST search of the National Centerfor Biotechnology Information (NCBI) nucleotide databasefor homologs of the gene encoding chicken FcRY (designatedPLA2R1 based on its homology to phospholipase A2 receptor1) revealed homologous genes in many bird species as wellas turtles lizards alligators and mammals However thefunctional significance of FcRYPLA2R1 in the transport ofIgY in reptiles (and possibly IgG in mammals) has not beenexplored A functional equivalent of FcRY in mammals isFcRn which mediates transport of IgG across endothelialand epithelial cells in such tissues as placenta and mucosalepithelia (reviewed in [110 111]) FcRn is homologous in struc-ture to major histocompatibility class (MHC) I moleculescomprising a ligand-binding alpha chain associated withsoluble 1205732-microglobulin (Figure 3)

A unique feature of the mammalian immune system isthe expression of Fc receptors for various Ig isotypes bycells of hematopoietic origin (Figure 3) (reviewed in [10])Engagement of these Fc receptors by Ig (in the presenceor absence of bound antigen depending on the particularFc receptor) initiates intracellular signaling pathways thatcan either augment or inhibit immune responses Withthe exception of Fc120576RII which has a single C-type lectin-like domain the extracellular Ig-binding regions of thesehematopoietic Fc receptors comprise 1 2 or 3 Ig-like domains[10] Genes encoding Fc120572120583R Fc120574RI Fc120574RIII Fc120576RI andFc120576RII are widely distributed among mammalian specieswhereas genes encoding Fc120572RI and Fc120574RII are restricted tothe primate lineage suggesting recent evolutionary originsThe genes encoding the120572120573 andor 120574 chains of Fc120576RI Fc120574RIIand Fc120574RIII are linked in a cluster on the long arm of humanchromosome 1 (1q23) not far removed from the gene for the120572 chain of Fc120574RI at 1q21 This tight linkage is consistent withduplication and diversification of a primordial FcR gene ina common ancestor of mammals The primate-specific genesencoding the 120572 and 120573 chains of Fc120574RII appear to have evolvedmore recently Another cluster of immune-related genes onthe long arm of chromosome 1 includes the genes for pIgR(1q31) and Fc120572120583R (1q32) Although the overall homologybetween pIgR and Fc120572120583R is relatively low they share aconserved binding site for IgA and IgM in the N-terminalIg-like domain Interestingly the genes encoding FcRn andFc120572RI are closely linked on the long arm of chromosome19 (19q133 and 19q1342 resp) although they bear littlehomology beyond the presence of a single Ig-like domain inthe extracellular region Finally the gene for the lectin-likereceptor Fc120576RII is located in an unrelated locus on the shortarm of chromosome 19 (19p133)

PIGR

dIgA

pIgR

Ag

SIgA

Free SC

Figure 4 Transcytosis of pIgR through a polarized epithelial celland formation of secretory Igs A polarized columnar epithelial cellis illustrated with the apical surface at the top and the basolateralsurface at the bottom Newly synthesized pIgR is targeted to thebasolateral surface where it binds polymeric Ig (pIg illustrated hereas dimeric (d)IgA) with or without bound antigen (Ag) Followingreceptor-mediated endocytosis pIg-bound and unoccupied pIgRmolecules are transported through a series of intracellular vesiclesto the apical surface Proteolytic cleavage of pIgR at the extracellularface of the plasma membrane releases free secretory component(SC) and secretory SIg (illustrated here as SIgA) Modified from [13]with permission from John Wiley and sons

5 Unique Biological Functions of pIgR

ThepIgR is expressed on the surface of glandular andmucosalepithelial binds where it binds selectively to polymericIg (pIg) and mediates its transport across epithelial cellsinto external secretions (reviewed in [17 111 112]) Most of

8 ISRN Immunology

02

100

Human IgA1Gorilla IgA1

Gorilla IgA281

6164

Human IgA2

Chimpanzee IgA2Chimpanzee IgA1

Gibbon IgA1Gibbon IgA2

Orangutan IgABaboon IgA

Rhesus macaque IgA53 100

98 69Dog IgA

Pig IgA100 Cattle IgA

52

Horse IgARabbit IgA (13 subclasses)

Mouse IgA57

99

Possum IgA

93

Chicken IgAPlatypus IgA1100

5095

Platypus IgA2

Trout IgTFrog IgX

Gecko IgldquoArdquo

(a)

02

Human pIgR

100Chimpanzee pIgRGorilla pIgR

55Gibbon pIgROrangutan pIgR100

100

100 Baboon pIgRRhesus macaque pIgR

Mouse pIgR

66

96

100 Pig pIgRCattle pIgR

85Horse pIgR

Dog pIgR

74

Rabbit pIgRPossum pIgR

Platypus pIgR

Chicken pIgR

10075

5979

Trout pIgRFrog pIgR

Anole pIgR

71

(b)

Figure 5 Coevolution of mucosal Igs and pIgR Simplified neighbor-joining phylogenetic trees of vertebrate (a) Ig and (b) pIgR proteinsequences with human IgA1 and pIgR denoted as outgroups Horizontal distances are proportional to the degree of divergence followinga multiple alignment of amino acid sequences Numbers at nodes denote bootstrap support for each bifurcation after 100 replicationsAccession numbers for mucosal Ig sequences human (Homo sapiens) IgA1 J00220 IgA2 (allotype m1) J00221 gorilla (Gorilla gorilla) IgA1X53703 IgA2 X53707 chimpanzee (Pan troglodytes) IgA1 X53702 IgA2 X53706 gibbon (Hylobates lar) IgA1 X53708 IgA2 X53709 Borneanorangutan (Pongo pygmaeus) IgA X53704 baboon (Papio anubis) IgA DQ868435 rhesus macaque (Macaca mulatta) AY039245 pig (Susscrofa) IgA U12594 cattle (Bos taurus) IgA AF109167 dog (Canis lupus familiaris) IgA L36871 horse (Equus caballus) IgA AY247966mouse (Mus musculus) IgA D11468 rabbit (Oryctolagus cuniculus) IgA1 X51647 brushtail possum (Trichosurus vulpecula) IgA AF027382duck-billed platypus (Ornithorhynchus anatinus) IgA1 AY055778 IgA2 AY055779 chicken (Gallus gallus) IgA AAB226142 leopard gecko(Eublepharis macularius) IgldquoArdquo (so designated because of its uncertain phylogeny with homology to both IgA and IgY) ABG726841African clawed frog (Xenopus laevis) IgX S03186 rainbow trout (Oncorhynchus mykiss) IgT AAW669811 Accession numbers for pIgRsequences with species that vary from those used for the mucosal Ig alignment in panel A noted in parentheses human NM 002644chimpanzee XM 003308710 gorilla XM 004028295 gibbon XM 003272974 Sumatran orangutan (Pongo abelii) NM 001131626 baboonXM 003893189 rhesus macaque XM 001083307 pig NM 214159 cattle NM 174143 dog XM 537133 horse XM 001492298 mouseNM 011082 rabbit NM 001171045 brushtail possum AF091137 duck-billed platypus XM 001508602 chicken NM 001044644 green anole(Anolis carolinensis) XM 003224013 African clawed frog EF079076 rainbow trout FJ940682

ISRN Immunology 9

our knowledge of pIgR-mediated transcytosis of mucosalIgs is derived from studies of mammalian secretory IgA(SIgA) as illustrated in Figure 4 Transcription of the PIGRgene and translation of pIgR mRNA is accompanied byinsertion of the nascent protein into the endoplasmic retic-ulum The pIgR undergoes substantial glycosylation duringtransport through the ER and Golgi apparatus and is thentargeted to the basolateral surface of polarized epithelialcells Membrane-bound pIgR binds pIg and pIg-containingimmune complexes which are internalized along with unoc-cupied pIgR via receptor-mediated endocytosis and thentranscytosed through a series of intracellular vesicles to theapical surface During transcytosis intracellular pIg antibod-ies can neutralize bacteria viruses and other antigens thathave gained access to the interior of the epithelial cell Atthe apical surface proteolytic cleavage of the membrane-spanning region of pIgR leads to the release of its extracellulardomain known as secretory component (SC) either in freeform or covalently bound to pIg Secretory Igs can neutralizepathogens and antigens within the mucosal lumen andfacilitate excretion of antigens that were transported throughthe epithelial cell as IgA immune complexes The SC moietyof SIgA has been shown to protect IgA from degradationby host and bacterial proteases and along with free SCconfers additional innate immune functions that protectthe epithelial surface from microbial invasion and limitpotentially damaging host inflammatory responses (reviewedin [113]) The finding of an SC-like polypeptide associatedwith polymeric IgT in rainbow trout [38] polymeric IgXin Xenopus [50] and polymeric IgA in birds [114] suggeststhat all vertebrate pIgRs share the function of transportingpolymeric Igs into external secretions In many mammalianspecies pIgR mediates epithelial transcytosis of both poly-meric IgM and IgA (reviewed in [111]) Although directevidence is not yet available it is reasonable to assume thatpIgR transports IgM in lower vertebrates It will be interestingto investigate whether the SCmoiety of secretory Igs in lowervertebrates mediates additional innate immune functions ashas been demonstrated for mammalian SC

6 Coevolution of pIgR and Mucosal Igs

Molecular cloning of the PIGR gene was first reportedfor mammalian species including eutherians marsupialsand monotremes [115ndash127] Subsequent elucidation of PIGRsequences from diverse species of jawed vertebrates hasallowed a comprehensive analysis of the evolutionary originsof the PIGR gene [38 128 128ndash132] and additional sequencesavailable in the Genbank database Whereas no ortholog ofthe PIGR gene has been found in any species of cartilaginousfish the PIGR gene has been annotated in all species of teleostfish for which the genome has been sequenced No orthologof the PIGR gene has been reported in lobe-finned bonyfishes but further analyses of whole genome sequences willbe required to determine whether the PIGR gene was lostfollowing the split of the Sarcopterygii It thus appears thatthe PIGR gene emerged in a common ancestor of highervertebrates after the split of cartilaginous fish and prior

to the evolution of modern teleosts likely driven by theselective pressure to provide a mechanism for transport ofpolymeric Igs such as IgM and IgT into mucosal secretionsThis hypothesis is supported by a comparison of phylogenetictrees based on amino acid sequences for IgT IgX and IgAheavy chains and pIgR (Figure 5)The predicted evolutionarydistance between trout IgT and frog IgX is similar to thedistance between trout and frog pIgR suggesting that thetransition from IgT to IgX as the dominantmucosal Ig isotypewas accompanied by adaptations in pIgR structure Similarparallels can be seen in the transition from IgX to IgA inreptiles birds and mammals and the concurrent evolutionof pIgR

Alignments of the amino acid sequences of mucosal Igheavy chains and pIgR from 10 representative vertebratespecies provide further support for the theory of coevolutionof mucosal IGH and PIGR genes (Figure 6) A commonfeature of Ig and pIgR proteins is the presence of repeatingIg-like domains (see Figure 2 for the basic structure of thesedomains) The structure of IgT IgX and IgA heavy chainsfrom fish amphibians reptiles and birds is similar to thatof IgM with 4 constant Ig-like domains In mammalianIgA (and IgG) the exon for the 2nd constant region wastruncated to encode a short ldquohingerdquo region which confersgreater mobility to the antigen-binding region at the N-terminusThus the CH3 domain of IgT IgX and IgA in lowervertebrates is structurally and functionally homologous tothe CH2 domain of mammalian IgA The heavy chains ofIgT IgX and IgA have retained a characteristic feature ofthe IgM heavy chain that is the presence of a conservedcysteine residue in the tailpiece that allows disulfide bondingbetween heavy chains of individual Ig proteins to formhigher molecular weight polymers These large Ig structurescontaining multiple antigen-binding sites are particularlywell suited for immune clearance of large antigens found atmucosal surfaces such as intact microbes and food particlesIn mucosal Igs from most vertebrate orders the J chainprotein initiates this polymerization process by disulfidebonding with 2 Ig heavy chains remaining associated withthe polymeric Ig at a stoichiometric ratio of 1 J chain subunitper 2 3 4 or 5 Ig units Despite the absence of J chainthe predominant form of IgM and IgT in mucus secretionsin rainbow trout was found to be polymeric in contrastto monomeric forms of IgM and IgT in the blood [38] Inmammals IgM is mainly found as a pentamer whereas theshorter heavy chain ofmammalian IgA restricts its polymericforms to dimers trimers and tetramers Further studies willbe required to characterize the polymeric structures of IgMIgT IgX and IgA in lower vertebrates

Alignment of pIgR amino acid sequences from 10 rep-resentative vertebrate species reveals structural changes thatwere evolved in parallel with structural changes in mucosalIgs (Figure 6(b)) All pIgR proteins have an N-terminalhydrophobic leader peptide required for targeting of thenascent protein into the ER The extracellular region ofpIgR protein is characterized by repeating ldquoIg-likerdquo domainssimilar to Ig heavy chains [115 133] Interestingly the num-ber of extracellular Ig-like domains has increased duringvertebrate evolution culminating with a total of 5 domains

10 ISRN Immunology

TailpieceHinge

Tailpiece

Mammalian IgA

VVVVVVVVVV

200121 300 400 4721

Human IgA1Rhesus IgA

Cattle IgAMouse IgA

Possum IgAPlatypus IgAChicken IgA

Frog IgXTrout IgT

Premammalian IgTXA

Gecko IgldquoArdquo

CH1

CH1

CH2

CH2

CH3

CH3

CH4

(a)

Leader 1 2 3 4 5

Ig homology extracellular domains

Linker CytoplasmicTM

1001 200 300 400 500 600 700 764

HumanRhesus

CattleMouse

PossumPlatypusChicken

AnoleFrog

Trout

(b)

Figure 6 Interspecies similarity in mucosal Ig and pIgR protein sequences from 10 representative vertebrate species Alignments in aminoacid sequences correspond to the phylogenetic trees shown in Figure 5 (a) Numbering ofmucosal Ig amino acids corresponds to the sequenceof human IgA1 beginning with the first residue of the variable domain CH heavy chain constant region domain (b) Numbering of pIgRamino acids corresponds to the sequence of human pIgR beginning with the first residue of the leader peptide TM transmembrane Forboth alignments the intensity of shading at each position signifies the degree of similarity amongmucosal Ig or pIgR sequences from differentspecies Gaps in sequence alignments signify regions of limited interspecies homology Approximate boundaries are noted of key structuralelements in mucosal Ig and pIgR proteins

in mammalian pIgR By contrast pIgR from amphibiansreptiles and birds contains 4 extracellular domains lackinga homolog of domain 2 of mammalian pIgR The mostprimitive form of pIgR found in teleost fish contains only2 extracellular domains homologous to domains 1 and 5of mammalian pIgR Interspecies homology is greatest indomain 1 which has been shown to be critical for binding ofmammalian pIgR to polymeric Igs (reviewed in [111]) Highlyconserved internal disulfide bonds are found in all the Ig-like domains of pIgR characteristic of the immunoglobulinfold An additional disulfide bond is found in domain 5 ofpIgR frommammals birds reptiles and amphibians but notfish In human SIgA this ldquoextrardquo disulfide bond in domain 5has been shown to rearrange to form a disulfide bond with

cysteine residues in one of the heavy chains of polymericIgA [134] Although the structure of SIgA has not beenfully characterized for lower vertebrates it is reasonable toassume that similar disulfide bonds form between domain 5of pIgR and polymeric IgA or IgX from birds reptiles andamphibians The linker region connecting domain 5 of pIgRto the transmembrane domain has a random structure that ispoorly conserved across species Proteolytic cleavage of pIgRwithin this domain leads to the release of SC from the apicalsurface of epithelial cells either free or bound to polymericIg The cytoplasmic domain of mammalian pIgR containsa number of intracellular sorting motifs that interact withcytoplasmic proteins to direct pIgR through the transcytoticpathway (reviewed in [111]) These motifs are reasonably

ISRN Immunology 11

Linker

TMCytoplasmic

J chain

Hinge 1

2

34

5

CL

VLVH

C1205721C1205722 C1205723

(a)

Linker

TMCytoplasmic

J chain

1

3 4

5

CL

VL

VH

C1205941205721

C1205941205722C1205941205723 C1205941205724

(b)

11

5

LinkerTM

Cytoplasmic

5

CL

VL

VH

C1205911C1205912

C1205913 C1205914

pIgR Ig-like domain

H chain Ig-like domain

L chain Ig-like domain

J chain

Disulfide bond

(c)

Figure 7 Theoretical model for changes in the structure of secretory Igs during evolution (a) The structure for mammalian SIgA is adaptedfrom the model of Woof and Russell [16] for human SIgA1 with permission from Nature Publishing Group (b) and (c) Theoretical modelsfor the structure of IgXA from amphibians and birds and SIgT from teleost fish respectively are predicted from alignment of Ig heavy chainand pIgR sequences with mammalian homologs

well conserved in pIgR from birds and reptiles but not inpIgR from amphibians and fish suggesting that complexmechanisms of intracellular trafficking of pIgR coevolvedwith the increasing complexity of the mucosal immunesystem

7 Hypothetical Models for Changes inSecretory Ig Structure during Coevolutionof Mucosal Igs and pIgR

A large number of structural and functional analyses overthe past 30 years allowed the development of detailed modelsfor the structure of mammalian SIgA (reviewed in [111 135])(Figure 7(a)) Domains 1 and 5 of pIgR the most highlyconserved Ig-like domains associate with theC1205722 subunits oftwo adjacent IgA heavy chains in a near-planar structure [136137] During transcytosis a disulfide bond forms betweenhighly conserved cysteine residues in domain 5 of pIgRand the C1205722 domain of one of the IgA heavy chains [134]Domains 2 3 and 4 allow mammalian pIgR to assume aflexible extended structure which is thought to wrap aroundthe IgA heavy chains and protect against degradation fromhost and microbial proteases Binding of mammalian pIgRto polymeric IgA or IgM requires the presence of J chain

connecting the Ig subunits (reviewed in [138]) and J chain-deficient mice fail to transport IgA and IgM into externalsecretions [139ndash141] Structure-function studies usingmutantforms of human J chain suggested that J chain binds directlyto pIgR and also maintains polymeric Ig in an optimalconformation for pIgR binding and transcytosis [142] Theunstructured linker region connecting domain 5 of pIgRto the transmembrane (TM) region gives membrane-boundpIgR the flexibility to bind large polymeric Igs (with orwithout associated antigens) and provides an exposed site forproteolytic cleavage of pIgR to SC The C-terminal region ofpIgR extends past the cytoplasmic face of the plasma mem-brane allowing association with cytoplasmic factors thatregulate trafficking of pIgR with or without bound polymericIg

Although detailed structural studies have not yet beenperformed on secretory Igs from lower vertebrates hypo-thetical models can be constructed based on alignmentswith their mammalian homologs A model for secretoryIgXA in birds reptiles and amphibians is illustrated inFigure 7(b) showing the C

1205941205722 domain in place of the hinge

region ofmammalian IgAThenumbering of the extracellulardomains of pIgR corresponds to the homologous domainsin mammalian pIgR noting the absence of domain 2 In

12 ISRN Immunology

this model the C120594120572

3 domains of two adjacent IgXA heavychains (homologous to the C

1205722 domain of mammalian IgA)

bind to the highly conserved domains 1 and 5 of pIgRGiven the conservation of the analogous cysteine residuesin domain 5 of pIgR and the C

1205941205723 domain of IgXA it

is assumed that a disulfide bond forms between pIgR andpolymeric Ig during epithelial transcytosis in birds reptilesand amphibiansThe absence of domain 2 in pIgR from thesevertebrate orders necessitates a more rigid structure thanthat of mammalian pIgR with a corresponding decrease inits ability to wrap around the IgXA heavy chains and pro-vide protection against proteoltyic degradation Despite theshorter length of pIgR in birds reptiles and amphibians theassociation with the J chain subunit of polymeric IgXA stillappears to be required Recombinant pIgR from the Africanfrog (Xenopus laevis) was shown to bind with moderatelyhigh affinity to human polymeric IgA containing J chain butnot to monomeric IgA [125] The affinity of Xenopus pIgRfor human pIgA was improved when Xenopus J chain wassubstituted for human J chain in a chimeric polymeric IgAmolecule The lack of sequence conservation across speciesin the linker region connecting domain 5 of pIgR to the TMregion suggests that it acts as a nonspecific ldquospacerrdquo As statedabove the cytoplasmic region of pIgR appears to have evolvedover time to provide enhanced regulation of pIgR trafficking

The hypothetical structure of secretory IgT from teleostfish in Figure 7(c) illustrates how the most primitive form ofpIgR comprising only extracellular domains 1 and 5 couldassociate with polymeric Ig and mediate epithelial transcy-tosis Association of pIgR domain 1 with the C

1205913 domain of

IgT would preserve the functional homology with secretoryIgs in higher vertebrates The short length of teleost pIgRwould necessitate the association of domain 5 with a C

1205913

domain on one of the heavy chains of the same IgT ratherthan spanning across to the adjaent IgT subunit While thismodel preserves the highly conserved association of pIgRdomain 1 with the orthologous domain of the IgT heavychain it does not explain the selectivity of teleost pIgR forpolymeric rather than monomeric IgT Although there is noexperimental evidence to support this model it could behypothesized that dimerization of two pIgR molecules in theplasmamembrane is required for high affinity binding of IgTas illustrated in the model in Figure 7(c) This hypotheticalmodel would also explain the lack of a necessity for J chainin polymeric IgT since each subunit in the pIgR dimer wouldonly be in contact with one IgT subunit The unstructuredlinker region connecting domain 5 of pIgR to the TM regionwould provide flexibility for association of 2 membrane-bound pIgR molecules with a large polymeric IgT molecule

Taken together the structural models for secretory Igsshown in Figure 7 are consistent with the selection of a morefunctional pIgR molecule over evolutionary time Duplica-tion and diversification of the extracellular Ig-like domainsof pIgR would provide a longer more flexible surface forbinding to polymeric Igs with higher affinity and protectingthe Ig heavy chains against proteolytic attack Expansion ofthe cytoplasmic domain of pIgR and incorporation of motifsfor binding cytoplasmic proteins would allow regulated

trafficking of pIgR and polymeric Igs across mucosal andglandular epithelial cells Importantly these models illustratea potential path for coevolution of IGH and PIGR genesdriven by the common selective pressure to provide antigen-specific humoral immune responses at mucosal surfaces

8 Evidence that the CommensalMicrobiota Provided the Driving Force forCoevolution of Mucosal Igs and pIgR

From the earliest evolution of vertebrate animals mucosal Igshave been an integral part of the emerging adaptive immunesystem Clearly many environmental factors served as driv-ing forces for the evolution of the adaptive immune systemin vertebrates including a longer lifespan thanmany (but notall) invertebrates and amore diverse diet that could introducea broader range of potential gut pathogens However it hasbeen proposed that the most significant force may havebeen the dramatic increase in the numbers and complexityof the resident microbiota in the evolution of vertebratesfrom their invertebrate ancestors [1 143 144] Antibodiesin mucosal secretions contribute to immune homeostasis bylimiting access of microbes and their products to the bodyproper maintaining the integrity of the epithelial barrier andshaping the composition of the commensal microbiota infavor of metabolically beneficial microorganisms [145] Thepredominance of polymeric Igs in these secretions promotesthese functions by providing multiple antigen-binding sitesper Ig complex thus increasing the overall avidity of antigen-antibody interactions Structural and functional refinementsin mucosal Igs culminating with the multifunctional secre-tory IgA molecule in mammals have further enhanced theirability to enhance immune homeostasis

The early emergence of pIgR in vertebrate evolutionprovided a mechanism for efficient transport of mucosal Igsinto external secretions It is well documented that crosstalkbetween mucosal epithelial cells and the resident microbiotamodulates expression of pIgR (reviewed in [17 111 112]) andit is reasonable to assume that these host-microbe interac-tions provided a driving force for evolution of the PIGR genein vertebrates The first demonstration that gut bacteria maymodulate pIgR expression in epithelial cells was the findingthat butyrate a bacterial fermentation product and importantenergy source in the colon upregulated expression of pIgRin the human colonic epithelial cell line HT-29 [146] A rolefor commensal bacteria in pIgR regulation was subsequentlydemonstrated by the observation that pIgR expression wasincreased when germ-free mice were colonized with Bacteri-oides thetaiotaomicron a prominent organism of the normalmouse and human intestinal microbiota [147] Amore recentstudy using a model of reversible colonization of germ-free mice with a nondividing mutant of Escherichia colidemonstrated that a long-lived SIgA response could besustained that specifically recognized the inducing bacteria[148] However exposure of E coli-colonized mice to otherbacteria limited the duration of the SIgA response against theoriginal colonizer suggesting a dynamic equilibriumbetweenmembers of the gut microbial community and host SIgA A

ISRN Immunology 13

study from the laboratory of Finn-Eirik Johansen demon-strated that diversity of the bacterial community in the cecallumen was reduced in pIgR-knockoutmice supporting a rolefor SIgA in limiting overgrowth of selected species [149] Incontrast the community of bacteria adherent to the epithelialsurface was more diverse in pIgR-knockout mice than inwild-typemice and these adherent bacteria caused enhancedexpression of several epithelial antimicrobial peptides Thesefindings suggest that bacteria-specific SIgA anchored in themucus layer restricts adhesion of bacteria to the epithelialsurface and limits bacterial stimulation of host epithelial cellsA recent study from the authorrsquos laboratory employing abreeding scheme in which119875119894119892119903minusminus damswere bred to119875119894119892119903+minusmales and vice versa demonstrated that SIgA antibodiesin breast milk promote long-term intestinal homeostasis byregulating the gut microbiota and gene expression in colonicepithelial cells [150]

A direct role for commensal andor pathogenic bacteriain the regulation of pIgR expression suggests that the innateimmune system may ldquoprimerdquo epithelial cells for transportof polymeric Ig produced during the adaptive immuneresponse Host cells mediate innate immune responses tomicrobial components through toll-like receptor (TLR) sig-naling (reviewed in [151 152]) Intestinal epithelial cells havebeen shown to express a wide variety of TLRs the expressionof which is upregulated during intestinal inflammation [153ndash155] Significantly expression of pIgR was shown to beupregulated in the HT-29 human intestinal epithelial cellline by bacterial LPS a ligand for TLR4 [156 157] Similarinduction of PIGR gene transcription was seen followingdirect binding of bacteria of the family Enterobacteriaceaewhich express a form of LPS that stimulates TLR4 [158]A recent study from the authorrsquos laboratory demonstratedthat shRNA-mediated knockdown of myeloid differentiationprimary response protein 88 (MyD88) a cytoplasmic adapterprotein that transduces signals from cell surface TLR4blocked the induction of PIGR gene transcription by LPS inHT-29 cells [159] The in vivo significance was confirmed bythe finding that mice with a targeted deletion of the Myd88gene only in intestinal epithelial cells had reduced expressionof pIgR compared to wild-type littermates [159] Mice withtargeted depletion of MyD88 in intestinal epithelial cells alsoexhibited reduced expression of mucin-2 the major compo-nent of the intestinal mucus layer and several antimicrobialpeptides and decreased transmucosal electrical resistanceThese alterations in epithelial barrier function were accom-panied by significant changes in the composition of the fecalmicrobiota increased numbers of bacteria adherent to theintestinal mucus layer and a dramatic increase in transloca-tion of gut bacteria into the drainingmesenteric lymphnodesincluding the opportunistic pathogen Klebsiella pneumoniaeThese findings demonstrate that MyD88-mediated crosstalkbetween the gut microbiota and intestinal epithelial cells iscrucial for optimal expression of pIgR production of SIgAdevelopment of a healthy gut microbiota and maintenanceof intestinal homeostasis

A model can be proposed in which continuous stimu-lation of intestinal epithelial cells by gut bacteria regulates

Lumen

Mucus

Epithelium

Lamina

PIGR

TLRs

MyD88

Bacteria

Plasma cells

propria

Polymeric Ig

Polymeric Ig receptor

Secretory component

Figure 8 Crosstalk between the polymeric immunoglobulin recep-tor secretory immunoglobulins and the gut microbiotaThe single-layered epithelium that lines the gastrointestinal tract is coveredwith a thick mucus layer which physically excludes members ofthe resident microbiota but allows diffusion of shed components ofmicrobial cells Stimulation of epithelial toll-like receptors (TLRs)with microbial products engages the cytoplasmic adaptor proteinMyD88 and initiates NF120581B-dependent signaling pathways Translo-cation of activated NF120581B and other transcription factors to thenucleus enhances transcription of thePIGR gene Activation of TLRsmay also stimulate pIgR transcytosis Polymeric Igs secreted bylamina propria plasma cells bind to pIgRon the basolateral surface ofepithelial cells and are transcytosed to the apical surface along withunoccupied pIgR Proteolytic cleavage of pIgR at the apical surfacereleases secretory SIg and free secretory component (SC) Binding ofSIg and SC to luminal bacteria promotes association with themucuslayer and prevents direct access of bacteria to the epithelial surfaceOver time the continuous crosstalk with SIg shapes the compositionof the gut microbiota Modified from [17] under terms of authorrsquoscopyright with Nature Publishing Group

pIgR expression and transport of SIgA and promotes immuneexclusion of resident and pathogenic bacteria (Figure 8) Adense layer of mucus which increases in thickness fromthe proximal to the distal colon serves to separate bacteriafrom direct contact with the epithelial surface Secretionof microbial-associated molecular patterns (MAMPs) bycommensal bacteria stimulates MyD88-dependent TLR sig-naling leading to enhanced expression of pIgR and antimi-crobial peptides and increased mucus production Bindingof pIgA to pIgR and possibly also signaling via MAMPs

14 ISRN Immunology

enhances transcytosis of pIgA pIgA-containing immunecomplexes and unoccupied pIgR which promotes clearanceof antigens and pathogens from the lamina propria intra-cellular neutralization and release of SIgA and SC at theluminal surface SIgA and SC serve to trap bacteria in themucus layer limiting their access to the epithelial surface Inmice with a targeted deletion of the Muc2 gene which havea severely depleted mucus layer in the colon SIgA and SCfail to associate with the surface of colonic epithelial cells[160] The presence of SIgA in the intestinal lumen whetherderived passively frommaternalmilk or actively via epithelialtranscytosis shapes the composition of the gut microbiotaand modulates intestinal epithelial gene expression

9 Concluding Remarks

The first microbes that emerged on Earth almost 4 billionyears ago encountered a hostile world where nutrients werescarce hazards were everywhere and life was short Withthe evolution of multicellular organisms about 3 billion yearslater a select group ofmicrobes chose to sacrifice an indepen-dent existence for the benefits of a mutualistic relationshipwith eukaryotic hosts Prokaryotic-eukaryotic mutualismreached its apex some 500 million years ago with theemergence of primitive vertebrates whose gastrointestinaltracts were populated by an abundant and diverse commensalmicrobiota In humans the large intestine is home to some100 trillion microorganisms 10 times more than the totalnumber of eukaryotic cells in the entire body The microbesthat inhabit the vertebrate GI tract provide many benefitsto the eukaryotic host including digestion of complex foodmolecules synthesis of vitamins and production of solublefactors that enhance the development of the host immunesystem In return the eukaryotic host provides the microbeswith a warm moist place to live abundant food low oxygentension and a soft bed of mucus on which to form biofilmsWhen this mutually beneficial arrangement is challenged bypathogenicmicrobes the eukaryotic host and the commensalmicrobiota join forces to battle the pathogens and protectthe body from invasion The vertebrate immune system isequipped with a well-trained army of immune cells and asophisticated arsenal of weapons (cell surface molecules andsecreted factors) that protect the host from all but the mostvirulent pathogens This immune ldquoarmyrdquo also serves as aconstant reminder to the commensal microbes that whilethey are free to enjoy the amenities of the mucosal surfacesthey are not welcome in the body proper The emergence ofantigen-specific Igs and T-cell receptors in jawed vertebratesbegan a process of immunological diversification that led tothe development of a specialized mucosal immune systemin higher vertebrates in which secretory Igs play a centralrole The relationship between host and microbiota is clearlyreciprocal the mucosal Igs that evolved in response toselective pressure from the commensal microbiota play acentral role throughout life in shaping the compositiongenetics andmetabolic activity of themicrobiota [1 161 162]

The epithelial layer lining mucosal surfaces provides aphysical and innate immune barrier against penetration of

the body proper by microbes undigested food antigens andpotentially noxious environmental substances The evolu-tionary challenge of transporting mucosal Igs into externalsecretions without compromising the epithelial barrier wasmet by the emergence of the PIGR gene in an ancestor ofbony fishes encoding an epithelial-specific transmembraneprotein that actively transports polymeric Igs across mucosaland glandular epithelia (Figure 4) Structural similaritiesbetween Igs and the extracellular Ig-binding domains of pIgR(Figure 6) suggest that duplication and diversification of agene encoding primordial Ig-like domain may have givenrise to the PIGR gene in a primitive vertebrate ancestorParallel refinement of the structures of mucosal Igs andpIgR during tetrapod evolution (Figures 6 and 7) culminatedin the evolution of the multifunctional SIgA molecule inmammals in which the pIgR-derived SC subunit providesinnate immune functions and protects the antigen-bindingIgA polymer from proteolytic degradation In addition toacting as a powerful force during vertebrate evolution thereciprocal relationship between pIgR mucosal Igs and thecommensal microbiota provides benefits throughout thelife of the individual Microbial colonization of newbornvertebrates stimulates development of mucosal B cells andclass switching to mucosal Ig isotypes [1 163] Microbialfactors upregulate expression of pIgR enhancing transportof mucosal Igs into external secretions where they in turnregulate the microbiotaThis beautifully orchestrated processallows us to maintain a healthy relationship with our resi-dent microbiota while providing mutual protection againstpathogens

Conflict of Interests

The author declares that there is no conflict of interestsregarding the publication of this paper

Acknowledgments

This work was supported by Grant no AI069027 from theNational Institutes of Health of the United States of America(and an associatedAmerican Recovery andReinvestmentActsupplement) and a Senior Research Award from the Crohnrsquosand Colitis Foundation of America

References

[1] C L Maynard C O Elson R D Hatton and C T WeaverldquoReciprocal interactions of the intestinal microbiota andimmune systemrdquo Nature vol 489 no 7415 pp 231ndash241 2012

[2] M F Flajnik and M Kasahara ldquoOrigin and evolution of theadaptive immune system genetic events and selective pres-suresrdquo Nature Reviews Genetics vol 11 no 1 pp 47ndash59 2010

[3] M F Flajnik and L du Pasquier ldquoEvolution of the immunesystemrdquo in Fundamental Immunology W E Paul Ed chapter4 pp 67ndash128 Lippincott Williams ampWilkins Philadelphia PaUSA 2012

[4] M Hirano S Das P Guo and M D Cooper ldquoThe evolutionof adaptive immunity in vertebratesrdquo Advances in Immunologyvol 109 pp 125ndash157 2011

ISRN Immunology 15

[5] T BoehmNMcCurley Y SutohM SchorppMKasahara andM D Cooper ldquoVLR-based adaptive immunityrdquo Annual Reviewof Immunology vol 30 pp 203ndash220 2012

[6] T Hunkapiller and L Hood ldquoImmunology the growing immu-noglobulin gene superfamilyrdquoNature vol 323 no 6083 pp 15ndash16 1986

[7] P Bork L Holm and C Sander ldquoThe immunoglobulin foldstructural classification sequence patterns and common corerdquoJournal of Molecular Biology vol 242 no 4 pp 309ndash320 1994

[8] C S Kaetzel and M W Russell ldquoPhylogeny and comparativephysiology of IgArdquo in Mucosal Immunology J Mestecky WStrober H Cheroutre B Kelsall B N Lambrecht and M WRussell Eds chapter 19 Academic PressElsevier WalthamMass USA 2014

[9] Y He and P J Bjorkman ldquoStructure of FcRY an avian immu-noglobulin receptor related to mammalian mannose receptorsand its complex with IgYrdquo Proceedings of the National Academyof Sciences of the United States of America vol 108 no 30 pp12431ndash12436 2011

[10] J M Woof and D R Burton ldquoHuman antibody-Fc receptorinteractions illuminated by crystal structuresrdquo Nature ReviewsImmunology vol 4 no 2 pp 89ndash99 2004

[11] W L Martin A P West Jr L Gan and P J Bjorkman ldquoCrystalstructure at 28 A of an FcRnheterodimeric Fc complexmechanism of pH-dependent bindingrdquo Molecular Cell vol 7no 4 pp 867ndash877 2001

[12] E S Ward ldquoAcquiring maternal immunoglobulin differentreceptors similar functionsrdquo Immunity vol 20 no 5 pp 507ndash508 2004

[13] C S Kaetzel ldquoThe polymeric immunoglobulin receptor bridg-ing innate and adaptive immune responses atmucosal surfacesrdquoImmunological Reviews vol 206 no 1 pp 83ndash99 2005

[14] M Acharya G Borland A L Edkins et al ldquoCD23Fc120576RIImolecular multi-taskingrdquo Clinical and Experimental Immunol-ogy vol 162 no 1 pp 12ndash23 2010

[15] V B Klimovich ldquoIgM and its receptors structural and func-tional aspectsrdquo Biochemistry vol 76 no 5 pp 534ndash549 2011

[16] J MWoof andMW Russell ldquoStructure and function relation-ships in IgArdquo Mucosal Immunology vol 4 no 6 pp 590ndash5972011

[17] F-E Johansen and C S Kaetzel ldquoRegulation of the polymericimmunoglobulin receptor and IgA transport new advances inenvironmental factors that stimulate pIgR expression and itsrole in mucosal immunityrdquo Mucosal Immunology vol 4 no 6pp 598ndash602 2011

[18] F Kokubu K Hinds R Litman M J Shamblott and G WLitman ldquoExtensive families of constant region genes in a phy-logenetically primitive vertebrate indicate an additional levelof immunoglobulin complexityrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 84 no16 pp 5868ndash5872 1987

[19] A S Greenberg A L Hughes J Guo D Avila E CMcKinneyand M F Flajnik ldquoA novel ldquochimericrdquo antibody class in carti-laginous fish IgMmay not be the primordial immunoglobulinrdquoEuropean Journal of Immunology vol 26 no 5 pp 1123ndash11291996

[20] H Dooley and M F Flajnik ldquoShark immunity bites back affin-ity maturation and memory response in the nurse shark Ging-lymostoma cirratumrdquo European Journal of Immunology vol 35no 3 pp 936ndash945 2005

[21] S F Schluter R M Bernstein and J J Marchalonis ldquoMolecularorigins and evolution of immunoglobulin heavy-chain genes ofjawed vertebratesrdquo Immunology Today vol 18 no 11 pp 543ndash549 1997

[22] Y Ohta and M Flajnik ldquoIgD like IgM is a primordial immu-noglobulin class perpetuated in most jawed vertebratesrdquo Pro-ceedings of the National Academy of Sciences of the United Statesof America vol 103 no 28 pp 10723ndash10728 2006

[23] S Fillatreau A Six S Magadan R Castro J O Sunyer andP Boudinot ldquoThe astonishing diversity of Ig classes and B cellrepertoires in teleost fishrdquo Frontiers in Immunology vol 4 no28 2013

[24] W Harriman H Volk N Defranoux and M Wabl ldquoImmu-noglobulin class switch recombinationrdquo Annual Review ofImmunology vol 11 pp 361ndash384 1993

[25] J Stavnezer and C T Amemiya ldquoEvolution of isotype switch-ingrdquo Seminars in Immunology vol 16 no 4 pp 257ndash275 2004

[26] V M Barreto Q Pan-Hammarstrom Y Zhao L Ham-marstrom Z Misulovin and M C Nussenzweig ldquoAID frombony fish catalyzes class switch recombinationrdquo Journal ofExperimental Medicine vol 202 no 6 pp 733ndash738 2005

[27] T C Fletcher and AWhite ldquoAntibody production in the plaice(Pleuronectes platessa L) after oral and parenteral immuniza-tion with Vibrio anguillarum antigensrdquo Aquaculture vol 1 pp417ndash428 1972

[28] J W H M Rombout L J Blok C H J Lamers and E EgbertsldquoImmunization of carp (Cyprinus carpio) with a Vibrio anguil-larum bacterin indications for a common mucosal immunesystemrdquo Developmental and Comparative Immunology vol 10no 3 pp 341ndash351 1986

[29] U Georgopoulou and J-M Vernier ldquoLocal immunologicalresponse in the posterior intestinal segment of the rainbowtrout after oral administration of macromoleculesrdquo Develop-mental andComparative Immunology vol 10 no 4 pp 529ndash5371986

[30] C J Lobb ldquoSecretory immunity induced in catfish Ictaluruspunctatus following bath immunizationrdquo Developmental andComparative Immunology vol 11 no 4 pp 727ndash738 1987

[31] J D Hansen E D Landis and R B Phillips ldquoDiscovery ofa unique Ig heavy-chain (IgT) in rainbow trout implicationsfor a distinctive B cell developmental pathway in teleost fishrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 102 no 19 pp 6919ndash6924 2005

[32] N Danilova J Bussmann K Jekosch and L A Steiner ldquoTheimmunoglobulin heavy-chain locus in zebrafish identificationand expression of a previously unknown isotype immunoglob-ulin Zrdquo Nature Immunology vol 6 no 3 pp 295ndash302 2005

[33] R Savan A Aman K Sato R Yamaguchi and M Sakai ldquoDis-covery of a new class of immunoglobulin heavy chain fromfugurdquo European Journal of Immunology vol 35 no 11 pp 3320ndash3331 2005

[34] R Savan A AmanMNakao HWatanuki andM Sakai ldquoDis-covery of a novel immunoglobulin heavy chain gene chimerafrom common carp (Cyprinus carpio L)rdquo Immunogenetics vol57 no 6 pp 458ndash463 2005

[35] F Gambon-Deza C Sanchez-Espinel and S Magadan-Mompo ldquoPresence of an unique IgT on the IGH locus in three-spined stickleback fish (Gasterosteus aculeatus) and the veryrecent generation of a repertoire of VH genesrdquo Developmentaland Comparative Immunology vol 34 no 2 pp 114ndash122 2010

[36] T M Tadiso K K Lie and I Hordvik ldquoMolecular cloning ofIgT fromAtlantic salmon and analysis of the relative expression

16 ISRN Immunology

of 120591 120583 and 120575 in different tissuesrdquo Veterinary Immunology andImmunopathology vol 139 no 1 pp 17ndash26 2011

[37] S Mashoof C Pohlenz P L Chen et al ldquoExpressed IgH 120583and 120591 transcripts share diversity segment in ranched Thunnusorientalisrdquo Developmental and Comparative Immunology vol43 no 1 pp 76ndash86 2014

[38] Y-A Zhang I Salinas J Li et al ldquoIgT a primitive immunoglob-ulin class specialized in mucosal immunityrdquo Nature Immunol-ogy vol 11 no 9 pp 827ndash835 2010

[39] S Magadan-Mompo C Sanchez-Espinel and F Gambon-Deza ldquoImmunoglobulin heavy chains in medaka (Oryziaslatipes)rdquo BMC Evolutionary Biology vol 11 no 1 article 1652011

[40] C T Amemiya J Alfoldi A P Lee et al ldquoThe African coela-canth genome provides insights into tetrapod evolutionrdquoNature vol 496 no 7445 pp 311ndash316 2013

[41] T Ota J P Rast G W Litman and C T Amemiya ldquoLineage-restricted retention of a primitive immunoglobulin heavy chainisotype within the Dipnoi reveals an evolutionary paradoxrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 100 no 5 pp 2501ndash2506 2003

[42] Y Sun Z Wei N Li and Y Zhao ldquoA comparative overview ofimmunoglobulin genes and the generation of their diversity intetrapodsrdquo Developmental and Comparative Immunology vol39 no 1-2 pp 103ndash109 2013

[43] I Hadji-Azimi ldquoAnuran immunoglobulins a reviewrdquo Develop-mental and Comparative Immunology vol 3 no 2 pp 223ndash2431979

[44] E Hsu M F Flajnik and L du Pasquier ldquoA third immunoglob-ulin class in amphibiansrdquo The Journal of Immunology vol 135no 3 pp 1998ndash2004 1985

[45] C T Amemiya R N Haire and G W Litman ldquoNucleotidesequence of a cDNA encoding a third distinct Xenopusimmunoglobulin heavy chain isotyperdquo Nucleic Acids Researchvol 17 no 13 p 5388 1989

[46] R Muszligmann M Wilson A Marcuz M Courtet and L duPasquier ldquoMembrane exon sequences of the three Xenopus Igclasses explain the evolutionary origin of mammalian isotypesrdquoEuropean Journal of Immunology vol 26 no 2 pp 409ndash4141996

[47] R Muszligmann L du Pasquier and E Hsu ldquoIs Xenopus IgX ananalog of IgArdquo European Journal of Immunology vol 26 no12 pp 2823ndash2830 1996

[48] B Schaerlinger and J-P Frippiat ldquoIgX antibodies in the urodeleamphibian Ambystoma mexicanumrdquo Developmental and Com-parative Immunology vol 32 no 8 pp 908ndash915 2008

[49] B Schaerlinger M Bascove and J-P Frippiat ldquoA new isotypeof immunoglobulin heavy chain in the urodele amphibianPleurodeles waltl predominantly expressed in larvaerdquoMolecularImmunology vol 45 no 3 pp 776ndash786 2008

[50] S Mashoof A Goodroe C C Du et al ldquoAncient T-independence of mucosal IgXA gut microbiota unaffected bylarval thymectomy in Xenopus laevisrdquo Mucosal Immunologyvol 6 no 2 pp 358ndash368 2013

[51] J P Vaerman J Picard and J F Heremans ldquoStructural dataon chicken IgA and failure to identify the IgA of the tortoiserdquoin Immunologic Phylogeny vol 64 of Advances in ExperimentalMedicine and Biology pp 185ndash195 Springer New York NYUSA 1975

[52] J L Portis and J E Coe ldquoIgM the secretory immunoglobulinof reptiles and amphibiansrdquo Nature vol 258 no 5535 pp 547ndash548 1975

[53] J E Coe D Leong J L Portis and L A Thomas ldquoImmuneresponse in the garter snake (Thamnophis ordinoides)rdquo Immu-nology vol 31 no 3 pp 417ndash424 1976

[54] D Hadge and H Ambrosius ldquoEvolution of low molecularweight immunoglobulinsmdashIV IgY-like immunoglobulins ofbirds reptiles and amphibians precursors of mammalian IgArdquoMolecular Immunology vol 21 no 8 pp 699ndash707 1984

[55] D Hadge and H Ambrosius ldquoEvolution of low molecularweight immunoglobulins V Degree of antigenic relationshipbetween the 7S immunoglobulins ofmammals birds and lowervertebrates to the turkey IgYrdquo Developmental and ComparativeImmunology vol 10 no 3 pp 377ndash385 1986

[56] S Magadan-Mompo C Sanchez-Espinel and F Gambon-Deza ldquoImmunoglobulin genes of the turtlesrdquo Immunogeneticsvol 65 no 3 pp 227ndash237 2013

[57] Z Wei Q Wu L Ren et al ldquoExpression of IgM IgD and IgYin a reptile Anolis carolinensisrdquoThe Journal of Immunology vol183 no 6 pp 3858ndash3864 2009

[58] F Gambon-Deza C Sanchez-Espinel and J V Beneitez ldquoAnovel IgA-like immunoglobulin in the reptile Eublepharis mac-ulariusrdquo Developmental and Comparative Immunology vol 31no 6 pp 596ndash605 2007

[59] G Cheng Y Gao T Wang et al ldquoExtensive diversification ofIgH subclass-encoding genes and IgM subclass switching incrocodiliansrdquo Nature Communications vol 4 article 1337 2013

[60] S Magadan-Mompo C Sanchez-Espinel and F Gambon-Deza ldquoIgH loci of American alligator and saltwater crocodileshed light on IgA evolutionrdquo Immunogenetics vol 65 no 7 pp531ndash541 2013

[61] E Orlans and M E Rose ldquoAn IgA-like immunoglobulin in thefowlrdquo Immunochemistry vol 9 no 8 pp 833ndash838 1972

[62] G A Leslie and L N Martin ldquoStudies on the secretory immu-nologic system of fowl 3 Serum and secretory IgA of thechickenrdquoThe Journal of Immunology vol 110 no 1 pp 1ndash9 1973

[63] J Bienenstock D Y Perey J Gauldie and B J UnderdownldquoChicken 120574A physicochemical and immunochemical charac-teristicsrdquoThe Journal of Immunology vol 110 no 2 pp 524ndash5331973

[64] A M Lebacq-Verheyden J P Vaerman and J F HeremansldquoQuantification and distribution of chicken immunoglobulinsIgA IgM and IgG in serum and secretionsrdquo Immunology vol27 no 4 pp 683ndash692 1974

[65] J Goudswaard A Noordzij R H van Dam J A vanderDonk and J P Vaerman ldquoThe immunoglobulins of the turkey(Meleagris gallopavo) Isolation and characterization of IgGIgM and IgA in body fluids eggs and intraocular tissuesrdquoPoultry science vol 56 no 6 pp 1847ndash1851 1977

[66] D Hadge and H Ambrosius ldquoComparative studies on thestructure of biliary immunoglobulins of some avian speciesII Antigenic properties of the biliary immunoglobulins ofchicken turkey duck and gooserdquo Developmental and Compar-ative Immunology vol 12 no 2 pp 319ndash329 1988

[67] J Goudswaard J P Vaerman and J F Heremans ldquoThreeimmunoglobulin classes in the pigeon (Columbia livia)rdquo Inter-national Archives of Allergy andApplied Immunology vol 53 no5 pp 409ndash419 1977

[68] P L K Ng and D A Higgins ldquoBile immunoglobulin of theduck (Anas platyrhynchos) I Preliminary characterization andontogenyrdquo Immunology vol 58 no 2 pp 323ndash327 1986

[69] K E Magor G W Warr Y Bando D L Middleton and DA Higgins ldquoSecretory immune system of the duck (Anas

ISRN Immunology 17

platyrhynchos) Identification and expression of the genesencoding IgA and IgM heavy chainsrdquo European Journal ofImmunology vol 28 no 3 pp 1063ndash1068 1998

[70] Y Zhao H Rabbani A Shimizu and L Hammarstrom ldquoMap-ping of the chicken immunoglobulin heavy-chain constantregion gene locus reveals an inverted 120572 gene upstream of acondensed 120592 generdquo Immunology vol 101 no 3 pp 348ndash3532000

[71] M L Lundqvist D L Middleton S Hazard and G W WarrldquoThe immunoglobulin heavy chain locus of the duck genomicorganization and expression of D J and C region genesrdquo TheJournal of Biological Chemistry vol 276 no 50 pp 46729ndash46736 2001

[72] T HuangM Zhang ZWei et al ldquoAnalysis of immunoglobulintranscripts in the ostrich Struthio camelus a primitive avianspeciesrdquo PLoS ONE vol 7 no 3 Article ID e34346 2012

[73] K H Roux ldquoImmunoglobulin structure and function asrevealed by electron microscopyrdquo International Archives ofAllergy and Immunology vol 120 no 2 pp 85ndash99 1999

[74] F Gambon-Deza C Sanchez-Espinel and S Magadan-Mompo ldquoThe immunoglobulin heavy chain locus in the platy-pus (Ornithorhynchus anatinus)rdquo Molecular Immunology vol46 no 13 pp 2515ndash2523 2009

[75] Y Zhao H Cui C M Whittington et al ldquoOrnithorhynchusanatinus (platypus) links the evolution of immunoglobulingenes in eutherian mammals and nonmammalian tetrapodsrdquoThe Journal of Immunology vol 183 no 5 pp 3285ndash3293 2009

[76] M Aveskogh and L Hellman ldquoEvidence for an early appear-ance of modern post-switch isotypes in mammalian evolutioncloning of IgE IgG and IgA from the marsupial Monodelphisdomesticardquo European Journal of Immunology vol 28 no 9 pp2738ndash2750 1998

[77] K Belov G A Harrison and DW Cooper ldquoMolecular cloningof the cDNA encoding the constant region of the immunoglob-ulin a heavy chain (C120572) from amarsupialTrichosurus vulpecula(common brushtail possum)rdquo Immunology Letters vol 60 no2-3 pp 165ndash170 1998

[78] K Belov K R Zenger L Hellman and DW Cooper ldquoEchidnaIgA supports mammalian unity and traditional Therian rela-tionshiprdquo Mammalian Genome vol 13 no 11 pp 656ndash6632002

[79] K Belov and L Hellman ldquoImmunoglobulin genetics of Orni-thorhynchus anatinus (platypus) and Tachyglossus aculeatus(short-beaked echidna)rdquo Comparative Biochemistry and Phys-iology vol 136 no 4 pp 811ndash819 2003

[80] M VernerssonM Aveskogh BMunday and L Hellman ldquoEvi-dence for an early appearance of modern post-switch immu-noglobulin isotypes in mammalian evolution (II) cloning ofIgE IgG1 and IgG2 fromamonotreme the duck-billed platypusOrnithorhynchus anatinusrdquo European Journal of Immunologyvol 32 no 8 pp 2145ndash2155 2002

[81] C Auffray R Nageotte and J L Sikorav ldquoMouse immunoglob-ulin A nucleotide sequence of the structural gene for the 120572heavy chain derived from cloned cDNAsrdquo Gene vol 13 no 4pp 365ndash374 1981

[82] T Ukaji D Sumiyama and O Kai ldquoSequence determinationof the heavy-chain constant region in four immunoglobulinclasses of Mongolian gerbils (Meriones unguiculatus)rdquo Experi-mental Animals vol 61 no 2 pp 99ndash107 2012

[83] R C Burnett W C Hanly S K Zhai and K L Knight ldquoTheIgA heavy chain gene family in rabbit cloning and sequence

analysis of 13 C120572 genesrdquo The EMBO Journal vol 8 no 13 pp4041ndash4047 1989

[84] D K Lanning S-K Zhai and K L Knight ldquoAnalysis of the 31015840C120583 region of the rabbit Ig heavy chain locusrdquoGene vol 309 no2 pp 135ndash144 2003

[85] F Ros J Puels N Reichenberger W van Schooten R Buelowand J Platzer ldquoSequence analysis of 05Mb of the rabbitgermline immunoglobulin heavy chain locusrdquo Gene vol 330no 1-2 pp 49ndash59 2004

[86] M Patel D Selinger G E Mark G J Hickey and G FHollis ldquoSequence of the dog immunoglobulin alpha and epsilonconstant region genesrdquo Immunogenetics vol 41 no 5 pp 282ndash286 1995

[87] Z Zhao Y Zhao Q Pan-Hammarstrom et al ldquoPhysical map-ping of the giant panda immunoglobulin heavy chain constantregion genesrdquo Developmental and Comparative Immunologyvol 31 no 10 pp 1034ndash1049 2007

[88] W R Brown and J E Butler ldquoCharacterization of a C120572 gene ofswinerdquoMolecular Immunology vol 31 no 8 pp 633ndash642 1994

[89] W R Brown H Rabbani J E Butler and L HammarstromldquoCharacterization of the bovine C120572 generdquo Immunology vol 91no 1 pp 1ndash6 1997

[90] G PWhite P Roche M R Brandon S E Newton and E N TMeeusen ldquoCloning and characterization of sheep (Ovis aries)immunoglobulin 120572 chainrdquo Immunogenetics vol 48 no 5 pp359ndash362 1998

[91] AMancia T A Romano H A Gefroh et al ldquoCharacterizationof the immunoglobulin A heavy chain gene of the Atlantic bot-tlenose dolphin (Tursiops truncatus)rdquo Veterinary Immunologyand Immunopathology vol 118 no 3-4 pp 304ndash309 2007

[92] B Wagner I Greiser-Wilke and D F Antczak ldquoCharacteriza-tion of the horse [Equus caballus] IGHA generdquo Immunogeneticsvol 55 no 8 pp 552ndash560 2003

[93] N Takahashi S Ueda and M Obata ldquoStructure of humanimmunoglobulin gamma genes implications for evolution of agene familyrdquo Cell vol 29 no 2 pp 671ndash679 1982

[94] J G Flanagan M-P Lefranc and T H Rabbitts ldquoMechanismsof divergence and convergence of the human immunoglobulin1205721 and 1205722 constant region gene sequencesrdquo Cell vol 36 no 3pp 681ndash688 1984

[95] S Kawamura K Omoto and S Ueda ldquoEvolutionary hypervari-ability in the hinge region of the immunoglobulin alpha generdquoJournal of Molecular Biology vol 215 no 2 pp 201ndash206 1990

[96] F Scinicariello F Masseoud L Jayashankar and R AttanasioldquoSooty mangabey (Cercocebus torquatus atys) IGHG and IGHAgenesrdquo Immunogenetics vol 58 no 12 pp 955ndash965 2006

[97] K A Rogers L Jayashankar F Scinicariello and R AttanasioldquoNonhuman primate IgA genetic heterogeneity and interac-tions with CD89rdquoThe Journal of Immunology vol 180 no 7 pp4816ndash4824 2008

[98] S Kawamura N Saitou and S Ueda ldquoConcerted evolution ofthe primate immunoglobulin 120572-gene through gene conversionrdquoThe Journal of Biological Chemistry vol 267 no 11 pp 7359ndash7367 1992

[99] S Kawamura and S Ueda ldquoImmunoglobulin C119867gene family in

hominoids and its evolutionary historyrdquo Genomics vol 13 no1 pp 194ndash200 1992

[100] A Brusco U Cariota A Bottaro et al ldquoStructural andimmunologic analysis of gene triplications in the Ig heavy chainconstant region locusrdquoThe Journal of Immunology vol 152 no1 pp 129ndash135 1994

18 ISRN Immunology

[101] H Rabbani Q Pan N Kondo C I E Smith and L Ham-marstrom ldquoDuplications and deletions of the human IGHClocus evolutionary implicationsrdquo Immunogenetics vol 45 no2 pp 136ndash141 1996

[102] P F Weinheimer J Mestecky and R T Acton ldquoSpecies distri-bution of J chainrdquoThe Journal of Immunology vol 107 no 4 pp1211ndash1212 1971

[103] F P Inman and J Mestecky ldquoThe J chain of polymeric immu-noglobulinsrdquo inContemporary Topics inMolecular Immunologyvol 3 pp 111ndash141 Springer New York NY USA 1974

[104] P Brandtzaeg ldquoPresence of J chain in human immunocytescontaining various immunoglobulin classesrdquo Nature vol 252no 5482 pp 418ndash420 1974

[105] L Tacchi E Larragoite and I Salinas ldquoDiscovery of J chain inAfrican lungfish (Protopterus dolloi Sarcopterygii) using highthroughput transcriptome sequencing implications in mucosalimmunityrdquo PLoS ONE vol 8 no 8 Article ID e70650 2013

[106] I K Zarkadis D Mastellos and J D Lambris ldquoPhylogeneticaspects of the complement systemrdquo Developmental and Com-parative Immunology vol 25 no 8-9 pp 745ndash762 2001

[107] A P West Jr A B Herr and P J Bjorkman ldquoThe chickenyolk sac IgY receptor a functional equivalent of themammalianMHC-related Fc receptor is a phospholipase A

2receptor

homologrdquo Immunity vol 20 no 5 pp 601ndash610 2004[108] D B Tesar E J Cheung and P J Bjorkman ldquoThe chicken

yolk sac IgY receptor a mammalian mannose receptor familymember transcytoses IgY across polarized epithelial cellsrdquoMolecular Biology of the Cell vol 19 no 4 pp 1587ndash1593 2008

[109] A I Taylor R L Beavil B J Sutton and R A Calvert ldquoAmonomeric chicken IgY receptor binds IgY with 21 stoichiom-etryrdquo The Journal of Biological Chemistry vol 284 no 36 pp24168ndash24175 2009

[110] K Baker S-W Qiao T Kuo et al ldquoImmune and non-immunefunctions of the (not so) neonatal Fc receptor FcRnrdquo Seminarsin Immunopathology vol 31 no 2 pp 223ndash236 2009

[111] K Baker R S Blumberg and C S Kaetzel ldquoImmunoglob-ulin transport and immunoglobulin receptorsrdquo in MucosalImmunology J Mestecky W Strober H Cheroutre B KelsallB N Lambrecht andMW Russell Eds chapter 20 AcademicPressElsevier Waltham Mass USA 2014

[112] C S Kaetzel ldquoThepolymeric immunoglobulin receptorrdquo in eLSJohn Wiley amp Sons Chichester UK 2013

[113] N J Mantis N Rol and B Corthesy ldquoSecretory IgArsquos complexroles in immunity andmucosal homeostasis in the gutrdquoMucosalImmunology vol 4 no 6 pp 603ndash611 2011

[114] J V Peppard M E Rose and P Hesketh ldquoA functional homo-logue of mammalian secretory component exists in chickensrdquoEuropean Journal of Immunology vol 13 no 7 pp 566ndash5701983

[115] K E Mostov M Friedlander and G Blobel ldquoThe receptorfor transepithelial transport of IgA and IgM contains multipleimmunoglobulin-like domainsrdquo Nature vol 308 no 5954 pp37ndash43 1984

[116] P Krajci R Solberg M Sandberg O Oyen T Jahnsen and PBrandtzaeg ldquoMolecular cloning of the human transmembranesecretory component (poly-Ig receptor) and its mRNA expres-sion in human tissuesrdquo Biochemical and Biophysical ResearchCommunications vol 158 no 3 pp 783ndash789 1989

[117] P Krajci D Kvale K Tasken and P Brandtzaeg ldquoMolecularcloning and exon-intron mapping of the gene encoding humantransmembrane secretory component (the poly-Ig receptor)rdquo

European Journal of Immunology vol 22 no 9 pp 2309ndash23151992

[118] J F Piskurich J A France C M Tamer C A Willmer CS Kaetzel and D M Kaetzel ldquoInterferon-120574 induces polymericimmunoglobulin receptormRNA in human intestinal epithelialcells by a protein synthesis dependent mechanismrdquo MolecularImmunology vol 30 no 4 pp 413ndash421 1993

[119] J F Piskurich M H Blanchard K R Youngman J A Franceand C S Kaetzel ldquoMolecular cloning of the mouse polymericIg receptor functional regions of the molecule are conservedamong five mammalian speciesrdquo The Journal of Immunologyvol 154 no 4 pp 1735ndash1747 1995

[120] M A Kulseth P Krajci O Myklebost and S RogneldquoCloning and characterization of two forms of bovine polymericimmunoglobulin receptor cDNArdquo DNA and Cell Biology vol14 no 3 pp 251ndash256 1995

[121] K S Koch A S Gleiberman T Aoki et al ldquoDiscordant expres-sion and variable numbers of neighboring GGA- and GAA-richtriplet repeats in the 31015840 untranslated regions of two groups ofmessenger RNAs encoded by the rat polymeric immunoglob-ulin receptor generdquo Nucleic Acids Research vol 23 no 7 pp1098ndash1112 1995

[122] F M Adamski and J Demmer ldquoTwo stages of increased IgAtransfer during lactation in themarsupialTrichosurus vulpecula(brushtail possum)rdquoThe Journal of Immunology vol 162 no 10pp 6009ndash6015 1999

[123] H Kumura T Sone K-I Shimazaki and E KobayashildquoSequence analysis of porcine polymeric immunoglobulinreceptor from mammary epithelial cells present in colostrumrdquoThe Journal of Dairy Research vol 67 no 4 pp 631ndash636 2000

[124] C L Taylor G A Harrison C M Watson and E M DeaneldquocDNA cloning of the polymeric immunoglobulin receptor ofthe marsupial Macropus eugenii (tammar wallaby)rdquo EuropeanJournal of Immunogenetics vol 29 no 2 pp 87ndash93 2002

[125] R Braathen V S Hohman P Brandtzaeg and F-E JohansenldquoSecretory antibody formation conserved binding interactionsbetween J chain and polymeric Ig receptor from humans andamphibiansrdquo The Journal of Immunology vol 178 no 3 pp1589ndash1597 2007

[126] M J Lewis BWagner R M Irvine and J MWoof ldquoIgA in thehorse cloning of equine polymeric Ig receptor and J chain andcharacterization of recombinant forms of equine IgArdquoMucosalImmunology vol 3 no 6 pp 610ndash621 2010

[127] A J Leon D Banner L Xu et al ldquoSequencing annotation andcharacterization of the influenza ferret infectomerdquo Journal ofVirology vol 87 no 4 pp 1957ndash1966 2013

[128] W H Wieland D Orzaez A Lammers H K ParmentierM W A Verstegen and A Schots ldquoA functional polymericimmunoglobulin receptor in chicken (Gallus gallus) indicatesancient role of secretory IgA inmucosal immunityrdquoBiochemicalJournal vol 380 no 3 pp 669ndash676 2004

[129] K Hamuro H Suetake N R Saha K Kikuchi and YSuzuki ldquoA teleost polymeric Ig receptor exhibiting two Ig-likedomains transports tetrameric IgM into the skinrdquo The Journalof Immunology vol 178 no 9 pp 5682ndash5689 2007

[130] J H W M Rombout S J L van der Tuin G Yang et alldquoExpression of the polymeric immunoglobulin receptor (pIgR)in mucosal tissues of common carp (Cyprinus carpio L)rdquo Fishand Shellfish Immunology vol 24 no 5 pp 620ndash628 2008

[131] L-N Feng D-Q Lu J-X Bei et al ldquoMolecular cloning andfunctional analysis of polymeric immunoglobulin receptor gene

ISRN Immunology 19

in orange-spotted grouper (Epinephelus coioides)rdquo ComparativeBiochemistry and Physiology B vol 154 no 3 pp 282ndash289 2009

[132] A E Oslashstergaard S A M Martin T Wang R J M Stet andC J Secombes ldquoRainbow trout (Oncorhynchus mykiss) pos-sessmultiple novel immunoglobulin-like transcripts containingeither an ITAM or ITIMsrdquo Developmental and ComparativeImmunology vol 33 no 4 pp 525ndash532 2009

[133] H Eiffert E Quentin and J Decker ldquoThe primary structureof the human free secretory component and the arrangementof disulfide bondsrdquo Hoppe-Seylerrsquos Zeitschrift fur PhysiologischeChemie vol 365 no 12 pp 1489ndash1495 1984

[134] E Fallgreen-Gebauer W Gebauer A Bastian et al ldquoThe cova-lent linkage of secretory component to IgA Structure of sIgArdquoBiological Chemistry Hoppe-Seyler vol 374 no 11 pp 1023ndash1028 1993

[135] J MWoof ldquoThe structure of IgArdquo inMucosal Immune DefenseImmunoglobulin A C S Kaetzel Ed chapter 1 pp 1ndash24Springer New York NY USA 2007

[136] A Bonner A Almogren P B Furtado M A Kerr and S JPerkins ldquoLocation of secretory component on the Fc edge ofdimeric IgA1 reveals insight into the role of secretory IgA1 inmucosal immunityrdquoMucosal Immunology vol 2 no 1 pp 74ndash84 2009

[137] A Bonner A Almogren P B Furtado M A Kerr and S JPerkins ldquoThe nonplanar secretory IgA2 and near planar secre-tory IgA1 solution structures rationalize their different mucosalimmune responsesrdquo The Journal of Biological Chemistry vol284 no 8 pp 5077ndash5087 2009

[138] J Johansen B Braathen and P Brandtzaeg ldquoRole of J chain insecretory immunoglobulin formationrdquo Scandinavian Journal ofImmunology vol 52 no 3 pp 240ndash248 2000

[139] B A Hendrickson D A Conner D J Ladd et al ldquoAlteredhepatic transport of immunoglobulin A in mice lacking the Jchainrdquo Journal of Experimental Medicine vol 182 no 6 pp1905ndash1911 1995

[140] B A Hendrickson L Rindisbacher B Corthesy et al ldquoLackof association of secretory component with IgA in J chain-deficient micerdquo The Journal of Immunology vol 157 no 2 pp750ndash754 1996

[141] N Lycke L Erlandsson L Ekman K Schon and T Lean-derson ldquoLack of J chain inhibits the transport of gut IgA andabrogates the development of intestinal antitoxic protectionrdquoThe Journal of Immunology vol 163 no 2 pp 913ndash919 1999

[142] F-E Johansen R Braathen and P Brandtzaeg ldquoThe J chainis essential for polymeric Ig receptor-mediated epithelial trans-port of IgArdquoThe Journal of Immunology vol 167 no 9 pp 5185ndash5192 2001

[143] R E Ley D A Peterson and J I Gordon ldquoEcological andevolutionary forces shaping microbial diversity in the humanintestinerdquo Cell vol 124 no 4 pp 837ndash848 2006

[144] M McFall-Ngai ldquoAdaptive immunity care for the communityrdquoNature vol 445 no 7124 p 153 2007

[145] A J Macpherson K D McCoy F-E Johansen and PBrandtzaeg ldquoThe immune geography of IgA induction andfunctionrdquoMucosal Immunology vol 1 no 1 pp 11ndash22 2008

[146] D Kvale and P Brandtzaeg ldquoConstitutive and cytokine inducedexpression of HLA molecules secretory component and inter-cellular adhesion molecule-1 is modulated by butyrate in thecolonic epithelial cell line HT-29rdquo Gut vol 36 no 5 pp 737ndash742 1995

[147] L VHooperMHWong AThelin L Hansson P G Falk andJ I Gordon ldquoMolecular analysis of commensal host-microbialrelationships in the intestinerdquo Science vol 291 no 5505 pp 881ndash884 2001

[148] S Hapfelmeier M A E Lawson E Slack et al ldquoReversiblemicrobial colonization of germ-free mice reveals the dynamicsof IgA immune responsesrdquo Science vol 328 no 5986 pp 1705ndash1709 2010

[149] DH ReikvamMDerrien R Islam et al ldquoEpithelial-microbialcross-talk in polymeric Ig receptor deficient micerdquo EuropeanJournal of Immunology vol 42 no 11 pp 2959ndash2970 2012

[150] EW Rogier A L Frantz M E C Bruno et al ldquoSecretory anti-bodies in breast milk promote long-term intestinal homeostasisby regulating the gut microbiota and host gene expressionrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 111 no 8 pp 3074ndash3079 2014

[151] G M Barton and R Medzhitov ldquoToll-like receptor signalingpathwaysrdquo Science vol 300 no 5625 pp 1524ndash1525 2003

[152] K Takeda and S Akira ldquoToll receptors and pathogen resis-tancerdquo Cellular Microbiology vol 5 no 3 pp 143ndash153 2003

[153] E Cario andD K Podolsky ldquoDifferential alteration in intestinalepithelial cell expression of Toll-like receptor 3 (TLR3) andTLR4 in inflammatory bowel diseaserdquo Infection and Immunityvol 68 no 12 pp 7010ndash7017 2000

[154] M Hausmann S Kiessling S Mestermann et al ldquoToll-likereceptors 2 and 4 are up-regulated during intestinal inflamma-tionrdquo Gastroenterology vol 122 no 7 pp 1987ndash2000 2002

[155] M T Abreu L S Thomas S Y Tesfay et al ldquoRegulation ofTLR4 and MD-2 in the intestinal epithelium evidence for dys-regulated LPS signaling in human inflammatory bowel diseaserdquoin Proceedings of the 90th Annual Meeting of the AmericanAssociation for Immunologists Abstract 3634 Denver ColoUSA 2003

[156] T A Schneeman M E C Bruno H Schjerven F-E JohansenL Chady and C S Kaetzel ldquoRegulation of the polymeric Igreceptor by signaling through TLRs 3 and 4 linking innate andadaptive immune responsesrdquo The Journal of Immunology vol175 no 1 pp 376ndash384 2005

[157] M E C Bruno A L Frantz E W Rogier F-E Johansen andC S Kaetzel ldquoRegulation of the polymeric immunoglobulinreceptor by the classical and alternative NF-120581B pathways inintestinal epithelial cellsrdquoMucosal Immunology vol 4 no 4 pp468ndash478 2011

[158] M E C Bruno E W Rogier A L Frantz A T Stefka SN Thompson and C S Kaetzel ldquoRegulation of the poly-meric immunoglobulin receptor in intestinal epithelial cellsby Enterobacteriaceae implications for mucosal homeostasisrdquoImmunological Investigations vol 39 no 4-5 pp 356ndash382 2010

[159] A L Frantz E W Rogier C R Weber et al ldquoTargeted deletionof MyD88 in intestinal epithelial cells results in compromisedantibacterial immunity associatedwith downregulation of poly-meric immunoglobulin receptor mucin-2 and antibacterialpeptidesrdquoMucosal Immunology vol 5 no 5 pp 501ndash512 2012

[160] E W Rogier A L Frantz M E C Bruno and C S KaetzelldquoSecretory IgA is concentrated in the outer layer of intestinalmucus along with gut bacteriardquo Pathogens In press

[161] M B Geuking K D McCoy and A J Macpherson ldquoThe func-tion of secretory IgA in the context of the intestinal continuumof adaptive immune responses in host-microbial mutualismrdquoSeminars in Immunology vol 24 no 1 pp 36ndash42 2012

20 ISRN Immunology

[162] L VHooper D R Littman andA JMacpherson ldquoInteractionsbetween the microbiota and the immune systemrdquo Science vol336 no 6086 pp 1268ndash1273 2012

[163] A J Macpherson M B Geuking E Slack S Hapfelmeierand K D McCoy ldquoThe habitat double life citizenship andforgetfulness of IgArdquo Immunological Reviews vol 245 no 1 pp132ndash146 2012

Submit your manuscripts athttpwwwhindawicom

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

6 ISRN Immunology

prior to the divergence of marsupials and monotremes fromeutherians Distinctive features include a single IgG subclass13 functional IgA subclasses and absence of IgD [83ndash85] Amore typical organization of the IGH locus including singlesubclasses of IgM IgD IgA and IgE and 2 subclasses ofIgG has been reported in mammals of the orders Carnivora[86 87] Cetartiodactyla (even-toed ungulates whales anddolphins) [88ndash91] and Perissodactyla (odd-toed ungulates)[92]

Mammals of the order Primates including humanshave the greatest number and diversity of Ig classes andsubclasses among all of the tetrapods Mapping of IGH locihas now been completed for a number of primate speciesincluding human (Homo sapiens) gorilla (Gorilla gorilla)chimpanzee (Pan troglodytes) orangutan (Pongo pygmaeus)gibbon (Hylobates lar) baboon (Papio anubis) mangabey(Cercocebus torquatus atys) and three species of macaquesthe crab-eating monkey (Macaca fascicularis) pig-tailedmonkey (Macaca nemestrina) and rhesus monkey (Macacamulatta) [93ndash97] A distinguishing feature of primates in thefamily Hominidae (great apes including humans gorillaschimpanzees and orangutans) and the family Hylobatidae(gibbons) is the presence of two IgA subclasses Althoughthe orangutan is a member of the family Hominidae its IGHlocus contains only one IgA subclass gene homologous to theIgA1 gene of other hominoids [95] By contrast primates inthe family Cercopithecidae (Old World monkeys includingbaboons mangabeys and macaques) have a single IgA geneGenetic analysis of the IGH locus of primates suggested thatduplication and diversification of the primordial C

1205741-C1205742-

C120576-C120572region occurred in a common ancestor of the great

apes after the divergence from Old World monkeys [98 99]These events resulted in the current organization of the IGHlocus in extant species of great apes with four IgG subclassesand two IgA subclasses (the duplicated C

120576gene became a

nonfunctional pseudogene hence only one class of IgE isexpressed) The close phylogenetic relationship among theC120572genes in the hominoids and Hylobatidae suggests that

the C1205721

and C1205722

genes evolved from a single C120572gene in a

common ancestor of the great apes and that the C1205722gene was

subsequently lost in the orangutan Evidence of continuingevolution in the IGH locus of humans was demonstrated bythe finding of triplication of the C

1205741-C1205742-C120576-C120572region in

several families [100] Subsequent genetic analyses inmultipleethnic groups revealed that gene duplications and deletionsin the human IGH locus are surprisingly common withfrequencies up to 22 in Japanese and Chinese populations[101]

3 Emergence of the IGJ Gene andEvolution of Polymeric Igs

The ability to produce Igs as both monomers (ie one unitcomprising 2 identical heavy chains and 2 identical lightchains) and polymers (covalently linked aggregates of 2 ormore Ig units) dates to the emergence of primitive Igs incartilaginous fish [23 42 50] Whereas pentameric IgM istypically found in serum as well as secretions the polymeric

forms of IgT IgX and IgA are generally restricted to mucosalsecretions The discovery of a low molecular weight ldquoJrdquo orldquojoiningrdquo chain as a component of polymeric Igs suggesteda potential mechanism for polymerization of individual Igmolecules into highermolecular weight complexes [102ndash104]The most primitive extant vertebrates in which the IGJ genehas been identified are the cartilaginous fish concurrent withthe presence of polymeric IgM Although the IGJ gene hasbeen identified in almost all lineages of jawed vertebratesit is surprisingly absent in some lineages of Osteichthyes(bony fishes) No ortholog of the IGJ gene has been identifiedin any species of the class Actinopterygii (ray-finned bonyfishes) for which the genome has been sequenced and anno-tated including Atlantic cod (Gadus morhua) common carp(Cyprinus carpio) tilapia (Oreochromis niloticus) zebrafish(Danio rerio) medaka (Oryzias latipes) and three-spinedstickleback (Gasterosteus aculeatus) In contrast to the ray-finned bony fishes IGJ genes and functional J chain proteinswere recently identified in two species of the class Sar-copterygii (lobe-finned bony fishes the West Indian Oceancoelacanth (Latimeria chalumnae) and the African lungfish(Protopterus dolloi) [105]) These findings suggest that theIGJ gene was lost during the evolution of the Actinopterygiiafter their divergence from a common ancestor with theSarcopterygii Despite the absence of J chain ray-finned bonyfishes are capable of forming polymeric IgM and IgT that canbe transported into mucosal secretions [38]

4 Evolution of Cellular Receptors for Igs

Theunique structure of vertebrate Igs allows for simultaneousbinding of antigen via the N-terminal variable regions ofthe Ig heavy and light chains and execution of effectorfunctions via the C-terminal constant (Fc) region of the Igheavy chains Evolution of multiple Ig heavy chain isotypesin higher vertebrates expanded the repertoire of Ig-mediatedeffector functions including specialized functions atmucosalsurfaces The simplest effector functions involve neutral-ization of microbes and their toxic byproducts whereaskilling of microbes can be affected by interaction of Igs withsoluble factors found in serumand secretionsThe concurrentemergence of Igs and proteins of the classical complementpathway in cartilaginous fishes is the earliest example of aspecific immune effector function mediated by the Fc regionof Ig heavy chains [106] As the immune system diversifiedduring vertebrate evolution cellular receptors for Ig heavychains (Fc receptors) allowed host cells to bind Igs forthe purpose of internalization transport andor activationof intracellular signaling pathways The most evolutionarilyancient of the vertebrate Fc receptors is the polymeric Igreceptor (pIgR) which first emerged in bony fishes (reviewedin [8]) (Figure 3)Theprimary function of pIgR is to transportpolymeric Igs (IgM IgT IgX and IgA) across glandular andmucosal epithelial cells into external secretions (see below)The fact that the extracellular Ig-binding region of pIgR iscomposed of multiple Ig-like domains suggests that the PIGR

ISRN Immunology 7

gene evolved by duplication of a primordial Ig gene is drivenby the need for an efficient mechanism for transport ofmucosal Igs into external secretions Similar forces may havedriven the evolution of FcRY a receptor first described forits function of transporting IgY from maternal blood tothe embryo yolk sac in chicken [9 107ndash109] FcRY is notstructurally homologous to pIgR or mammalian Fc receptorsbut is instead homologous to mammalian receptors formannose and phospholipase A2 with lectin-like extracellulardomains (Figure 3) A BLAST search of the National Centerfor Biotechnology Information (NCBI) nucleotide databasefor homologs of the gene encoding chicken FcRY (designatedPLA2R1 based on its homology to phospholipase A2 receptor1) revealed homologous genes in many bird species as wellas turtles lizards alligators and mammals However thefunctional significance of FcRYPLA2R1 in the transport ofIgY in reptiles (and possibly IgG in mammals) has not beenexplored A functional equivalent of FcRY in mammals isFcRn which mediates transport of IgG across endothelialand epithelial cells in such tissues as placenta and mucosalepithelia (reviewed in [110 111]) FcRn is homologous in struc-ture to major histocompatibility class (MHC) I moleculescomprising a ligand-binding alpha chain associated withsoluble 1205732-microglobulin (Figure 3)

A unique feature of the mammalian immune system isthe expression of Fc receptors for various Ig isotypes bycells of hematopoietic origin (Figure 3) (reviewed in [10])Engagement of these Fc receptors by Ig (in the presenceor absence of bound antigen depending on the particularFc receptor) initiates intracellular signaling pathways thatcan either augment or inhibit immune responses Withthe exception of Fc120576RII which has a single C-type lectin-like domain the extracellular Ig-binding regions of thesehematopoietic Fc receptors comprise 1 2 or 3 Ig-like domains[10] Genes encoding Fc120572120583R Fc120574RI Fc120574RIII Fc120576RI andFc120576RII are widely distributed among mammalian specieswhereas genes encoding Fc120572RI and Fc120574RII are restricted tothe primate lineage suggesting recent evolutionary originsThe genes encoding the120572120573 andor 120574 chains of Fc120576RI Fc120574RIIand Fc120574RIII are linked in a cluster on the long arm of humanchromosome 1 (1q23) not far removed from the gene for the120572 chain of Fc120574RI at 1q21 This tight linkage is consistent withduplication and diversification of a primordial FcR gene ina common ancestor of mammals The primate-specific genesencoding the 120572 and 120573 chains of Fc120574RII appear to have evolvedmore recently Another cluster of immune-related genes onthe long arm of chromosome 1 includes the genes for pIgR(1q31) and Fc120572120583R (1q32) Although the overall homologybetween pIgR and Fc120572120583R is relatively low they share aconserved binding site for IgA and IgM in the N-terminalIg-like domain Interestingly the genes encoding FcRn andFc120572RI are closely linked on the long arm of chromosome19 (19q133 and 19q1342 resp) although they bear littlehomology beyond the presence of a single Ig-like domain inthe extracellular region Finally the gene for the lectin-likereceptor Fc120576RII is located in an unrelated locus on the shortarm of chromosome 19 (19p133)

PIGR

dIgA

pIgR

Ag

SIgA

Free SC

Figure 4 Transcytosis of pIgR through a polarized epithelial celland formation of secretory Igs A polarized columnar epithelial cellis illustrated with the apical surface at the top and the basolateralsurface at the bottom Newly synthesized pIgR is targeted to thebasolateral surface where it binds polymeric Ig (pIg illustrated hereas dimeric (d)IgA) with or without bound antigen (Ag) Followingreceptor-mediated endocytosis pIg-bound and unoccupied pIgRmolecules are transported through a series of intracellular vesiclesto the apical surface Proteolytic cleavage of pIgR at the extracellularface of the plasma membrane releases free secretory component(SC) and secretory SIg (illustrated here as SIgA) Modified from [13]with permission from John Wiley and sons

5 Unique Biological Functions of pIgR

ThepIgR is expressed on the surface of glandular andmucosalepithelial binds where it binds selectively to polymericIg (pIg) and mediates its transport across epithelial cellsinto external secretions (reviewed in [17 111 112]) Most of

8 ISRN Immunology

02

100

Human IgA1Gorilla IgA1

Gorilla IgA281

6164

Human IgA2

Chimpanzee IgA2Chimpanzee IgA1

Gibbon IgA1Gibbon IgA2

Orangutan IgABaboon IgA

Rhesus macaque IgA53 100

98 69Dog IgA

Pig IgA100 Cattle IgA

52

Horse IgARabbit IgA (13 subclasses)

Mouse IgA57

99

Possum IgA

93

Chicken IgAPlatypus IgA1100

5095

Platypus IgA2

Trout IgTFrog IgX

Gecko IgldquoArdquo

(a)

02

Human pIgR

100Chimpanzee pIgRGorilla pIgR

55Gibbon pIgROrangutan pIgR100

100

100 Baboon pIgRRhesus macaque pIgR

Mouse pIgR

66

96

100 Pig pIgRCattle pIgR

85Horse pIgR

Dog pIgR

74

Rabbit pIgRPossum pIgR

Platypus pIgR

Chicken pIgR

10075

5979

Trout pIgRFrog pIgR

Anole pIgR

71

(b)

Figure 5 Coevolution of mucosal Igs and pIgR Simplified neighbor-joining phylogenetic trees of vertebrate (a) Ig and (b) pIgR proteinsequences with human IgA1 and pIgR denoted as outgroups Horizontal distances are proportional to the degree of divergence followinga multiple alignment of amino acid sequences Numbers at nodes denote bootstrap support for each bifurcation after 100 replicationsAccession numbers for mucosal Ig sequences human (Homo sapiens) IgA1 J00220 IgA2 (allotype m1) J00221 gorilla (Gorilla gorilla) IgA1X53703 IgA2 X53707 chimpanzee (Pan troglodytes) IgA1 X53702 IgA2 X53706 gibbon (Hylobates lar) IgA1 X53708 IgA2 X53709 Borneanorangutan (Pongo pygmaeus) IgA X53704 baboon (Papio anubis) IgA DQ868435 rhesus macaque (Macaca mulatta) AY039245 pig (Susscrofa) IgA U12594 cattle (Bos taurus) IgA AF109167 dog (Canis lupus familiaris) IgA L36871 horse (Equus caballus) IgA AY247966mouse (Mus musculus) IgA D11468 rabbit (Oryctolagus cuniculus) IgA1 X51647 brushtail possum (Trichosurus vulpecula) IgA AF027382duck-billed platypus (Ornithorhynchus anatinus) IgA1 AY055778 IgA2 AY055779 chicken (Gallus gallus) IgA AAB226142 leopard gecko(Eublepharis macularius) IgldquoArdquo (so designated because of its uncertain phylogeny with homology to both IgA and IgY) ABG726841African clawed frog (Xenopus laevis) IgX S03186 rainbow trout (Oncorhynchus mykiss) IgT AAW669811 Accession numbers for pIgRsequences with species that vary from those used for the mucosal Ig alignment in panel A noted in parentheses human NM 002644chimpanzee XM 003308710 gorilla XM 004028295 gibbon XM 003272974 Sumatran orangutan (Pongo abelii) NM 001131626 baboonXM 003893189 rhesus macaque XM 001083307 pig NM 214159 cattle NM 174143 dog XM 537133 horse XM 001492298 mouseNM 011082 rabbit NM 001171045 brushtail possum AF091137 duck-billed platypus XM 001508602 chicken NM 001044644 green anole(Anolis carolinensis) XM 003224013 African clawed frog EF079076 rainbow trout FJ940682

ISRN Immunology 9

our knowledge of pIgR-mediated transcytosis of mucosalIgs is derived from studies of mammalian secretory IgA(SIgA) as illustrated in Figure 4 Transcription of the PIGRgene and translation of pIgR mRNA is accompanied byinsertion of the nascent protein into the endoplasmic retic-ulum The pIgR undergoes substantial glycosylation duringtransport through the ER and Golgi apparatus and is thentargeted to the basolateral surface of polarized epithelialcells Membrane-bound pIgR binds pIg and pIg-containingimmune complexes which are internalized along with unoc-cupied pIgR via receptor-mediated endocytosis and thentranscytosed through a series of intracellular vesicles to theapical surface During transcytosis intracellular pIg antibod-ies can neutralize bacteria viruses and other antigens thathave gained access to the interior of the epithelial cell Atthe apical surface proteolytic cleavage of the membrane-spanning region of pIgR leads to the release of its extracellulardomain known as secretory component (SC) either in freeform or covalently bound to pIg Secretory Igs can neutralizepathogens and antigens within the mucosal lumen andfacilitate excretion of antigens that were transported throughthe epithelial cell as IgA immune complexes The SC moietyof SIgA has been shown to protect IgA from degradationby host and bacterial proteases and along with free SCconfers additional innate immune functions that protectthe epithelial surface from microbial invasion and limitpotentially damaging host inflammatory responses (reviewedin [113]) The finding of an SC-like polypeptide associatedwith polymeric IgT in rainbow trout [38] polymeric IgXin Xenopus [50] and polymeric IgA in birds [114] suggeststhat all vertebrate pIgRs share the function of transportingpolymeric Igs into external secretions In many mammalianspecies pIgR mediates epithelial transcytosis of both poly-meric IgM and IgA (reviewed in [111]) Although directevidence is not yet available it is reasonable to assume thatpIgR transports IgM in lower vertebrates It will be interestingto investigate whether the SCmoiety of secretory Igs in lowervertebrates mediates additional innate immune functions ashas been demonstrated for mammalian SC

6 Coevolution of pIgR and Mucosal Igs

Molecular cloning of the PIGR gene was first reportedfor mammalian species including eutherians marsupialsand monotremes [115ndash127] Subsequent elucidation of PIGRsequences from diverse species of jawed vertebrates hasallowed a comprehensive analysis of the evolutionary originsof the PIGR gene [38 128 128ndash132] and additional sequencesavailable in the Genbank database Whereas no ortholog ofthe PIGR gene has been found in any species of cartilaginousfish the PIGR gene has been annotated in all species of teleostfish for which the genome has been sequenced No orthologof the PIGR gene has been reported in lobe-finned bonyfishes but further analyses of whole genome sequences willbe required to determine whether the PIGR gene was lostfollowing the split of the Sarcopterygii It thus appears thatthe PIGR gene emerged in a common ancestor of highervertebrates after the split of cartilaginous fish and prior

to the evolution of modern teleosts likely driven by theselective pressure to provide a mechanism for transport ofpolymeric Igs such as IgM and IgT into mucosal secretionsThis hypothesis is supported by a comparison of phylogenetictrees based on amino acid sequences for IgT IgX and IgAheavy chains and pIgR (Figure 5)The predicted evolutionarydistance between trout IgT and frog IgX is similar to thedistance between trout and frog pIgR suggesting that thetransition from IgT to IgX as the dominantmucosal Ig isotypewas accompanied by adaptations in pIgR structure Similarparallels can be seen in the transition from IgX to IgA inreptiles birds and mammals and the concurrent evolutionof pIgR

Alignments of the amino acid sequences of mucosal Igheavy chains and pIgR from 10 representative vertebratespecies provide further support for the theory of coevolutionof mucosal IGH and PIGR genes (Figure 6) A commonfeature of Ig and pIgR proteins is the presence of repeatingIg-like domains (see Figure 2 for the basic structure of thesedomains) The structure of IgT IgX and IgA heavy chainsfrom fish amphibians reptiles and birds is similar to thatof IgM with 4 constant Ig-like domains In mammalianIgA (and IgG) the exon for the 2nd constant region wastruncated to encode a short ldquohingerdquo region which confersgreater mobility to the antigen-binding region at the N-terminusThus the CH3 domain of IgT IgX and IgA in lowervertebrates is structurally and functionally homologous tothe CH2 domain of mammalian IgA The heavy chains ofIgT IgX and IgA have retained a characteristic feature ofthe IgM heavy chain that is the presence of a conservedcysteine residue in the tailpiece that allows disulfide bondingbetween heavy chains of individual Ig proteins to formhigher molecular weight polymers These large Ig structurescontaining multiple antigen-binding sites are particularlywell suited for immune clearance of large antigens found atmucosal surfaces such as intact microbes and food particlesIn mucosal Igs from most vertebrate orders the J chainprotein initiates this polymerization process by disulfidebonding with 2 Ig heavy chains remaining associated withthe polymeric Ig at a stoichiometric ratio of 1 J chain subunitper 2 3 4 or 5 Ig units Despite the absence of J chainthe predominant form of IgM and IgT in mucus secretionsin rainbow trout was found to be polymeric in contrastto monomeric forms of IgM and IgT in the blood [38] Inmammals IgM is mainly found as a pentamer whereas theshorter heavy chain ofmammalian IgA restricts its polymericforms to dimers trimers and tetramers Further studies willbe required to characterize the polymeric structures of IgMIgT IgX and IgA in lower vertebrates

Alignment of pIgR amino acid sequences from 10 rep-resentative vertebrate species reveals structural changes thatwere evolved in parallel with structural changes in mucosalIgs (Figure 6(b)) All pIgR proteins have an N-terminalhydrophobic leader peptide required for targeting of thenascent protein into the ER The extracellular region ofpIgR protein is characterized by repeating ldquoIg-likerdquo domainssimilar to Ig heavy chains [115 133] Interestingly the num-ber of extracellular Ig-like domains has increased duringvertebrate evolution culminating with a total of 5 domains

10 ISRN Immunology

TailpieceHinge

Tailpiece

Mammalian IgA

VVVVVVVVVV

200121 300 400 4721

Human IgA1Rhesus IgA

Cattle IgAMouse IgA

Possum IgAPlatypus IgAChicken IgA

Frog IgXTrout IgT

Premammalian IgTXA

Gecko IgldquoArdquo

CH1

CH1

CH2

CH2

CH3

CH3

CH4

(a)

Leader 1 2 3 4 5

Ig homology extracellular domains

Linker CytoplasmicTM

1001 200 300 400 500 600 700 764

HumanRhesus

CattleMouse

PossumPlatypusChicken

AnoleFrog

Trout

(b)

Figure 6 Interspecies similarity in mucosal Ig and pIgR protein sequences from 10 representative vertebrate species Alignments in aminoacid sequences correspond to the phylogenetic trees shown in Figure 5 (a) Numbering ofmucosal Ig amino acids corresponds to the sequenceof human IgA1 beginning with the first residue of the variable domain CH heavy chain constant region domain (b) Numbering of pIgRamino acids corresponds to the sequence of human pIgR beginning with the first residue of the leader peptide TM transmembrane Forboth alignments the intensity of shading at each position signifies the degree of similarity amongmucosal Ig or pIgR sequences from differentspecies Gaps in sequence alignments signify regions of limited interspecies homology Approximate boundaries are noted of key structuralelements in mucosal Ig and pIgR proteins

in mammalian pIgR By contrast pIgR from amphibiansreptiles and birds contains 4 extracellular domains lackinga homolog of domain 2 of mammalian pIgR The mostprimitive form of pIgR found in teleost fish contains only2 extracellular domains homologous to domains 1 and 5of mammalian pIgR Interspecies homology is greatest indomain 1 which has been shown to be critical for binding ofmammalian pIgR to polymeric Igs (reviewed in [111]) Highlyconserved internal disulfide bonds are found in all the Ig-like domains of pIgR characteristic of the immunoglobulinfold An additional disulfide bond is found in domain 5 ofpIgR frommammals birds reptiles and amphibians but notfish In human SIgA this ldquoextrardquo disulfide bond in domain 5has been shown to rearrange to form a disulfide bond with

cysteine residues in one of the heavy chains of polymericIgA [134] Although the structure of SIgA has not beenfully characterized for lower vertebrates it is reasonable toassume that similar disulfide bonds form between domain 5of pIgR and polymeric IgA or IgX from birds reptiles andamphibians The linker region connecting domain 5 of pIgRto the transmembrane domain has a random structure that ispoorly conserved across species Proteolytic cleavage of pIgRwithin this domain leads to the release of SC from the apicalsurface of epithelial cells either free or bound to polymericIg The cytoplasmic domain of mammalian pIgR containsa number of intracellular sorting motifs that interact withcytoplasmic proteins to direct pIgR through the transcytoticpathway (reviewed in [111]) These motifs are reasonably

ISRN Immunology 11

Linker

TMCytoplasmic

J chain

Hinge 1

2

34

5

CL

VLVH

C1205721C1205722 C1205723

(a)

Linker

TMCytoplasmic

J chain

1

3 4

5

CL

VL

VH

C1205941205721

C1205941205722C1205941205723 C1205941205724

(b)

11

5

LinkerTM

Cytoplasmic

5

CL

VL

VH

C1205911C1205912

C1205913 C1205914

pIgR Ig-like domain

H chain Ig-like domain

L chain Ig-like domain

J chain

Disulfide bond

(c)

Figure 7 Theoretical model for changes in the structure of secretory Igs during evolution (a) The structure for mammalian SIgA is adaptedfrom the model of Woof and Russell [16] for human SIgA1 with permission from Nature Publishing Group (b) and (c) Theoretical modelsfor the structure of IgXA from amphibians and birds and SIgT from teleost fish respectively are predicted from alignment of Ig heavy chainand pIgR sequences with mammalian homologs

well conserved in pIgR from birds and reptiles but not inpIgR from amphibians and fish suggesting that complexmechanisms of intracellular trafficking of pIgR coevolvedwith the increasing complexity of the mucosal immunesystem

7 Hypothetical Models for Changes inSecretory Ig Structure during Coevolutionof Mucosal Igs and pIgR

A large number of structural and functional analyses overthe past 30 years allowed the development of detailed modelsfor the structure of mammalian SIgA (reviewed in [111 135])(Figure 7(a)) Domains 1 and 5 of pIgR the most highlyconserved Ig-like domains associate with theC1205722 subunits oftwo adjacent IgA heavy chains in a near-planar structure [136137] During transcytosis a disulfide bond forms betweenhighly conserved cysteine residues in domain 5 of pIgRand the C1205722 domain of one of the IgA heavy chains [134]Domains 2 3 and 4 allow mammalian pIgR to assume aflexible extended structure which is thought to wrap aroundthe IgA heavy chains and protect against degradation fromhost and microbial proteases Binding of mammalian pIgRto polymeric IgA or IgM requires the presence of J chain

connecting the Ig subunits (reviewed in [138]) and J chain-deficient mice fail to transport IgA and IgM into externalsecretions [139ndash141] Structure-function studies usingmutantforms of human J chain suggested that J chain binds directlyto pIgR and also maintains polymeric Ig in an optimalconformation for pIgR binding and transcytosis [142] Theunstructured linker region connecting domain 5 of pIgRto the transmembrane (TM) region gives membrane-boundpIgR the flexibility to bind large polymeric Igs (with orwithout associated antigens) and provides an exposed site forproteolytic cleavage of pIgR to SC The C-terminal region ofpIgR extends past the cytoplasmic face of the plasma mem-brane allowing association with cytoplasmic factors thatregulate trafficking of pIgR with or without bound polymericIg

Although detailed structural studies have not yet beenperformed on secretory Igs from lower vertebrates hypo-thetical models can be constructed based on alignmentswith their mammalian homologs A model for secretoryIgXA in birds reptiles and amphibians is illustrated inFigure 7(b) showing the C

1205941205722 domain in place of the hinge

region ofmammalian IgAThenumbering of the extracellulardomains of pIgR corresponds to the homologous domainsin mammalian pIgR noting the absence of domain 2 In

12 ISRN Immunology

this model the C120594120572

3 domains of two adjacent IgXA heavychains (homologous to the C

1205722 domain of mammalian IgA)

bind to the highly conserved domains 1 and 5 of pIgRGiven the conservation of the analogous cysteine residuesin domain 5 of pIgR and the C

1205941205723 domain of IgXA it

is assumed that a disulfide bond forms between pIgR andpolymeric Ig during epithelial transcytosis in birds reptilesand amphibiansThe absence of domain 2 in pIgR from thesevertebrate orders necessitates a more rigid structure thanthat of mammalian pIgR with a corresponding decrease inits ability to wrap around the IgXA heavy chains and pro-vide protection against proteoltyic degradation Despite theshorter length of pIgR in birds reptiles and amphibians theassociation with the J chain subunit of polymeric IgXA stillappears to be required Recombinant pIgR from the Africanfrog (Xenopus laevis) was shown to bind with moderatelyhigh affinity to human polymeric IgA containing J chain butnot to monomeric IgA [125] The affinity of Xenopus pIgRfor human pIgA was improved when Xenopus J chain wassubstituted for human J chain in a chimeric polymeric IgAmolecule The lack of sequence conservation across speciesin the linker region connecting domain 5 of pIgR to the TMregion suggests that it acts as a nonspecific ldquospacerrdquo As statedabove the cytoplasmic region of pIgR appears to have evolvedover time to provide enhanced regulation of pIgR trafficking

The hypothetical structure of secretory IgT from teleostfish in Figure 7(c) illustrates how the most primitive form ofpIgR comprising only extracellular domains 1 and 5 couldassociate with polymeric Ig and mediate epithelial transcy-tosis Association of pIgR domain 1 with the C

1205913 domain of

IgT would preserve the functional homology with secretoryIgs in higher vertebrates The short length of teleost pIgRwould necessitate the association of domain 5 with a C

1205913

domain on one of the heavy chains of the same IgT ratherthan spanning across to the adjaent IgT subunit While thismodel preserves the highly conserved association of pIgRdomain 1 with the orthologous domain of the IgT heavychain it does not explain the selectivity of teleost pIgR forpolymeric rather than monomeric IgT Although there is noexperimental evidence to support this model it could behypothesized that dimerization of two pIgR molecules in theplasmamembrane is required for high affinity binding of IgTas illustrated in the model in Figure 7(c) This hypotheticalmodel would also explain the lack of a necessity for J chainin polymeric IgT since each subunit in the pIgR dimer wouldonly be in contact with one IgT subunit The unstructuredlinker region connecting domain 5 of pIgR to the TM regionwould provide flexibility for association of 2 membrane-bound pIgR molecules with a large polymeric IgT molecule

Taken together the structural models for secretory Igsshown in Figure 7 are consistent with the selection of a morefunctional pIgR molecule over evolutionary time Duplica-tion and diversification of the extracellular Ig-like domainsof pIgR would provide a longer more flexible surface forbinding to polymeric Igs with higher affinity and protectingthe Ig heavy chains against proteolytic attack Expansion ofthe cytoplasmic domain of pIgR and incorporation of motifsfor binding cytoplasmic proteins would allow regulated

trafficking of pIgR and polymeric Igs across mucosal andglandular epithelial cells Importantly these models illustratea potential path for coevolution of IGH and PIGR genesdriven by the common selective pressure to provide antigen-specific humoral immune responses at mucosal surfaces

8 Evidence that the CommensalMicrobiota Provided the Driving Force forCoevolution of Mucosal Igs and pIgR

From the earliest evolution of vertebrate animals mucosal Igshave been an integral part of the emerging adaptive immunesystem Clearly many environmental factors served as driv-ing forces for the evolution of the adaptive immune systemin vertebrates including a longer lifespan thanmany (but notall) invertebrates and amore diverse diet that could introducea broader range of potential gut pathogens However it hasbeen proposed that the most significant force may havebeen the dramatic increase in the numbers and complexityof the resident microbiota in the evolution of vertebratesfrom their invertebrate ancestors [1 143 144] Antibodiesin mucosal secretions contribute to immune homeostasis bylimiting access of microbes and their products to the bodyproper maintaining the integrity of the epithelial barrier andshaping the composition of the commensal microbiota infavor of metabolically beneficial microorganisms [145] Thepredominance of polymeric Igs in these secretions promotesthese functions by providing multiple antigen-binding sitesper Ig complex thus increasing the overall avidity of antigen-antibody interactions Structural and functional refinementsin mucosal Igs culminating with the multifunctional secre-tory IgA molecule in mammals have further enhanced theirability to enhance immune homeostasis

The early emergence of pIgR in vertebrate evolutionprovided a mechanism for efficient transport of mucosal Igsinto external secretions It is well documented that crosstalkbetween mucosal epithelial cells and the resident microbiotamodulates expression of pIgR (reviewed in [17 111 112]) andit is reasonable to assume that these host-microbe interac-tions provided a driving force for evolution of the PIGR genein vertebrates The first demonstration that gut bacteria maymodulate pIgR expression in epithelial cells was the findingthat butyrate a bacterial fermentation product and importantenergy source in the colon upregulated expression of pIgRin the human colonic epithelial cell line HT-29 [146] A rolefor commensal bacteria in pIgR regulation was subsequentlydemonstrated by the observation that pIgR expression wasincreased when germ-free mice were colonized with Bacteri-oides thetaiotaomicron a prominent organism of the normalmouse and human intestinal microbiota [147] Amore recentstudy using a model of reversible colonization of germ-free mice with a nondividing mutant of Escherichia colidemonstrated that a long-lived SIgA response could besustained that specifically recognized the inducing bacteria[148] However exposure of E coli-colonized mice to otherbacteria limited the duration of the SIgA response against theoriginal colonizer suggesting a dynamic equilibriumbetweenmembers of the gut microbial community and host SIgA A

ISRN Immunology 13

study from the laboratory of Finn-Eirik Johansen demon-strated that diversity of the bacterial community in the cecallumen was reduced in pIgR-knockoutmice supporting a rolefor SIgA in limiting overgrowth of selected species [149] Incontrast the community of bacteria adherent to the epithelialsurface was more diverse in pIgR-knockout mice than inwild-typemice and these adherent bacteria caused enhancedexpression of several epithelial antimicrobial peptides Thesefindings suggest that bacteria-specific SIgA anchored in themucus layer restricts adhesion of bacteria to the epithelialsurface and limits bacterial stimulation of host epithelial cellsA recent study from the authorrsquos laboratory employing abreeding scheme in which119875119894119892119903minusminus damswere bred to119875119894119892119903+minusmales and vice versa demonstrated that SIgA antibodiesin breast milk promote long-term intestinal homeostasis byregulating the gut microbiota and gene expression in colonicepithelial cells [150]

A direct role for commensal andor pathogenic bacteriain the regulation of pIgR expression suggests that the innateimmune system may ldquoprimerdquo epithelial cells for transportof polymeric Ig produced during the adaptive immuneresponse Host cells mediate innate immune responses tomicrobial components through toll-like receptor (TLR) sig-naling (reviewed in [151 152]) Intestinal epithelial cells havebeen shown to express a wide variety of TLRs the expressionof which is upregulated during intestinal inflammation [153ndash155] Significantly expression of pIgR was shown to beupregulated in the HT-29 human intestinal epithelial cellline by bacterial LPS a ligand for TLR4 [156 157] Similarinduction of PIGR gene transcription was seen followingdirect binding of bacteria of the family Enterobacteriaceaewhich express a form of LPS that stimulates TLR4 [158]A recent study from the authorrsquos laboratory demonstratedthat shRNA-mediated knockdown of myeloid differentiationprimary response protein 88 (MyD88) a cytoplasmic adapterprotein that transduces signals from cell surface TLR4blocked the induction of PIGR gene transcription by LPS inHT-29 cells [159] The in vivo significance was confirmed bythe finding that mice with a targeted deletion of the Myd88gene only in intestinal epithelial cells had reduced expressionof pIgR compared to wild-type littermates [159] Mice withtargeted depletion of MyD88 in intestinal epithelial cells alsoexhibited reduced expression of mucin-2 the major compo-nent of the intestinal mucus layer and several antimicrobialpeptides and decreased transmucosal electrical resistanceThese alterations in epithelial barrier function were accom-panied by significant changes in the composition of the fecalmicrobiota increased numbers of bacteria adherent to theintestinal mucus layer and a dramatic increase in transloca-tion of gut bacteria into the drainingmesenteric lymphnodesincluding the opportunistic pathogen Klebsiella pneumoniaeThese findings demonstrate that MyD88-mediated crosstalkbetween the gut microbiota and intestinal epithelial cells iscrucial for optimal expression of pIgR production of SIgAdevelopment of a healthy gut microbiota and maintenanceof intestinal homeostasis

A model can be proposed in which continuous stimu-lation of intestinal epithelial cells by gut bacteria regulates

Lumen

Mucus

Epithelium

Lamina

PIGR

TLRs

MyD88

Bacteria

Plasma cells

propria

Polymeric Ig

Polymeric Ig receptor

Secretory component

Figure 8 Crosstalk between the polymeric immunoglobulin recep-tor secretory immunoglobulins and the gut microbiotaThe single-layered epithelium that lines the gastrointestinal tract is coveredwith a thick mucus layer which physically excludes members ofthe resident microbiota but allows diffusion of shed components ofmicrobial cells Stimulation of epithelial toll-like receptors (TLRs)with microbial products engages the cytoplasmic adaptor proteinMyD88 and initiates NF120581B-dependent signaling pathways Translo-cation of activated NF120581B and other transcription factors to thenucleus enhances transcription of thePIGR gene Activation of TLRsmay also stimulate pIgR transcytosis Polymeric Igs secreted bylamina propria plasma cells bind to pIgRon the basolateral surface ofepithelial cells and are transcytosed to the apical surface along withunoccupied pIgR Proteolytic cleavage of pIgR at the apical surfacereleases secretory SIg and free secretory component (SC) Binding ofSIg and SC to luminal bacteria promotes association with themucuslayer and prevents direct access of bacteria to the epithelial surfaceOver time the continuous crosstalk with SIg shapes the compositionof the gut microbiota Modified from [17] under terms of authorrsquoscopyright with Nature Publishing Group

pIgR expression and transport of SIgA and promotes immuneexclusion of resident and pathogenic bacteria (Figure 8) Adense layer of mucus which increases in thickness fromthe proximal to the distal colon serves to separate bacteriafrom direct contact with the epithelial surface Secretionof microbial-associated molecular patterns (MAMPs) bycommensal bacteria stimulates MyD88-dependent TLR sig-naling leading to enhanced expression of pIgR and antimi-crobial peptides and increased mucus production Bindingof pIgA to pIgR and possibly also signaling via MAMPs

14 ISRN Immunology

enhances transcytosis of pIgA pIgA-containing immunecomplexes and unoccupied pIgR which promotes clearanceof antigens and pathogens from the lamina propria intra-cellular neutralization and release of SIgA and SC at theluminal surface SIgA and SC serve to trap bacteria in themucus layer limiting their access to the epithelial surface Inmice with a targeted deletion of the Muc2 gene which havea severely depleted mucus layer in the colon SIgA and SCfail to associate with the surface of colonic epithelial cells[160] The presence of SIgA in the intestinal lumen whetherderived passively frommaternalmilk or actively via epithelialtranscytosis shapes the composition of the gut microbiotaand modulates intestinal epithelial gene expression

9 Concluding Remarks

The first microbes that emerged on Earth almost 4 billionyears ago encountered a hostile world where nutrients werescarce hazards were everywhere and life was short Withthe evolution of multicellular organisms about 3 billion yearslater a select group ofmicrobes chose to sacrifice an indepen-dent existence for the benefits of a mutualistic relationshipwith eukaryotic hosts Prokaryotic-eukaryotic mutualismreached its apex some 500 million years ago with theemergence of primitive vertebrates whose gastrointestinaltracts were populated by an abundant and diverse commensalmicrobiota In humans the large intestine is home to some100 trillion microorganisms 10 times more than the totalnumber of eukaryotic cells in the entire body The microbesthat inhabit the vertebrate GI tract provide many benefitsto the eukaryotic host including digestion of complex foodmolecules synthesis of vitamins and production of solublefactors that enhance the development of the host immunesystem In return the eukaryotic host provides the microbeswith a warm moist place to live abundant food low oxygentension and a soft bed of mucus on which to form biofilmsWhen this mutually beneficial arrangement is challenged bypathogenicmicrobes the eukaryotic host and the commensalmicrobiota join forces to battle the pathogens and protectthe body from invasion The vertebrate immune system isequipped with a well-trained army of immune cells and asophisticated arsenal of weapons (cell surface molecules andsecreted factors) that protect the host from all but the mostvirulent pathogens This immune ldquoarmyrdquo also serves as aconstant reminder to the commensal microbes that whilethey are free to enjoy the amenities of the mucosal surfacesthey are not welcome in the body proper The emergence ofantigen-specific Igs and T-cell receptors in jawed vertebratesbegan a process of immunological diversification that led tothe development of a specialized mucosal immune systemin higher vertebrates in which secretory Igs play a centralrole The relationship between host and microbiota is clearlyreciprocal the mucosal Igs that evolved in response toselective pressure from the commensal microbiota play acentral role throughout life in shaping the compositiongenetics andmetabolic activity of themicrobiota [1 161 162]

The epithelial layer lining mucosal surfaces provides aphysical and innate immune barrier against penetration of

the body proper by microbes undigested food antigens andpotentially noxious environmental substances The evolu-tionary challenge of transporting mucosal Igs into externalsecretions without compromising the epithelial barrier wasmet by the emergence of the PIGR gene in an ancestor ofbony fishes encoding an epithelial-specific transmembraneprotein that actively transports polymeric Igs across mucosaland glandular epithelia (Figure 4) Structural similaritiesbetween Igs and the extracellular Ig-binding domains of pIgR(Figure 6) suggest that duplication and diversification of agene encoding primordial Ig-like domain may have givenrise to the PIGR gene in a primitive vertebrate ancestorParallel refinement of the structures of mucosal Igs andpIgR during tetrapod evolution (Figures 6 and 7) culminatedin the evolution of the multifunctional SIgA molecule inmammals in which the pIgR-derived SC subunit providesinnate immune functions and protects the antigen-bindingIgA polymer from proteolytic degradation In addition toacting as a powerful force during vertebrate evolution thereciprocal relationship between pIgR mucosal Igs and thecommensal microbiota provides benefits throughout thelife of the individual Microbial colonization of newbornvertebrates stimulates development of mucosal B cells andclass switching to mucosal Ig isotypes [1 163] Microbialfactors upregulate expression of pIgR enhancing transportof mucosal Igs into external secretions where they in turnregulate the microbiotaThis beautifully orchestrated processallows us to maintain a healthy relationship with our resi-dent microbiota while providing mutual protection againstpathogens

Conflict of Interests

The author declares that there is no conflict of interestsregarding the publication of this paper

Acknowledgments

This work was supported by Grant no AI069027 from theNational Institutes of Health of the United States of America(and an associatedAmerican Recovery andReinvestmentActsupplement) and a Senior Research Award from the Crohnrsquosand Colitis Foundation of America

References

[1] C L Maynard C O Elson R D Hatton and C T WeaverldquoReciprocal interactions of the intestinal microbiota andimmune systemrdquo Nature vol 489 no 7415 pp 231ndash241 2012

[2] M F Flajnik and M Kasahara ldquoOrigin and evolution of theadaptive immune system genetic events and selective pres-suresrdquo Nature Reviews Genetics vol 11 no 1 pp 47ndash59 2010

[3] M F Flajnik and L du Pasquier ldquoEvolution of the immunesystemrdquo in Fundamental Immunology W E Paul Ed chapter4 pp 67ndash128 Lippincott Williams ampWilkins Philadelphia PaUSA 2012

[4] M Hirano S Das P Guo and M D Cooper ldquoThe evolutionof adaptive immunity in vertebratesrdquo Advances in Immunologyvol 109 pp 125ndash157 2011

ISRN Immunology 15

[5] T BoehmNMcCurley Y SutohM SchorppMKasahara andM D Cooper ldquoVLR-based adaptive immunityrdquo Annual Reviewof Immunology vol 30 pp 203ndash220 2012

[6] T Hunkapiller and L Hood ldquoImmunology the growing immu-noglobulin gene superfamilyrdquoNature vol 323 no 6083 pp 15ndash16 1986

[7] P Bork L Holm and C Sander ldquoThe immunoglobulin foldstructural classification sequence patterns and common corerdquoJournal of Molecular Biology vol 242 no 4 pp 309ndash320 1994

[8] C S Kaetzel and M W Russell ldquoPhylogeny and comparativephysiology of IgArdquo in Mucosal Immunology J Mestecky WStrober H Cheroutre B Kelsall B N Lambrecht and M WRussell Eds chapter 19 Academic PressElsevier WalthamMass USA 2014

[9] Y He and P J Bjorkman ldquoStructure of FcRY an avian immu-noglobulin receptor related to mammalian mannose receptorsand its complex with IgYrdquo Proceedings of the National Academyof Sciences of the United States of America vol 108 no 30 pp12431ndash12436 2011

[10] J M Woof and D R Burton ldquoHuman antibody-Fc receptorinteractions illuminated by crystal structuresrdquo Nature ReviewsImmunology vol 4 no 2 pp 89ndash99 2004

[11] W L Martin A P West Jr L Gan and P J Bjorkman ldquoCrystalstructure at 28 A of an FcRnheterodimeric Fc complexmechanism of pH-dependent bindingrdquo Molecular Cell vol 7no 4 pp 867ndash877 2001

[12] E S Ward ldquoAcquiring maternal immunoglobulin differentreceptors similar functionsrdquo Immunity vol 20 no 5 pp 507ndash508 2004

[13] C S Kaetzel ldquoThe polymeric immunoglobulin receptor bridg-ing innate and adaptive immune responses atmucosal surfacesrdquoImmunological Reviews vol 206 no 1 pp 83ndash99 2005

[14] M Acharya G Borland A L Edkins et al ldquoCD23Fc120576RIImolecular multi-taskingrdquo Clinical and Experimental Immunol-ogy vol 162 no 1 pp 12ndash23 2010

[15] V B Klimovich ldquoIgM and its receptors structural and func-tional aspectsrdquo Biochemistry vol 76 no 5 pp 534ndash549 2011

[16] J MWoof andMW Russell ldquoStructure and function relation-ships in IgArdquo Mucosal Immunology vol 4 no 6 pp 590ndash5972011

[17] F-E Johansen and C S Kaetzel ldquoRegulation of the polymericimmunoglobulin receptor and IgA transport new advances inenvironmental factors that stimulate pIgR expression and itsrole in mucosal immunityrdquo Mucosal Immunology vol 4 no 6pp 598ndash602 2011

[18] F Kokubu K Hinds R Litman M J Shamblott and G WLitman ldquoExtensive families of constant region genes in a phy-logenetically primitive vertebrate indicate an additional levelof immunoglobulin complexityrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 84 no16 pp 5868ndash5872 1987

[19] A S Greenberg A L Hughes J Guo D Avila E CMcKinneyand M F Flajnik ldquoA novel ldquochimericrdquo antibody class in carti-laginous fish IgMmay not be the primordial immunoglobulinrdquoEuropean Journal of Immunology vol 26 no 5 pp 1123ndash11291996

[20] H Dooley and M F Flajnik ldquoShark immunity bites back affin-ity maturation and memory response in the nurse shark Ging-lymostoma cirratumrdquo European Journal of Immunology vol 35no 3 pp 936ndash945 2005

[21] S F Schluter R M Bernstein and J J Marchalonis ldquoMolecularorigins and evolution of immunoglobulin heavy-chain genes ofjawed vertebratesrdquo Immunology Today vol 18 no 11 pp 543ndash549 1997

[22] Y Ohta and M Flajnik ldquoIgD like IgM is a primordial immu-noglobulin class perpetuated in most jawed vertebratesrdquo Pro-ceedings of the National Academy of Sciences of the United Statesof America vol 103 no 28 pp 10723ndash10728 2006

[23] S Fillatreau A Six S Magadan R Castro J O Sunyer andP Boudinot ldquoThe astonishing diversity of Ig classes and B cellrepertoires in teleost fishrdquo Frontiers in Immunology vol 4 no28 2013

[24] W Harriman H Volk N Defranoux and M Wabl ldquoImmu-noglobulin class switch recombinationrdquo Annual Review ofImmunology vol 11 pp 361ndash384 1993

[25] J Stavnezer and C T Amemiya ldquoEvolution of isotype switch-ingrdquo Seminars in Immunology vol 16 no 4 pp 257ndash275 2004

[26] V M Barreto Q Pan-Hammarstrom Y Zhao L Ham-marstrom Z Misulovin and M C Nussenzweig ldquoAID frombony fish catalyzes class switch recombinationrdquo Journal ofExperimental Medicine vol 202 no 6 pp 733ndash738 2005

[27] T C Fletcher and AWhite ldquoAntibody production in the plaice(Pleuronectes platessa L) after oral and parenteral immuniza-tion with Vibrio anguillarum antigensrdquo Aquaculture vol 1 pp417ndash428 1972

[28] J W H M Rombout L J Blok C H J Lamers and E EgbertsldquoImmunization of carp (Cyprinus carpio) with a Vibrio anguil-larum bacterin indications for a common mucosal immunesystemrdquo Developmental and Comparative Immunology vol 10no 3 pp 341ndash351 1986

[29] U Georgopoulou and J-M Vernier ldquoLocal immunologicalresponse in the posterior intestinal segment of the rainbowtrout after oral administration of macromoleculesrdquo Develop-mental andComparative Immunology vol 10 no 4 pp 529ndash5371986

[30] C J Lobb ldquoSecretory immunity induced in catfish Ictaluruspunctatus following bath immunizationrdquo Developmental andComparative Immunology vol 11 no 4 pp 727ndash738 1987

[31] J D Hansen E D Landis and R B Phillips ldquoDiscovery ofa unique Ig heavy-chain (IgT) in rainbow trout implicationsfor a distinctive B cell developmental pathway in teleost fishrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 102 no 19 pp 6919ndash6924 2005

[32] N Danilova J Bussmann K Jekosch and L A Steiner ldquoTheimmunoglobulin heavy-chain locus in zebrafish identificationand expression of a previously unknown isotype immunoglob-ulin Zrdquo Nature Immunology vol 6 no 3 pp 295ndash302 2005

[33] R Savan A Aman K Sato R Yamaguchi and M Sakai ldquoDis-covery of a new class of immunoglobulin heavy chain fromfugurdquo European Journal of Immunology vol 35 no 11 pp 3320ndash3331 2005

[34] R Savan A AmanMNakao HWatanuki andM Sakai ldquoDis-covery of a novel immunoglobulin heavy chain gene chimerafrom common carp (Cyprinus carpio L)rdquo Immunogenetics vol57 no 6 pp 458ndash463 2005

[35] F Gambon-Deza C Sanchez-Espinel and S Magadan-Mompo ldquoPresence of an unique IgT on the IGH locus in three-spined stickleback fish (Gasterosteus aculeatus) and the veryrecent generation of a repertoire of VH genesrdquo Developmentaland Comparative Immunology vol 34 no 2 pp 114ndash122 2010

[36] T M Tadiso K K Lie and I Hordvik ldquoMolecular cloning ofIgT fromAtlantic salmon and analysis of the relative expression

16 ISRN Immunology

of 120591 120583 and 120575 in different tissuesrdquo Veterinary Immunology andImmunopathology vol 139 no 1 pp 17ndash26 2011

[37] S Mashoof C Pohlenz P L Chen et al ldquoExpressed IgH 120583and 120591 transcripts share diversity segment in ranched Thunnusorientalisrdquo Developmental and Comparative Immunology vol43 no 1 pp 76ndash86 2014

[38] Y-A Zhang I Salinas J Li et al ldquoIgT a primitive immunoglob-ulin class specialized in mucosal immunityrdquo Nature Immunol-ogy vol 11 no 9 pp 827ndash835 2010

[39] S Magadan-Mompo C Sanchez-Espinel and F Gambon-Deza ldquoImmunoglobulin heavy chains in medaka (Oryziaslatipes)rdquo BMC Evolutionary Biology vol 11 no 1 article 1652011

[40] C T Amemiya J Alfoldi A P Lee et al ldquoThe African coela-canth genome provides insights into tetrapod evolutionrdquoNature vol 496 no 7445 pp 311ndash316 2013

[41] T Ota J P Rast G W Litman and C T Amemiya ldquoLineage-restricted retention of a primitive immunoglobulin heavy chainisotype within the Dipnoi reveals an evolutionary paradoxrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 100 no 5 pp 2501ndash2506 2003

[42] Y Sun Z Wei N Li and Y Zhao ldquoA comparative overview ofimmunoglobulin genes and the generation of their diversity intetrapodsrdquo Developmental and Comparative Immunology vol39 no 1-2 pp 103ndash109 2013

[43] I Hadji-Azimi ldquoAnuran immunoglobulins a reviewrdquo Develop-mental and Comparative Immunology vol 3 no 2 pp 223ndash2431979

[44] E Hsu M F Flajnik and L du Pasquier ldquoA third immunoglob-ulin class in amphibiansrdquo The Journal of Immunology vol 135no 3 pp 1998ndash2004 1985

[45] C T Amemiya R N Haire and G W Litman ldquoNucleotidesequence of a cDNA encoding a third distinct Xenopusimmunoglobulin heavy chain isotyperdquo Nucleic Acids Researchvol 17 no 13 p 5388 1989

[46] R Muszligmann M Wilson A Marcuz M Courtet and L duPasquier ldquoMembrane exon sequences of the three Xenopus Igclasses explain the evolutionary origin of mammalian isotypesrdquoEuropean Journal of Immunology vol 26 no 2 pp 409ndash4141996

[47] R Muszligmann L du Pasquier and E Hsu ldquoIs Xenopus IgX ananalog of IgArdquo European Journal of Immunology vol 26 no12 pp 2823ndash2830 1996

[48] B Schaerlinger and J-P Frippiat ldquoIgX antibodies in the urodeleamphibian Ambystoma mexicanumrdquo Developmental and Com-parative Immunology vol 32 no 8 pp 908ndash915 2008

[49] B Schaerlinger M Bascove and J-P Frippiat ldquoA new isotypeof immunoglobulin heavy chain in the urodele amphibianPleurodeles waltl predominantly expressed in larvaerdquoMolecularImmunology vol 45 no 3 pp 776ndash786 2008

[50] S Mashoof A Goodroe C C Du et al ldquoAncient T-independence of mucosal IgXA gut microbiota unaffected bylarval thymectomy in Xenopus laevisrdquo Mucosal Immunologyvol 6 no 2 pp 358ndash368 2013

[51] J P Vaerman J Picard and J F Heremans ldquoStructural dataon chicken IgA and failure to identify the IgA of the tortoiserdquoin Immunologic Phylogeny vol 64 of Advances in ExperimentalMedicine and Biology pp 185ndash195 Springer New York NYUSA 1975

[52] J L Portis and J E Coe ldquoIgM the secretory immunoglobulinof reptiles and amphibiansrdquo Nature vol 258 no 5535 pp 547ndash548 1975

[53] J E Coe D Leong J L Portis and L A Thomas ldquoImmuneresponse in the garter snake (Thamnophis ordinoides)rdquo Immu-nology vol 31 no 3 pp 417ndash424 1976

[54] D Hadge and H Ambrosius ldquoEvolution of low molecularweight immunoglobulinsmdashIV IgY-like immunoglobulins ofbirds reptiles and amphibians precursors of mammalian IgArdquoMolecular Immunology vol 21 no 8 pp 699ndash707 1984

[55] D Hadge and H Ambrosius ldquoEvolution of low molecularweight immunoglobulins V Degree of antigenic relationshipbetween the 7S immunoglobulins ofmammals birds and lowervertebrates to the turkey IgYrdquo Developmental and ComparativeImmunology vol 10 no 3 pp 377ndash385 1986

[56] S Magadan-Mompo C Sanchez-Espinel and F Gambon-Deza ldquoImmunoglobulin genes of the turtlesrdquo Immunogeneticsvol 65 no 3 pp 227ndash237 2013

[57] Z Wei Q Wu L Ren et al ldquoExpression of IgM IgD and IgYin a reptile Anolis carolinensisrdquoThe Journal of Immunology vol183 no 6 pp 3858ndash3864 2009

[58] F Gambon-Deza C Sanchez-Espinel and J V Beneitez ldquoAnovel IgA-like immunoglobulin in the reptile Eublepharis mac-ulariusrdquo Developmental and Comparative Immunology vol 31no 6 pp 596ndash605 2007

[59] G Cheng Y Gao T Wang et al ldquoExtensive diversification ofIgH subclass-encoding genes and IgM subclass switching incrocodiliansrdquo Nature Communications vol 4 article 1337 2013

[60] S Magadan-Mompo C Sanchez-Espinel and F Gambon-Deza ldquoIgH loci of American alligator and saltwater crocodileshed light on IgA evolutionrdquo Immunogenetics vol 65 no 7 pp531ndash541 2013

[61] E Orlans and M E Rose ldquoAn IgA-like immunoglobulin in thefowlrdquo Immunochemistry vol 9 no 8 pp 833ndash838 1972

[62] G A Leslie and L N Martin ldquoStudies on the secretory immu-nologic system of fowl 3 Serum and secretory IgA of thechickenrdquoThe Journal of Immunology vol 110 no 1 pp 1ndash9 1973

[63] J Bienenstock D Y Perey J Gauldie and B J UnderdownldquoChicken 120574A physicochemical and immunochemical charac-teristicsrdquoThe Journal of Immunology vol 110 no 2 pp 524ndash5331973

[64] A M Lebacq-Verheyden J P Vaerman and J F HeremansldquoQuantification and distribution of chicken immunoglobulinsIgA IgM and IgG in serum and secretionsrdquo Immunology vol27 no 4 pp 683ndash692 1974

[65] J Goudswaard A Noordzij R H van Dam J A vanderDonk and J P Vaerman ldquoThe immunoglobulins of the turkey(Meleagris gallopavo) Isolation and characterization of IgGIgM and IgA in body fluids eggs and intraocular tissuesrdquoPoultry science vol 56 no 6 pp 1847ndash1851 1977

[66] D Hadge and H Ambrosius ldquoComparative studies on thestructure of biliary immunoglobulins of some avian speciesII Antigenic properties of the biliary immunoglobulins ofchicken turkey duck and gooserdquo Developmental and Compar-ative Immunology vol 12 no 2 pp 319ndash329 1988

[67] J Goudswaard J P Vaerman and J F Heremans ldquoThreeimmunoglobulin classes in the pigeon (Columbia livia)rdquo Inter-national Archives of Allergy andApplied Immunology vol 53 no5 pp 409ndash419 1977

[68] P L K Ng and D A Higgins ldquoBile immunoglobulin of theduck (Anas platyrhynchos) I Preliminary characterization andontogenyrdquo Immunology vol 58 no 2 pp 323ndash327 1986

[69] K E Magor G W Warr Y Bando D L Middleton and DA Higgins ldquoSecretory immune system of the duck (Anas

ISRN Immunology 17

platyrhynchos) Identification and expression of the genesencoding IgA and IgM heavy chainsrdquo European Journal ofImmunology vol 28 no 3 pp 1063ndash1068 1998

[70] Y Zhao H Rabbani A Shimizu and L Hammarstrom ldquoMap-ping of the chicken immunoglobulin heavy-chain constantregion gene locus reveals an inverted 120572 gene upstream of acondensed 120592 generdquo Immunology vol 101 no 3 pp 348ndash3532000

[71] M L Lundqvist D L Middleton S Hazard and G W WarrldquoThe immunoglobulin heavy chain locus of the duck genomicorganization and expression of D J and C region genesrdquo TheJournal of Biological Chemistry vol 276 no 50 pp 46729ndash46736 2001

[72] T HuangM Zhang ZWei et al ldquoAnalysis of immunoglobulintranscripts in the ostrich Struthio camelus a primitive avianspeciesrdquo PLoS ONE vol 7 no 3 Article ID e34346 2012

[73] K H Roux ldquoImmunoglobulin structure and function asrevealed by electron microscopyrdquo International Archives ofAllergy and Immunology vol 120 no 2 pp 85ndash99 1999

[74] F Gambon-Deza C Sanchez-Espinel and S Magadan-Mompo ldquoThe immunoglobulin heavy chain locus in the platy-pus (Ornithorhynchus anatinus)rdquo Molecular Immunology vol46 no 13 pp 2515ndash2523 2009

[75] Y Zhao H Cui C M Whittington et al ldquoOrnithorhynchusanatinus (platypus) links the evolution of immunoglobulingenes in eutherian mammals and nonmammalian tetrapodsrdquoThe Journal of Immunology vol 183 no 5 pp 3285ndash3293 2009

[76] M Aveskogh and L Hellman ldquoEvidence for an early appear-ance of modern post-switch isotypes in mammalian evolutioncloning of IgE IgG and IgA from the marsupial Monodelphisdomesticardquo European Journal of Immunology vol 28 no 9 pp2738ndash2750 1998

[77] K Belov G A Harrison and DW Cooper ldquoMolecular cloningof the cDNA encoding the constant region of the immunoglob-ulin a heavy chain (C120572) from amarsupialTrichosurus vulpecula(common brushtail possum)rdquo Immunology Letters vol 60 no2-3 pp 165ndash170 1998

[78] K Belov K R Zenger L Hellman and DW Cooper ldquoEchidnaIgA supports mammalian unity and traditional Therian rela-tionshiprdquo Mammalian Genome vol 13 no 11 pp 656ndash6632002

[79] K Belov and L Hellman ldquoImmunoglobulin genetics of Orni-thorhynchus anatinus (platypus) and Tachyglossus aculeatus(short-beaked echidna)rdquo Comparative Biochemistry and Phys-iology vol 136 no 4 pp 811ndash819 2003

[80] M VernerssonM Aveskogh BMunday and L Hellman ldquoEvi-dence for an early appearance of modern post-switch immu-noglobulin isotypes in mammalian evolution (II) cloning ofIgE IgG1 and IgG2 fromamonotreme the duck-billed platypusOrnithorhynchus anatinusrdquo European Journal of Immunologyvol 32 no 8 pp 2145ndash2155 2002

[81] C Auffray R Nageotte and J L Sikorav ldquoMouse immunoglob-ulin A nucleotide sequence of the structural gene for the 120572heavy chain derived from cloned cDNAsrdquo Gene vol 13 no 4pp 365ndash374 1981

[82] T Ukaji D Sumiyama and O Kai ldquoSequence determinationof the heavy-chain constant region in four immunoglobulinclasses of Mongolian gerbils (Meriones unguiculatus)rdquo Experi-mental Animals vol 61 no 2 pp 99ndash107 2012

[83] R C Burnett W C Hanly S K Zhai and K L Knight ldquoTheIgA heavy chain gene family in rabbit cloning and sequence

analysis of 13 C120572 genesrdquo The EMBO Journal vol 8 no 13 pp4041ndash4047 1989

[84] D K Lanning S-K Zhai and K L Knight ldquoAnalysis of the 31015840C120583 region of the rabbit Ig heavy chain locusrdquoGene vol 309 no2 pp 135ndash144 2003

[85] F Ros J Puels N Reichenberger W van Schooten R Buelowand J Platzer ldquoSequence analysis of 05Mb of the rabbitgermline immunoglobulin heavy chain locusrdquo Gene vol 330no 1-2 pp 49ndash59 2004

[86] M Patel D Selinger G E Mark G J Hickey and G FHollis ldquoSequence of the dog immunoglobulin alpha and epsilonconstant region genesrdquo Immunogenetics vol 41 no 5 pp 282ndash286 1995

[87] Z Zhao Y Zhao Q Pan-Hammarstrom et al ldquoPhysical map-ping of the giant panda immunoglobulin heavy chain constantregion genesrdquo Developmental and Comparative Immunologyvol 31 no 10 pp 1034ndash1049 2007

[88] W R Brown and J E Butler ldquoCharacterization of a C120572 gene ofswinerdquoMolecular Immunology vol 31 no 8 pp 633ndash642 1994

[89] W R Brown H Rabbani J E Butler and L HammarstromldquoCharacterization of the bovine C120572 generdquo Immunology vol 91no 1 pp 1ndash6 1997

[90] G PWhite P Roche M R Brandon S E Newton and E N TMeeusen ldquoCloning and characterization of sheep (Ovis aries)immunoglobulin 120572 chainrdquo Immunogenetics vol 48 no 5 pp359ndash362 1998

[91] AMancia T A Romano H A Gefroh et al ldquoCharacterizationof the immunoglobulin A heavy chain gene of the Atlantic bot-tlenose dolphin (Tursiops truncatus)rdquo Veterinary Immunologyand Immunopathology vol 118 no 3-4 pp 304ndash309 2007

[92] B Wagner I Greiser-Wilke and D F Antczak ldquoCharacteriza-tion of the horse [Equus caballus] IGHA generdquo Immunogeneticsvol 55 no 8 pp 552ndash560 2003

[93] N Takahashi S Ueda and M Obata ldquoStructure of humanimmunoglobulin gamma genes implications for evolution of agene familyrdquo Cell vol 29 no 2 pp 671ndash679 1982

[94] J G Flanagan M-P Lefranc and T H Rabbitts ldquoMechanismsof divergence and convergence of the human immunoglobulin1205721 and 1205722 constant region gene sequencesrdquo Cell vol 36 no 3pp 681ndash688 1984

[95] S Kawamura K Omoto and S Ueda ldquoEvolutionary hypervari-ability in the hinge region of the immunoglobulin alpha generdquoJournal of Molecular Biology vol 215 no 2 pp 201ndash206 1990

[96] F Scinicariello F Masseoud L Jayashankar and R AttanasioldquoSooty mangabey (Cercocebus torquatus atys) IGHG and IGHAgenesrdquo Immunogenetics vol 58 no 12 pp 955ndash965 2006

[97] K A Rogers L Jayashankar F Scinicariello and R AttanasioldquoNonhuman primate IgA genetic heterogeneity and interac-tions with CD89rdquoThe Journal of Immunology vol 180 no 7 pp4816ndash4824 2008

[98] S Kawamura N Saitou and S Ueda ldquoConcerted evolution ofthe primate immunoglobulin 120572-gene through gene conversionrdquoThe Journal of Biological Chemistry vol 267 no 11 pp 7359ndash7367 1992

[99] S Kawamura and S Ueda ldquoImmunoglobulin C119867gene family in

hominoids and its evolutionary historyrdquo Genomics vol 13 no1 pp 194ndash200 1992

[100] A Brusco U Cariota A Bottaro et al ldquoStructural andimmunologic analysis of gene triplications in the Ig heavy chainconstant region locusrdquoThe Journal of Immunology vol 152 no1 pp 129ndash135 1994

18 ISRN Immunology

[101] H Rabbani Q Pan N Kondo C I E Smith and L Ham-marstrom ldquoDuplications and deletions of the human IGHClocus evolutionary implicationsrdquo Immunogenetics vol 45 no2 pp 136ndash141 1996

[102] P F Weinheimer J Mestecky and R T Acton ldquoSpecies distri-bution of J chainrdquoThe Journal of Immunology vol 107 no 4 pp1211ndash1212 1971

[103] F P Inman and J Mestecky ldquoThe J chain of polymeric immu-noglobulinsrdquo inContemporary Topics inMolecular Immunologyvol 3 pp 111ndash141 Springer New York NY USA 1974

[104] P Brandtzaeg ldquoPresence of J chain in human immunocytescontaining various immunoglobulin classesrdquo Nature vol 252no 5482 pp 418ndash420 1974

[105] L Tacchi E Larragoite and I Salinas ldquoDiscovery of J chain inAfrican lungfish (Protopterus dolloi Sarcopterygii) using highthroughput transcriptome sequencing implications in mucosalimmunityrdquo PLoS ONE vol 8 no 8 Article ID e70650 2013

[106] I K Zarkadis D Mastellos and J D Lambris ldquoPhylogeneticaspects of the complement systemrdquo Developmental and Com-parative Immunology vol 25 no 8-9 pp 745ndash762 2001

[107] A P West Jr A B Herr and P J Bjorkman ldquoThe chickenyolk sac IgY receptor a functional equivalent of themammalianMHC-related Fc receptor is a phospholipase A

2receptor

homologrdquo Immunity vol 20 no 5 pp 601ndash610 2004[108] D B Tesar E J Cheung and P J Bjorkman ldquoThe chicken

yolk sac IgY receptor a mammalian mannose receptor familymember transcytoses IgY across polarized epithelial cellsrdquoMolecular Biology of the Cell vol 19 no 4 pp 1587ndash1593 2008

[109] A I Taylor R L Beavil B J Sutton and R A Calvert ldquoAmonomeric chicken IgY receptor binds IgY with 21 stoichiom-etryrdquo The Journal of Biological Chemistry vol 284 no 36 pp24168ndash24175 2009

[110] K Baker S-W Qiao T Kuo et al ldquoImmune and non-immunefunctions of the (not so) neonatal Fc receptor FcRnrdquo Seminarsin Immunopathology vol 31 no 2 pp 223ndash236 2009

[111] K Baker R S Blumberg and C S Kaetzel ldquoImmunoglob-ulin transport and immunoglobulin receptorsrdquo in MucosalImmunology J Mestecky W Strober H Cheroutre B KelsallB N Lambrecht andMW Russell Eds chapter 20 AcademicPressElsevier Waltham Mass USA 2014

[112] C S Kaetzel ldquoThepolymeric immunoglobulin receptorrdquo in eLSJohn Wiley amp Sons Chichester UK 2013

[113] N J Mantis N Rol and B Corthesy ldquoSecretory IgArsquos complexroles in immunity andmucosal homeostasis in the gutrdquoMucosalImmunology vol 4 no 6 pp 603ndash611 2011

[114] J V Peppard M E Rose and P Hesketh ldquoA functional homo-logue of mammalian secretory component exists in chickensrdquoEuropean Journal of Immunology vol 13 no 7 pp 566ndash5701983

[115] K E Mostov M Friedlander and G Blobel ldquoThe receptorfor transepithelial transport of IgA and IgM contains multipleimmunoglobulin-like domainsrdquo Nature vol 308 no 5954 pp37ndash43 1984

[116] P Krajci R Solberg M Sandberg O Oyen T Jahnsen and PBrandtzaeg ldquoMolecular cloning of the human transmembranesecretory component (poly-Ig receptor) and its mRNA expres-sion in human tissuesrdquo Biochemical and Biophysical ResearchCommunications vol 158 no 3 pp 783ndash789 1989

[117] P Krajci D Kvale K Tasken and P Brandtzaeg ldquoMolecularcloning and exon-intron mapping of the gene encoding humantransmembrane secretory component (the poly-Ig receptor)rdquo

European Journal of Immunology vol 22 no 9 pp 2309ndash23151992

[118] J F Piskurich J A France C M Tamer C A Willmer CS Kaetzel and D M Kaetzel ldquoInterferon-120574 induces polymericimmunoglobulin receptormRNA in human intestinal epithelialcells by a protein synthesis dependent mechanismrdquo MolecularImmunology vol 30 no 4 pp 413ndash421 1993

[119] J F Piskurich M H Blanchard K R Youngman J A Franceand C S Kaetzel ldquoMolecular cloning of the mouse polymericIg receptor functional regions of the molecule are conservedamong five mammalian speciesrdquo The Journal of Immunologyvol 154 no 4 pp 1735ndash1747 1995

[120] M A Kulseth P Krajci O Myklebost and S RogneldquoCloning and characterization of two forms of bovine polymericimmunoglobulin receptor cDNArdquo DNA and Cell Biology vol14 no 3 pp 251ndash256 1995

[121] K S Koch A S Gleiberman T Aoki et al ldquoDiscordant expres-sion and variable numbers of neighboring GGA- and GAA-richtriplet repeats in the 31015840 untranslated regions of two groups ofmessenger RNAs encoded by the rat polymeric immunoglob-ulin receptor generdquo Nucleic Acids Research vol 23 no 7 pp1098ndash1112 1995

[122] F M Adamski and J Demmer ldquoTwo stages of increased IgAtransfer during lactation in themarsupialTrichosurus vulpecula(brushtail possum)rdquoThe Journal of Immunology vol 162 no 10pp 6009ndash6015 1999

[123] H Kumura T Sone K-I Shimazaki and E KobayashildquoSequence analysis of porcine polymeric immunoglobulinreceptor from mammary epithelial cells present in colostrumrdquoThe Journal of Dairy Research vol 67 no 4 pp 631ndash636 2000

[124] C L Taylor G A Harrison C M Watson and E M DeaneldquocDNA cloning of the polymeric immunoglobulin receptor ofthe marsupial Macropus eugenii (tammar wallaby)rdquo EuropeanJournal of Immunogenetics vol 29 no 2 pp 87ndash93 2002

[125] R Braathen V S Hohman P Brandtzaeg and F-E JohansenldquoSecretory antibody formation conserved binding interactionsbetween J chain and polymeric Ig receptor from humans andamphibiansrdquo The Journal of Immunology vol 178 no 3 pp1589ndash1597 2007

[126] M J Lewis BWagner R M Irvine and J MWoof ldquoIgA in thehorse cloning of equine polymeric Ig receptor and J chain andcharacterization of recombinant forms of equine IgArdquoMucosalImmunology vol 3 no 6 pp 610ndash621 2010

[127] A J Leon D Banner L Xu et al ldquoSequencing annotation andcharacterization of the influenza ferret infectomerdquo Journal ofVirology vol 87 no 4 pp 1957ndash1966 2013

[128] W H Wieland D Orzaez A Lammers H K ParmentierM W A Verstegen and A Schots ldquoA functional polymericimmunoglobulin receptor in chicken (Gallus gallus) indicatesancient role of secretory IgA inmucosal immunityrdquoBiochemicalJournal vol 380 no 3 pp 669ndash676 2004

[129] K Hamuro H Suetake N R Saha K Kikuchi and YSuzuki ldquoA teleost polymeric Ig receptor exhibiting two Ig-likedomains transports tetrameric IgM into the skinrdquo The Journalof Immunology vol 178 no 9 pp 5682ndash5689 2007

[130] J H W M Rombout S J L van der Tuin G Yang et alldquoExpression of the polymeric immunoglobulin receptor (pIgR)in mucosal tissues of common carp (Cyprinus carpio L)rdquo Fishand Shellfish Immunology vol 24 no 5 pp 620ndash628 2008

[131] L-N Feng D-Q Lu J-X Bei et al ldquoMolecular cloning andfunctional analysis of polymeric immunoglobulin receptor gene

ISRN Immunology 19

in orange-spotted grouper (Epinephelus coioides)rdquo ComparativeBiochemistry and Physiology B vol 154 no 3 pp 282ndash289 2009

[132] A E Oslashstergaard S A M Martin T Wang R J M Stet andC J Secombes ldquoRainbow trout (Oncorhynchus mykiss) pos-sessmultiple novel immunoglobulin-like transcripts containingeither an ITAM or ITIMsrdquo Developmental and ComparativeImmunology vol 33 no 4 pp 525ndash532 2009

[133] H Eiffert E Quentin and J Decker ldquoThe primary structureof the human free secretory component and the arrangementof disulfide bondsrdquo Hoppe-Seylerrsquos Zeitschrift fur PhysiologischeChemie vol 365 no 12 pp 1489ndash1495 1984

[134] E Fallgreen-Gebauer W Gebauer A Bastian et al ldquoThe cova-lent linkage of secretory component to IgA Structure of sIgArdquoBiological Chemistry Hoppe-Seyler vol 374 no 11 pp 1023ndash1028 1993

[135] J MWoof ldquoThe structure of IgArdquo inMucosal Immune DefenseImmunoglobulin A C S Kaetzel Ed chapter 1 pp 1ndash24Springer New York NY USA 2007

[136] A Bonner A Almogren P B Furtado M A Kerr and S JPerkins ldquoLocation of secretory component on the Fc edge ofdimeric IgA1 reveals insight into the role of secretory IgA1 inmucosal immunityrdquoMucosal Immunology vol 2 no 1 pp 74ndash84 2009

[137] A Bonner A Almogren P B Furtado M A Kerr and S JPerkins ldquoThe nonplanar secretory IgA2 and near planar secre-tory IgA1 solution structures rationalize their different mucosalimmune responsesrdquo The Journal of Biological Chemistry vol284 no 8 pp 5077ndash5087 2009

[138] J Johansen B Braathen and P Brandtzaeg ldquoRole of J chain insecretory immunoglobulin formationrdquo Scandinavian Journal ofImmunology vol 52 no 3 pp 240ndash248 2000

[139] B A Hendrickson D A Conner D J Ladd et al ldquoAlteredhepatic transport of immunoglobulin A in mice lacking the Jchainrdquo Journal of Experimental Medicine vol 182 no 6 pp1905ndash1911 1995

[140] B A Hendrickson L Rindisbacher B Corthesy et al ldquoLackof association of secretory component with IgA in J chain-deficient micerdquo The Journal of Immunology vol 157 no 2 pp750ndash754 1996

[141] N Lycke L Erlandsson L Ekman K Schon and T Lean-derson ldquoLack of J chain inhibits the transport of gut IgA andabrogates the development of intestinal antitoxic protectionrdquoThe Journal of Immunology vol 163 no 2 pp 913ndash919 1999

[142] F-E Johansen R Braathen and P Brandtzaeg ldquoThe J chainis essential for polymeric Ig receptor-mediated epithelial trans-port of IgArdquoThe Journal of Immunology vol 167 no 9 pp 5185ndash5192 2001

[143] R E Ley D A Peterson and J I Gordon ldquoEcological andevolutionary forces shaping microbial diversity in the humanintestinerdquo Cell vol 124 no 4 pp 837ndash848 2006

[144] M McFall-Ngai ldquoAdaptive immunity care for the communityrdquoNature vol 445 no 7124 p 153 2007

[145] A J Macpherson K D McCoy F-E Johansen and PBrandtzaeg ldquoThe immune geography of IgA induction andfunctionrdquoMucosal Immunology vol 1 no 1 pp 11ndash22 2008

[146] D Kvale and P Brandtzaeg ldquoConstitutive and cytokine inducedexpression of HLA molecules secretory component and inter-cellular adhesion molecule-1 is modulated by butyrate in thecolonic epithelial cell line HT-29rdquo Gut vol 36 no 5 pp 737ndash742 1995

[147] L VHooperMHWong AThelin L Hansson P G Falk andJ I Gordon ldquoMolecular analysis of commensal host-microbialrelationships in the intestinerdquo Science vol 291 no 5505 pp 881ndash884 2001

[148] S Hapfelmeier M A E Lawson E Slack et al ldquoReversiblemicrobial colonization of germ-free mice reveals the dynamicsof IgA immune responsesrdquo Science vol 328 no 5986 pp 1705ndash1709 2010

[149] DH ReikvamMDerrien R Islam et al ldquoEpithelial-microbialcross-talk in polymeric Ig receptor deficient micerdquo EuropeanJournal of Immunology vol 42 no 11 pp 2959ndash2970 2012

[150] EW Rogier A L Frantz M E C Bruno et al ldquoSecretory anti-bodies in breast milk promote long-term intestinal homeostasisby regulating the gut microbiota and host gene expressionrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 111 no 8 pp 3074ndash3079 2014

[151] G M Barton and R Medzhitov ldquoToll-like receptor signalingpathwaysrdquo Science vol 300 no 5625 pp 1524ndash1525 2003

[152] K Takeda and S Akira ldquoToll receptors and pathogen resis-tancerdquo Cellular Microbiology vol 5 no 3 pp 143ndash153 2003

[153] E Cario andD K Podolsky ldquoDifferential alteration in intestinalepithelial cell expression of Toll-like receptor 3 (TLR3) andTLR4 in inflammatory bowel diseaserdquo Infection and Immunityvol 68 no 12 pp 7010ndash7017 2000

[154] M Hausmann S Kiessling S Mestermann et al ldquoToll-likereceptors 2 and 4 are up-regulated during intestinal inflamma-tionrdquo Gastroenterology vol 122 no 7 pp 1987ndash2000 2002

[155] M T Abreu L S Thomas S Y Tesfay et al ldquoRegulation ofTLR4 and MD-2 in the intestinal epithelium evidence for dys-regulated LPS signaling in human inflammatory bowel diseaserdquoin Proceedings of the 90th Annual Meeting of the AmericanAssociation for Immunologists Abstract 3634 Denver ColoUSA 2003

[156] T A Schneeman M E C Bruno H Schjerven F-E JohansenL Chady and C S Kaetzel ldquoRegulation of the polymeric Igreceptor by signaling through TLRs 3 and 4 linking innate andadaptive immune responsesrdquo The Journal of Immunology vol175 no 1 pp 376ndash384 2005

[157] M E C Bruno A L Frantz E W Rogier F-E Johansen andC S Kaetzel ldquoRegulation of the polymeric immunoglobulinreceptor by the classical and alternative NF-120581B pathways inintestinal epithelial cellsrdquoMucosal Immunology vol 4 no 4 pp468ndash478 2011

[158] M E C Bruno E W Rogier A L Frantz A T Stefka SN Thompson and C S Kaetzel ldquoRegulation of the poly-meric immunoglobulin receptor in intestinal epithelial cellsby Enterobacteriaceae implications for mucosal homeostasisrdquoImmunological Investigations vol 39 no 4-5 pp 356ndash382 2010

[159] A L Frantz E W Rogier C R Weber et al ldquoTargeted deletionof MyD88 in intestinal epithelial cells results in compromisedantibacterial immunity associatedwith downregulation of poly-meric immunoglobulin receptor mucin-2 and antibacterialpeptidesrdquoMucosal Immunology vol 5 no 5 pp 501ndash512 2012

[160] E W Rogier A L Frantz M E C Bruno and C S KaetzelldquoSecretory IgA is concentrated in the outer layer of intestinalmucus along with gut bacteriardquo Pathogens In press

[161] M B Geuking K D McCoy and A J Macpherson ldquoThe func-tion of secretory IgA in the context of the intestinal continuumof adaptive immune responses in host-microbial mutualismrdquoSeminars in Immunology vol 24 no 1 pp 36ndash42 2012

20 ISRN Immunology

[162] L VHooper D R Littman andA JMacpherson ldquoInteractionsbetween the microbiota and the immune systemrdquo Science vol336 no 6086 pp 1268ndash1273 2012

[163] A J Macpherson M B Geuking E Slack S Hapfelmeierand K D McCoy ldquoThe habitat double life citizenship andforgetfulness of IgArdquo Immunological Reviews vol 245 no 1 pp132ndash146 2012

Submit your manuscripts athttpwwwhindawicom

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

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Diabetes ResearchJournal of

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Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

ISRN Immunology 7

gene evolved by duplication of a primordial Ig gene is drivenby the need for an efficient mechanism for transport ofmucosal Igs into external secretions Similar forces may havedriven the evolution of FcRY a receptor first described forits function of transporting IgY from maternal blood tothe embryo yolk sac in chicken [9 107ndash109] FcRY is notstructurally homologous to pIgR or mammalian Fc receptorsbut is instead homologous to mammalian receptors formannose and phospholipase A2 with lectin-like extracellulardomains (Figure 3) A BLAST search of the National Centerfor Biotechnology Information (NCBI) nucleotide databasefor homologs of the gene encoding chicken FcRY (designatedPLA2R1 based on its homology to phospholipase A2 receptor1) revealed homologous genes in many bird species as wellas turtles lizards alligators and mammals However thefunctional significance of FcRYPLA2R1 in the transport ofIgY in reptiles (and possibly IgG in mammals) has not beenexplored A functional equivalent of FcRY in mammals isFcRn which mediates transport of IgG across endothelialand epithelial cells in such tissues as placenta and mucosalepithelia (reviewed in [110 111]) FcRn is homologous in struc-ture to major histocompatibility class (MHC) I moleculescomprising a ligand-binding alpha chain associated withsoluble 1205732-microglobulin (Figure 3)

A unique feature of the mammalian immune system isthe expression of Fc receptors for various Ig isotypes bycells of hematopoietic origin (Figure 3) (reviewed in [10])Engagement of these Fc receptors by Ig (in the presenceor absence of bound antigen depending on the particularFc receptor) initiates intracellular signaling pathways thatcan either augment or inhibit immune responses Withthe exception of Fc120576RII which has a single C-type lectin-like domain the extracellular Ig-binding regions of thesehematopoietic Fc receptors comprise 1 2 or 3 Ig-like domains[10] Genes encoding Fc120572120583R Fc120574RI Fc120574RIII Fc120576RI andFc120576RII are widely distributed among mammalian specieswhereas genes encoding Fc120572RI and Fc120574RII are restricted tothe primate lineage suggesting recent evolutionary originsThe genes encoding the120572120573 andor 120574 chains of Fc120576RI Fc120574RIIand Fc120574RIII are linked in a cluster on the long arm of humanchromosome 1 (1q23) not far removed from the gene for the120572 chain of Fc120574RI at 1q21 This tight linkage is consistent withduplication and diversification of a primordial FcR gene ina common ancestor of mammals The primate-specific genesencoding the 120572 and 120573 chains of Fc120574RII appear to have evolvedmore recently Another cluster of immune-related genes onthe long arm of chromosome 1 includes the genes for pIgR(1q31) and Fc120572120583R (1q32) Although the overall homologybetween pIgR and Fc120572120583R is relatively low they share aconserved binding site for IgA and IgM in the N-terminalIg-like domain Interestingly the genes encoding FcRn andFc120572RI are closely linked on the long arm of chromosome19 (19q133 and 19q1342 resp) although they bear littlehomology beyond the presence of a single Ig-like domain inthe extracellular region Finally the gene for the lectin-likereceptor Fc120576RII is located in an unrelated locus on the shortarm of chromosome 19 (19p133)

PIGR

dIgA

pIgR

Ag

SIgA

Free SC

Figure 4 Transcytosis of pIgR through a polarized epithelial celland formation of secretory Igs A polarized columnar epithelial cellis illustrated with the apical surface at the top and the basolateralsurface at the bottom Newly synthesized pIgR is targeted to thebasolateral surface where it binds polymeric Ig (pIg illustrated hereas dimeric (d)IgA) with or without bound antigen (Ag) Followingreceptor-mediated endocytosis pIg-bound and unoccupied pIgRmolecules are transported through a series of intracellular vesiclesto the apical surface Proteolytic cleavage of pIgR at the extracellularface of the plasma membrane releases free secretory component(SC) and secretory SIg (illustrated here as SIgA) Modified from [13]with permission from John Wiley and sons

5 Unique Biological Functions of pIgR

ThepIgR is expressed on the surface of glandular andmucosalepithelial binds where it binds selectively to polymericIg (pIg) and mediates its transport across epithelial cellsinto external secretions (reviewed in [17 111 112]) Most of

8 ISRN Immunology

02

100

Human IgA1Gorilla IgA1

Gorilla IgA281

6164

Human IgA2

Chimpanzee IgA2Chimpanzee IgA1

Gibbon IgA1Gibbon IgA2

Orangutan IgABaboon IgA

Rhesus macaque IgA53 100

98 69Dog IgA

Pig IgA100 Cattle IgA

52

Horse IgARabbit IgA (13 subclasses)

Mouse IgA57

99

Possum IgA

93

Chicken IgAPlatypus IgA1100

5095

Platypus IgA2

Trout IgTFrog IgX

Gecko IgldquoArdquo

(a)

02

Human pIgR

100Chimpanzee pIgRGorilla pIgR

55Gibbon pIgROrangutan pIgR100

100

100 Baboon pIgRRhesus macaque pIgR

Mouse pIgR

66

96

100 Pig pIgRCattle pIgR

85Horse pIgR

Dog pIgR

74

Rabbit pIgRPossum pIgR

Platypus pIgR

Chicken pIgR

10075

5979

Trout pIgRFrog pIgR

Anole pIgR

71

(b)

Figure 5 Coevolution of mucosal Igs and pIgR Simplified neighbor-joining phylogenetic trees of vertebrate (a) Ig and (b) pIgR proteinsequences with human IgA1 and pIgR denoted as outgroups Horizontal distances are proportional to the degree of divergence followinga multiple alignment of amino acid sequences Numbers at nodes denote bootstrap support for each bifurcation after 100 replicationsAccession numbers for mucosal Ig sequences human (Homo sapiens) IgA1 J00220 IgA2 (allotype m1) J00221 gorilla (Gorilla gorilla) IgA1X53703 IgA2 X53707 chimpanzee (Pan troglodytes) IgA1 X53702 IgA2 X53706 gibbon (Hylobates lar) IgA1 X53708 IgA2 X53709 Borneanorangutan (Pongo pygmaeus) IgA X53704 baboon (Papio anubis) IgA DQ868435 rhesus macaque (Macaca mulatta) AY039245 pig (Susscrofa) IgA U12594 cattle (Bos taurus) IgA AF109167 dog (Canis lupus familiaris) IgA L36871 horse (Equus caballus) IgA AY247966mouse (Mus musculus) IgA D11468 rabbit (Oryctolagus cuniculus) IgA1 X51647 brushtail possum (Trichosurus vulpecula) IgA AF027382duck-billed platypus (Ornithorhynchus anatinus) IgA1 AY055778 IgA2 AY055779 chicken (Gallus gallus) IgA AAB226142 leopard gecko(Eublepharis macularius) IgldquoArdquo (so designated because of its uncertain phylogeny with homology to both IgA and IgY) ABG726841African clawed frog (Xenopus laevis) IgX S03186 rainbow trout (Oncorhynchus mykiss) IgT AAW669811 Accession numbers for pIgRsequences with species that vary from those used for the mucosal Ig alignment in panel A noted in parentheses human NM 002644chimpanzee XM 003308710 gorilla XM 004028295 gibbon XM 003272974 Sumatran orangutan (Pongo abelii) NM 001131626 baboonXM 003893189 rhesus macaque XM 001083307 pig NM 214159 cattle NM 174143 dog XM 537133 horse XM 001492298 mouseNM 011082 rabbit NM 001171045 brushtail possum AF091137 duck-billed platypus XM 001508602 chicken NM 001044644 green anole(Anolis carolinensis) XM 003224013 African clawed frog EF079076 rainbow trout FJ940682

ISRN Immunology 9

our knowledge of pIgR-mediated transcytosis of mucosalIgs is derived from studies of mammalian secretory IgA(SIgA) as illustrated in Figure 4 Transcription of the PIGRgene and translation of pIgR mRNA is accompanied byinsertion of the nascent protein into the endoplasmic retic-ulum The pIgR undergoes substantial glycosylation duringtransport through the ER and Golgi apparatus and is thentargeted to the basolateral surface of polarized epithelialcells Membrane-bound pIgR binds pIg and pIg-containingimmune complexes which are internalized along with unoc-cupied pIgR via receptor-mediated endocytosis and thentranscytosed through a series of intracellular vesicles to theapical surface During transcytosis intracellular pIg antibod-ies can neutralize bacteria viruses and other antigens thathave gained access to the interior of the epithelial cell Atthe apical surface proteolytic cleavage of the membrane-spanning region of pIgR leads to the release of its extracellulardomain known as secretory component (SC) either in freeform or covalently bound to pIg Secretory Igs can neutralizepathogens and antigens within the mucosal lumen andfacilitate excretion of antigens that were transported throughthe epithelial cell as IgA immune complexes The SC moietyof SIgA has been shown to protect IgA from degradationby host and bacterial proteases and along with free SCconfers additional innate immune functions that protectthe epithelial surface from microbial invasion and limitpotentially damaging host inflammatory responses (reviewedin [113]) The finding of an SC-like polypeptide associatedwith polymeric IgT in rainbow trout [38] polymeric IgXin Xenopus [50] and polymeric IgA in birds [114] suggeststhat all vertebrate pIgRs share the function of transportingpolymeric Igs into external secretions In many mammalianspecies pIgR mediates epithelial transcytosis of both poly-meric IgM and IgA (reviewed in [111]) Although directevidence is not yet available it is reasonable to assume thatpIgR transports IgM in lower vertebrates It will be interestingto investigate whether the SCmoiety of secretory Igs in lowervertebrates mediates additional innate immune functions ashas been demonstrated for mammalian SC

6 Coevolution of pIgR and Mucosal Igs

Molecular cloning of the PIGR gene was first reportedfor mammalian species including eutherians marsupialsand monotremes [115ndash127] Subsequent elucidation of PIGRsequences from diverse species of jawed vertebrates hasallowed a comprehensive analysis of the evolutionary originsof the PIGR gene [38 128 128ndash132] and additional sequencesavailable in the Genbank database Whereas no ortholog ofthe PIGR gene has been found in any species of cartilaginousfish the PIGR gene has been annotated in all species of teleostfish for which the genome has been sequenced No orthologof the PIGR gene has been reported in lobe-finned bonyfishes but further analyses of whole genome sequences willbe required to determine whether the PIGR gene was lostfollowing the split of the Sarcopterygii It thus appears thatthe PIGR gene emerged in a common ancestor of highervertebrates after the split of cartilaginous fish and prior

to the evolution of modern teleosts likely driven by theselective pressure to provide a mechanism for transport ofpolymeric Igs such as IgM and IgT into mucosal secretionsThis hypothesis is supported by a comparison of phylogenetictrees based on amino acid sequences for IgT IgX and IgAheavy chains and pIgR (Figure 5)The predicted evolutionarydistance between trout IgT and frog IgX is similar to thedistance between trout and frog pIgR suggesting that thetransition from IgT to IgX as the dominantmucosal Ig isotypewas accompanied by adaptations in pIgR structure Similarparallels can be seen in the transition from IgX to IgA inreptiles birds and mammals and the concurrent evolutionof pIgR

Alignments of the amino acid sequences of mucosal Igheavy chains and pIgR from 10 representative vertebratespecies provide further support for the theory of coevolutionof mucosal IGH and PIGR genes (Figure 6) A commonfeature of Ig and pIgR proteins is the presence of repeatingIg-like domains (see Figure 2 for the basic structure of thesedomains) The structure of IgT IgX and IgA heavy chainsfrom fish amphibians reptiles and birds is similar to thatof IgM with 4 constant Ig-like domains In mammalianIgA (and IgG) the exon for the 2nd constant region wastruncated to encode a short ldquohingerdquo region which confersgreater mobility to the antigen-binding region at the N-terminusThus the CH3 domain of IgT IgX and IgA in lowervertebrates is structurally and functionally homologous tothe CH2 domain of mammalian IgA The heavy chains ofIgT IgX and IgA have retained a characteristic feature ofthe IgM heavy chain that is the presence of a conservedcysteine residue in the tailpiece that allows disulfide bondingbetween heavy chains of individual Ig proteins to formhigher molecular weight polymers These large Ig structurescontaining multiple antigen-binding sites are particularlywell suited for immune clearance of large antigens found atmucosal surfaces such as intact microbes and food particlesIn mucosal Igs from most vertebrate orders the J chainprotein initiates this polymerization process by disulfidebonding with 2 Ig heavy chains remaining associated withthe polymeric Ig at a stoichiometric ratio of 1 J chain subunitper 2 3 4 or 5 Ig units Despite the absence of J chainthe predominant form of IgM and IgT in mucus secretionsin rainbow trout was found to be polymeric in contrastto monomeric forms of IgM and IgT in the blood [38] Inmammals IgM is mainly found as a pentamer whereas theshorter heavy chain ofmammalian IgA restricts its polymericforms to dimers trimers and tetramers Further studies willbe required to characterize the polymeric structures of IgMIgT IgX and IgA in lower vertebrates

Alignment of pIgR amino acid sequences from 10 rep-resentative vertebrate species reveals structural changes thatwere evolved in parallel with structural changes in mucosalIgs (Figure 6(b)) All pIgR proteins have an N-terminalhydrophobic leader peptide required for targeting of thenascent protein into the ER The extracellular region ofpIgR protein is characterized by repeating ldquoIg-likerdquo domainssimilar to Ig heavy chains [115 133] Interestingly the num-ber of extracellular Ig-like domains has increased duringvertebrate evolution culminating with a total of 5 domains

10 ISRN Immunology

TailpieceHinge

Tailpiece

Mammalian IgA

VVVVVVVVVV

200121 300 400 4721

Human IgA1Rhesus IgA

Cattle IgAMouse IgA

Possum IgAPlatypus IgAChicken IgA

Frog IgXTrout IgT

Premammalian IgTXA

Gecko IgldquoArdquo

CH1

CH1

CH2

CH2

CH3

CH3

CH4

(a)

Leader 1 2 3 4 5

Ig homology extracellular domains

Linker CytoplasmicTM

1001 200 300 400 500 600 700 764

HumanRhesus

CattleMouse

PossumPlatypusChicken

AnoleFrog

Trout

(b)

Figure 6 Interspecies similarity in mucosal Ig and pIgR protein sequences from 10 representative vertebrate species Alignments in aminoacid sequences correspond to the phylogenetic trees shown in Figure 5 (a) Numbering ofmucosal Ig amino acids corresponds to the sequenceof human IgA1 beginning with the first residue of the variable domain CH heavy chain constant region domain (b) Numbering of pIgRamino acids corresponds to the sequence of human pIgR beginning with the first residue of the leader peptide TM transmembrane Forboth alignments the intensity of shading at each position signifies the degree of similarity amongmucosal Ig or pIgR sequences from differentspecies Gaps in sequence alignments signify regions of limited interspecies homology Approximate boundaries are noted of key structuralelements in mucosal Ig and pIgR proteins

in mammalian pIgR By contrast pIgR from amphibiansreptiles and birds contains 4 extracellular domains lackinga homolog of domain 2 of mammalian pIgR The mostprimitive form of pIgR found in teleost fish contains only2 extracellular domains homologous to domains 1 and 5of mammalian pIgR Interspecies homology is greatest indomain 1 which has been shown to be critical for binding ofmammalian pIgR to polymeric Igs (reviewed in [111]) Highlyconserved internal disulfide bonds are found in all the Ig-like domains of pIgR characteristic of the immunoglobulinfold An additional disulfide bond is found in domain 5 ofpIgR frommammals birds reptiles and amphibians but notfish In human SIgA this ldquoextrardquo disulfide bond in domain 5has been shown to rearrange to form a disulfide bond with

cysteine residues in one of the heavy chains of polymericIgA [134] Although the structure of SIgA has not beenfully characterized for lower vertebrates it is reasonable toassume that similar disulfide bonds form between domain 5of pIgR and polymeric IgA or IgX from birds reptiles andamphibians The linker region connecting domain 5 of pIgRto the transmembrane domain has a random structure that ispoorly conserved across species Proteolytic cleavage of pIgRwithin this domain leads to the release of SC from the apicalsurface of epithelial cells either free or bound to polymericIg The cytoplasmic domain of mammalian pIgR containsa number of intracellular sorting motifs that interact withcytoplasmic proteins to direct pIgR through the transcytoticpathway (reviewed in [111]) These motifs are reasonably

ISRN Immunology 11

Linker

TMCytoplasmic

J chain

Hinge 1

2

34

5

CL

VLVH

C1205721C1205722 C1205723

(a)

Linker

TMCytoplasmic

J chain

1

3 4

5

CL

VL

VH

C1205941205721

C1205941205722C1205941205723 C1205941205724

(b)

11

5

LinkerTM

Cytoplasmic

5

CL

VL

VH

C1205911C1205912

C1205913 C1205914

pIgR Ig-like domain

H chain Ig-like domain

L chain Ig-like domain

J chain

Disulfide bond

(c)

Figure 7 Theoretical model for changes in the structure of secretory Igs during evolution (a) The structure for mammalian SIgA is adaptedfrom the model of Woof and Russell [16] for human SIgA1 with permission from Nature Publishing Group (b) and (c) Theoretical modelsfor the structure of IgXA from amphibians and birds and SIgT from teleost fish respectively are predicted from alignment of Ig heavy chainand pIgR sequences with mammalian homologs

well conserved in pIgR from birds and reptiles but not inpIgR from amphibians and fish suggesting that complexmechanisms of intracellular trafficking of pIgR coevolvedwith the increasing complexity of the mucosal immunesystem

7 Hypothetical Models for Changes inSecretory Ig Structure during Coevolutionof Mucosal Igs and pIgR

A large number of structural and functional analyses overthe past 30 years allowed the development of detailed modelsfor the structure of mammalian SIgA (reviewed in [111 135])(Figure 7(a)) Domains 1 and 5 of pIgR the most highlyconserved Ig-like domains associate with theC1205722 subunits oftwo adjacent IgA heavy chains in a near-planar structure [136137] During transcytosis a disulfide bond forms betweenhighly conserved cysteine residues in domain 5 of pIgRand the C1205722 domain of one of the IgA heavy chains [134]Domains 2 3 and 4 allow mammalian pIgR to assume aflexible extended structure which is thought to wrap aroundthe IgA heavy chains and protect against degradation fromhost and microbial proteases Binding of mammalian pIgRto polymeric IgA or IgM requires the presence of J chain

connecting the Ig subunits (reviewed in [138]) and J chain-deficient mice fail to transport IgA and IgM into externalsecretions [139ndash141] Structure-function studies usingmutantforms of human J chain suggested that J chain binds directlyto pIgR and also maintains polymeric Ig in an optimalconformation for pIgR binding and transcytosis [142] Theunstructured linker region connecting domain 5 of pIgRto the transmembrane (TM) region gives membrane-boundpIgR the flexibility to bind large polymeric Igs (with orwithout associated antigens) and provides an exposed site forproteolytic cleavage of pIgR to SC The C-terminal region ofpIgR extends past the cytoplasmic face of the plasma mem-brane allowing association with cytoplasmic factors thatregulate trafficking of pIgR with or without bound polymericIg

Although detailed structural studies have not yet beenperformed on secretory Igs from lower vertebrates hypo-thetical models can be constructed based on alignmentswith their mammalian homologs A model for secretoryIgXA in birds reptiles and amphibians is illustrated inFigure 7(b) showing the C

1205941205722 domain in place of the hinge

region ofmammalian IgAThenumbering of the extracellulardomains of pIgR corresponds to the homologous domainsin mammalian pIgR noting the absence of domain 2 In

12 ISRN Immunology

this model the C120594120572

3 domains of two adjacent IgXA heavychains (homologous to the C

1205722 domain of mammalian IgA)

bind to the highly conserved domains 1 and 5 of pIgRGiven the conservation of the analogous cysteine residuesin domain 5 of pIgR and the C

1205941205723 domain of IgXA it

is assumed that a disulfide bond forms between pIgR andpolymeric Ig during epithelial transcytosis in birds reptilesand amphibiansThe absence of domain 2 in pIgR from thesevertebrate orders necessitates a more rigid structure thanthat of mammalian pIgR with a corresponding decrease inits ability to wrap around the IgXA heavy chains and pro-vide protection against proteoltyic degradation Despite theshorter length of pIgR in birds reptiles and amphibians theassociation with the J chain subunit of polymeric IgXA stillappears to be required Recombinant pIgR from the Africanfrog (Xenopus laevis) was shown to bind with moderatelyhigh affinity to human polymeric IgA containing J chain butnot to monomeric IgA [125] The affinity of Xenopus pIgRfor human pIgA was improved when Xenopus J chain wassubstituted for human J chain in a chimeric polymeric IgAmolecule The lack of sequence conservation across speciesin the linker region connecting domain 5 of pIgR to the TMregion suggests that it acts as a nonspecific ldquospacerrdquo As statedabove the cytoplasmic region of pIgR appears to have evolvedover time to provide enhanced regulation of pIgR trafficking

The hypothetical structure of secretory IgT from teleostfish in Figure 7(c) illustrates how the most primitive form ofpIgR comprising only extracellular domains 1 and 5 couldassociate with polymeric Ig and mediate epithelial transcy-tosis Association of pIgR domain 1 with the C

1205913 domain of

IgT would preserve the functional homology with secretoryIgs in higher vertebrates The short length of teleost pIgRwould necessitate the association of domain 5 with a C

1205913

domain on one of the heavy chains of the same IgT ratherthan spanning across to the adjaent IgT subunit While thismodel preserves the highly conserved association of pIgRdomain 1 with the orthologous domain of the IgT heavychain it does not explain the selectivity of teleost pIgR forpolymeric rather than monomeric IgT Although there is noexperimental evidence to support this model it could behypothesized that dimerization of two pIgR molecules in theplasmamembrane is required for high affinity binding of IgTas illustrated in the model in Figure 7(c) This hypotheticalmodel would also explain the lack of a necessity for J chainin polymeric IgT since each subunit in the pIgR dimer wouldonly be in contact with one IgT subunit The unstructuredlinker region connecting domain 5 of pIgR to the TM regionwould provide flexibility for association of 2 membrane-bound pIgR molecules with a large polymeric IgT molecule

Taken together the structural models for secretory Igsshown in Figure 7 are consistent with the selection of a morefunctional pIgR molecule over evolutionary time Duplica-tion and diversification of the extracellular Ig-like domainsof pIgR would provide a longer more flexible surface forbinding to polymeric Igs with higher affinity and protectingthe Ig heavy chains against proteolytic attack Expansion ofthe cytoplasmic domain of pIgR and incorporation of motifsfor binding cytoplasmic proteins would allow regulated

trafficking of pIgR and polymeric Igs across mucosal andglandular epithelial cells Importantly these models illustratea potential path for coevolution of IGH and PIGR genesdriven by the common selective pressure to provide antigen-specific humoral immune responses at mucosal surfaces

8 Evidence that the CommensalMicrobiota Provided the Driving Force forCoevolution of Mucosal Igs and pIgR

From the earliest evolution of vertebrate animals mucosal Igshave been an integral part of the emerging adaptive immunesystem Clearly many environmental factors served as driv-ing forces for the evolution of the adaptive immune systemin vertebrates including a longer lifespan thanmany (but notall) invertebrates and amore diverse diet that could introducea broader range of potential gut pathogens However it hasbeen proposed that the most significant force may havebeen the dramatic increase in the numbers and complexityof the resident microbiota in the evolution of vertebratesfrom their invertebrate ancestors [1 143 144] Antibodiesin mucosal secretions contribute to immune homeostasis bylimiting access of microbes and their products to the bodyproper maintaining the integrity of the epithelial barrier andshaping the composition of the commensal microbiota infavor of metabolically beneficial microorganisms [145] Thepredominance of polymeric Igs in these secretions promotesthese functions by providing multiple antigen-binding sitesper Ig complex thus increasing the overall avidity of antigen-antibody interactions Structural and functional refinementsin mucosal Igs culminating with the multifunctional secre-tory IgA molecule in mammals have further enhanced theirability to enhance immune homeostasis

The early emergence of pIgR in vertebrate evolutionprovided a mechanism for efficient transport of mucosal Igsinto external secretions It is well documented that crosstalkbetween mucosal epithelial cells and the resident microbiotamodulates expression of pIgR (reviewed in [17 111 112]) andit is reasonable to assume that these host-microbe interac-tions provided a driving force for evolution of the PIGR genein vertebrates The first demonstration that gut bacteria maymodulate pIgR expression in epithelial cells was the findingthat butyrate a bacterial fermentation product and importantenergy source in the colon upregulated expression of pIgRin the human colonic epithelial cell line HT-29 [146] A rolefor commensal bacteria in pIgR regulation was subsequentlydemonstrated by the observation that pIgR expression wasincreased when germ-free mice were colonized with Bacteri-oides thetaiotaomicron a prominent organism of the normalmouse and human intestinal microbiota [147] Amore recentstudy using a model of reversible colonization of germ-free mice with a nondividing mutant of Escherichia colidemonstrated that a long-lived SIgA response could besustained that specifically recognized the inducing bacteria[148] However exposure of E coli-colonized mice to otherbacteria limited the duration of the SIgA response against theoriginal colonizer suggesting a dynamic equilibriumbetweenmembers of the gut microbial community and host SIgA A

ISRN Immunology 13

study from the laboratory of Finn-Eirik Johansen demon-strated that diversity of the bacterial community in the cecallumen was reduced in pIgR-knockoutmice supporting a rolefor SIgA in limiting overgrowth of selected species [149] Incontrast the community of bacteria adherent to the epithelialsurface was more diverse in pIgR-knockout mice than inwild-typemice and these adherent bacteria caused enhancedexpression of several epithelial antimicrobial peptides Thesefindings suggest that bacteria-specific SIgA anchored in themucus layer restricts adhesion of bacteria to the epithelialsurface and limits bacterial stimulation of host epithelial cellsA recent study from the authorrsquos laboratory employing abreeding scheme in which119875119894119892119903minusminus damswere bred to119875119894119892119903+minusmales and vice versa demonstrated that SIgA antibodiesin breast milk promote long-term intestinal homeostasis byregulating the gut microbiota and gene expression in colonicepithelial cells [150]

A direct role for commensal andor pathogenic bacteriain the regulation of pIgR expression suggests that the innateimmune system may ldquoprimerdquo epithelial cells for transportof polymeric Ig produced during the adaptive immuneresponse Host cells mediate innate immune responses tomicrobial components through toll-like receptor (TLR) sig-naling (reviewed in [151 152]) Intestinal epithelial cells havebeen shown to express a wide variety of TLRs the expressionof which is upregulated during intestinal inflammation [153ndash155] Significantly expression of pIgR was shown to beupregulated in the HT-29 human intestinal epithelial cellline by bacterial LPS a ligand for TLR4 [156 157] Similarinduction of PIGR gene transcription was seen followingdirect binding of bacteria of the family Enterobacteriaceaewhich express a form of LPS that stimulates TLR4 [158]A recent study from the authorrsquos laboratory demonstratedthat shRNA-mediated knockdown of myeloid differentiationprimary response protein 88 (MyD88) a cytoplasmic adapterprotein that transduces signals from cell surface TLR4blocked the induction of PIGR gene transcription by LPS inHT-29 cells [159] The in vivo significance was confirmed bythe finding that mice with a targeted deletion of the Myd88gene only in intestinal epithelial cells had reduced expressionof pIgR compared to wild-type littermates [159] Mice withtargeted depletion of MyD88 in intestinal epithelial cells alsoexhibited reduced expression of mucin-2 the major compo-nent of the intestinal mucus layer and several antimicrobialpeptides and decreased transmucosal electrical resistanceThese alterations in epithelial barrier function were accom-panied by significant changes in the composition of the fecalmicrobiota increased numbers of bacteria adherent to theintestinal mucus layer and a dramatic increase in transloca-tion of gut bacteria into the drainingmesenteric lymphnodesincluding the opportunistic pathogen Klebsiella pneumoniaeThese findings demonstrate that MyD88-mediated crosstalkbetween the gut microbiota and intestinal epithelial cells iscrucial for optimal expression of pIgR production of SIgAdevelopment of a healthy gut microbiota and maintenanceof intestinal homeostasis

A model can be proposed in which continuous stimu-lation of intestinal epithelial cells by gut bacteria regulates

Lumen

Mucus

Epithelium

Lamina

PIGR

TLRs

MyD88

Bacteria

Plasma cells

propria

Polymeric Ig

Polymeric Ig receptor

Secretory component

Figure 8 Crosstalk between the polymeric immunoglobulin recep-tor secretory immunoglobulins and the gut microbiotaThe single-layered epithelium that lines the gastrointestinal tract is coveredwith a thick mucus layer which physically excludes members ofthe resident microbiota but allows diffusion of shed components ofmicrobial cells Stimulation of epithelial toll-like receptors (TLRs)with microbial products engages the cytoplasmic adaptor proteinMyD88 and initiates NF120581B-dependent signaling pathways Translo-cation of activated NF120581B and other transcription factors to thenucleus enhances transcription of thePIGR gene Activation of TLRsmay also stimulate pIgR transcytosis Polymeric Igs secreted bylamina propria plasma cells bind to pIgRon the basolateral surface ofepithelial cells and are transcytosed to the apical surface along withunoccupied pIgR Proteolytic cleavage of pIgR at the apical surfacereleases secretory SIg and free secretory component (SC) Binding ofSIg and SC to luminal bacteria promotes association with themucuslayer and prevents direct access of bacteria to the epithelial surfaceOver time the continuous crosstalk with SIg shapes the compositionof the gut microbiota Modified from [17] under terms of authorrsquoscopyright with Nature Publishing Group

pIgR expression and transport of SIgA and promotes immuneexclusion of resident and pathogenic bacteria (Figure 8) Adense layer of mucus which increases in thickness fromthe proximal to the distal colon serves to separate bacteriafrom direct contact with the epithelial surface Secretionof microbial-associated molecular patterns (MAMPs) bycommensal bacteria stimulates MyD88-dependent TLR sig-naling leading to enhanced expression of pIgR and antimi-crobial peptides and increased mucus production Bindingof pIgA to pIgR and possibly also signaling via MAMPs

14 ISRN Immunology

enhances transcytosis of pIgA pIgA-containing immunecomplexes and unoccupied pIgR which promotes clearanceof antigens and pathogens from the lamina propria intra-cellular neutralization and release of SIgA and SC at theluminal surface SIgA and SC serve to trap bacteria in themucus layer limiting their access to the epithelial surface Inmice with a targeted deletion of the Muc2 gene which havea severely depleted mucus layer in the colon SIgA and SCfail to associate with the surface of colonic epithelial cells[160] The presence of SIgA in the intestinal lumen whetherderived passively frommaternalmilk or actively via epithelialtranscytosis shapes the composition of the gut microbiotaand modulates intestinal epithelial gene expression

9 Concluding Remarks

The first microbes that emerged on Earth almost 4 billionyears ago encountered a hostile world where nutrients werescarce hazards were everywhere and life was short Withthe evolution of multicellular organisms about 3 billion yearslater a select group ofmicrobes chose to sacrifice an indepen-dent existence for the benefits of a mutualistic relationshipwith eukaryotic hosts Prokaryotic-eukaryotic mutualismreached its apex some 500 million years ago with theemergence of primitive vertebrates whose gastrointestinaltracts were populated by an abundant and diverse commensalmicrobiota In humans the large intestine is home to some100 trillion microorganisms 10 times more than the totalnumber of eukaryotic cells in the entire body The microbesthat inhabit the vertebrate GI tract provide many benefitsto the eukaryotic host including digestion of complex foodmolecules synthesis of vitamins and production of solublefactors that enhance the development of the host immunesystem In return the eukaryotic host provides the microbeswith a warm moist place to live abundant food low oxygentension and a soft bed of mucus on which to form biofilmsWhen this mutually beneficial arrangement is challenged bypathogenicmicrobes the eukaryotic host and the commensalmicrobiota join forces to battle the pathogens and protectthe body from invasion The vertebrate immune system isequipped with a well-trained army of immune cells and asophisticated arsenal of weapons (cell surface molecules andsecreted factors) that protect the host from all but the mostvirulent pathogens This immune ldquoarmyrdquo also serves as aconstant reminder to the commensal microbes that whilethey are free to enjoy the amenities of the mucosal surfacesthey are not welcome in the body proper The emergence ofantigen-specific Igs and T-cell receptors in jawed vertebratesbegan a process of immunological diversification that led tothe development of a specialized mucosal immune systemin higher vertebrates in which secretory Igs play a centralrole The relationship between host and microbiota is clearlyreciprocal the mucosal Igs that evolved in response toselective pressure from the commensal microbiota play acentral role throughout life in shaping the compositiongenetics andmetabolic activity of themicrobiota [1 161 162]

The epithelial layer lining mucosal surfaces provides aphysical and innate immune barrier against penetration of

the body proper by microbes undigested food antigens andpotentially noxious environmental substances The evolu-tionary challenge of transporting mucosal Igs into externalsecretions without compromising the epithelial barrier wasmet by the emergence of the PIGR gene in an ancestor ofbony fishes encoding an epithelial-specific transmembraneprotein that actively transports polymeric Igs across mucosaland glandular epithelia (Figure 4) Structural similaritiesbetween Igs and the extracellular Ig-binding domains of pIgR(Figure 6) suggest that duplication and diversification of agene encoding primordial Ig-like domain may have givenrise to the PIGR gene in a primitive vertebrate ancestorParallel refinement of the structures of mucosal Igs andpIgR during tetrapod evolution (Figures 6 and 7) culminatedin the evolution of the multifunctional SIgA molecule inmammals in which the pIgR-derived SC subunit providesinnate immune functions and protects the antigen-bindingIgA polymer from proteolytic degradation In addition toacting as a powerful force during vertebrate evolution thereciprocal relationship between pIgR mucosal Igs and thecommensal microbiota provides benefits throughout thelife of the individual Microbial colonization of newbornvertebrates stimulates development of mucosal B cells andclass switching to mucosal Ig isotypes [1 163] Microbialfactors upregulate expression of pIgR enhancing transportof mucosal Igs into external secretions where they in turnregulate the microbiotaThis beautifully orchestrated processallows us to maintain a healthy relationship with our resi-dent microbiota while providing mutual protection againstpathogens

Conflict of Interests

The author declares that there is no conflict of interestsregarding the publication of this paper

Acknowledgments

This work was supported by Grant no AI069027 from theNational Institutes of Health of the United States of America(and an associatedAmerican Recovery andReinvestmentActsupplement) and a Senior Research Award from the Crohnrsquosand Colitis Foundation of America

References

[1] C L Maynard C O Elson R D Hatton and C T WeaverldquoReciprocal interactions of the intestinal microbiota andimmune systemrdquo Nature vol 489 no 7415 pp 231ndash241 2012

[2] M F Flajnik and M Kasahara ldquoOrigin and evolution of theadaptive immune system genetic events and selective pres-suresrdquo Nature Reviews Genetics vol 11 no 1 pp 47ndash59 2010

[3] M F Flajnik and L du Pasquier ldquoEvolution of the immunesystemrdquo in Fundamental Immunology W E Paul Ed chapter4 pp 67ndash128 Lippincott Williams ampWilkins Philadelphia PaUSA 2012

[4] M Hirano S Das P Guo and M D Cooper ldquoThe evolutionof adaptive immunity in vertebratesrdquo Advances in Immunologyvol 109 pp 125ndash157 2011

ISRN Immunology 15

[5] T BoehmNMcCurley Y SutohM SchorppMKasahara andM D Cooper ldquoVLR-based adaptive immunityrdquo Annual Reviewof Immunology vol 30 pp 203ndash220 2012

[6] T Hunkapiller and L Hood ldquoImmunology the growing immu-noglobulin gene superfamilyrdquoNature vol 323 no 6083 pp 15ndash16 1986

[7] P Bork L Holm and C Sander ldquoThe immunoglobulin foldstructural classification sequence patterns and common corerdquoJournal of Molecular Biology vol 242 no 4 pp 309ndash320 1994

[8] C S Kaetzel and M W Russell ldquoPhylogeny and comparativephysiology of IgArdquo in Mucosal Immunology J Mestecky WStrober H Cheroutre B Kelsall B N Lambrecht and M WRussell Eds chapter 19 Academic PressElsevier WalthamMass USA 2014

[9] Y He and P J Bjorkman ldquoStructure of FcRY an avian immu-noglobulin receptor related to mammalian mannose receptorsand its complex with IgYrdquo Proceedings of the National Academyof Sciences of the United States of America vol 108 no 30 pp12431ndash12436 2011

[10] J M Woof and D R Burton ldquoHuman antibody-Fc receptorinteractions illuminated by crystal structuresrdquo Nature ReviewsImmunology vol 4 no 2 pp 89ndash99 2004

[11] W L Martin A P West Jr L Gan and P J Bjorkman ldquoCrystalstructure at 28 A of an FcRnheterodimeric Fc complexmechanism of pH-dependent bindingrdquo Molecular Cell vol 7no 4 pp 867ndash877 2001

[12] E S Ward ldquoAcquiring maternal immunoglobulin differentreceptors similar functionsrdquo Immunity vol 20 no 5 pp 507ndash508 2004

[13] C S Kaetzel ldquoThe polymeric immunoglobulin receptor bridg-ing innate and adaptive immune responses atmucosal surfacesrdquoImmunological Reviews vol 206 no 1 pp 83ndash99 2005

[14] M Acharya G Borland A L Edkins et al ldquoCD23Fc120576RIImolecular multi-taskingrdquo Clinical and Experimental Immunol-ogy vol 162 no 1 pp 12ndash23 2010

[15] V B Klimovich ldquoIgM and its receptors structural and func-tional aspectsrdquo Biochemistry vol 76 no 5 pp 534ndash549 2011

[16] J MWoof andMW Russell ldquoStructure and function relation-ships in IgArdquo Mucosal Immunology vol 4 no 6 pp 590ndash5972011

[17] F-E Johansen and C S Kaetzel ldquoRegulation of the polymericimmunoglobulin receptor and IgA transport new advances inenvironmental factors that stimulate pIgR expression and itsrole in mucosal immunityrdquo Mucosal Immunology vol 4 no 6pp 598ndash602 2011

[18] F Kokubu K Hinds R Litman M J Shamblott and G WLitman ldquoExtensive families of constant region genes in a phy-logenetically primitive vertebrate indicate an additional levelof immunoglobulin complexityrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 84 no16 pp 5868ndash5872 1987

[19] A S Greenberg A L Hughes J Guo D Avila E CMcKinneyand M F Flajnik ldquoA novel ldquochimericrdquo antibody class in carti-laginous fish IgMmay not be the primordial immunoglobulinrdquoEuropean Journal of Immunology vol 26 no 5 pp 1123ndash11291996

[20] H Dooley and M F Flajnik ldquoShark immunity bites back affin-ity maturation and memory response in the nurse shark Ging-lymostoma cirratumrdquo European Journal of Immunology vol 35no 3 pp 936ndash945 2005

[21] S F Schluter R M Bernstein and J J Marchalonis ldquoMolecularorigins and evolution of immunoglobulin heavy-chain genes ofjawed vertebratesrdquo Immunology Today vol 18 no 11 pp 543ndash549 1997

[22] Y Ohta and M Flajnik ldquoIgD like IgM is a primordial immu-noglobulin class perpetuated in most jawed vertebratesrdquo Pro-ceedings of the National Academy of Sciences of the United Statesof America vol 103 no 28 pp 10723ndash10728 2006

[23] S Fillatreau A Six S Magadan R Castro J O Sunyer andP Boudinot ldquoThe astonishing diversity of Ig classes and B cellrepertoires in teleost fishrdquo Frontiers in Immunology vol 4 no28 2013

[24] W Harriman H Volk N Defranoux and M Wabl ldquoImmu-noglobulin class switch recombinationrdquo Annual Review ofImmunology vol 11 pp 361ndash384 1993

[25] J Stavnezer and C T Amemiya ldquoEvolution of isotype switch-ingrdquo Seminars in Immunology vol 16 no 4 pp 257ndash275 2004

[26] V M Barreto Q Pan-Hammarstrom Y Zhao L Ham-marstrom Z Misulovin and M C Nussenzweig ldquoAID frombony fish catalyzes class switch recombinationrdquo Journal ofExperimental Medicine vol 202 no 6 pp 733ndash738 2005

[27] T C Fletcher and AWhite ldquoAntibody production in the plaice(Pleuronectes platessa L) after oral and parenteral immuniza-tion with Vibrio anguillarum antigensrdquo Aquaculture vol 1 pp417ndash428 1972

[28] J W H M Rombout L J Blok C H J Lamers and E EgbertsldquoImmunization of carp (Cyprinus carpio) with a Vibrio anguil-larum bacterin indications for a common mucosal immunesystemrdquo Developmental and Comparative Immunology vol 10no 3 pp 341ndash351 1986

[29] U Georgopoulou and J-M Vernier ldquoLocal immunologicalresponse in the posterior intestinal segment of the rainbowtrout after oral administration of macromoleculesrdquo Develop-mental andComparative Immunology vol 10 no 4 pp 529ndash5371986

[30] C J Lobb ldquoSecretory immunity induced in catfish Ictaluruspunctatus following bath immunizationrdquo Developmental andComparative Immunology vol 11 no 4 pp 727ndash738 1987

[31] J D Hansen E D Landis and R B Phillips ldquoDiscovery ofa unique Ig heavy-chain (IgT) in rainbow trout implicationsfor a distinctive B cell developmental pathway in teleost fishrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 102 no 19 pp 6919ndash6924 2005

[32] N Danilova J Bussmann K Jekosch and L A Steiner ldquoTheimmunoglobulin heavy-chain locus in zebrafish identificationand expression of a previously unknown isotype immunoglob-ulin Zrdquo Nature Immunology vol 6 no 3 pp 295ndash302 2005

[33] R Savan A Aman K Sato R Yamaguchi and M Sakai ldquoDis-covery of a new class of immunoglobulin heavy chain fromfugurdquo European Journal of Immunology vol 35 no 11 pp 3320ndash3331 2005

[34] R Savan A AmanMNakao HWatanuki andM Sakai ldquoDis-covery of a novel immunoglobulin heavy chain gene chimerafrom common carp (Cyprinus carpio L)rdquo Immunogenetics vol57 no 6 pp 458ndash463 2005

[35] F Gambon-Deza C Sanchez-Espinel and S Magadan-Mompo ldquoPresence of an unique IgT on the IGH locus in three-spined stickleback fish (Gasterosteus aculeatus) and the veryrecent generation of a repertoire of VH genesrdquo Developmentaland Comparative Immunology vol 34 no 2 pp 114ndash122 2010

[36] T M Tadiso K K Lie and I Hordvik ldquoMolecular cloning ofIgT fromAtlantic salmon and analysis of the relative expression

16 ISRN Immunology

of 120591 120583 and 120575 in different tissuesrdquo Veterinary Immunology andImmunopathology vol 139 no 1 pp 17ndash26 2011

[37] S Mashoof C Pohlenz P L Chen et al ldquoExpressed IgH 120583and 120591 transcripts share diversity segment in ranched Thunnusorientalisrdquo Developmental and Comparative Immunology vol43 no 1 pp 76ndash86 2014

[38] Y-A Zhang I Salinas J Li et al ldquoIgT a primitive immunoglob-ulin class specialized in mucosal immunityrdquo Nature Immunol-ogy vol 11 no 9 pp 827ndash835 2010

[39] S Magadan-Mompo C Sanchez-Espinel and F Gambon-Deza ldquoImmunoglobulin heavy chains in medaka (Oryziaslatipes)rdquo BMC Evolutionary Biology vol 11 no 1 article 1652011

[40] C T Amemiya J Alfoldi A P Lee et al ldquoThe African coela-canth genome provides insights into tetrapod evolutionrdquoNature vol 496 no 7445 pp 311ndash316 2013

[41] T Ota J P Rast G W Litman and C T Amemiya ldquoLineage-restricted retention of a primitive immunoglobulin heavy chainisotype within the Dipnoi reveals an evolutionary paradoxrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 100 no 5 pp 2501ndash2506 2003

[42] Y Sun Z Wei N Li and Y Zhao ldquoA comparative overview ofimmunoglobulin genes and the generation of their diversity intetrapodsrdquo Developmental and Comparative Immunology vol39 no 1-2 pp 103ndash109 2013

[43] I Hadji-Azimi ldquoAnuran immunoglobulins a reviewrdquo Develop-mental and Comparative Immunology vol 3 no 2 pp 223ndash2431979

[44] E Hsu M F Flajnik and L du Pasquier ldquoA third immunoglob-ulin class in amphibiansrdquo The Journal of Immunology vol 135no 3 pp 1998ndash2004 1985

[45] C T Amemiya R N Haire and G W Litman ldquoNucleotidesequence of a cDNA encoding a third distinct Xenopusimmunoglobulin heavy chain isotyperdquo Nucleic Acids Researchvol 17 no 13 p 5388 1989

[46] R Muszligmann M Wilson A Marcuz M Courtet and L duPasquier ldquoMembrane exon sequences of the three Xenopus Igclasses explain the evolutionary origin of mammalian isotypesrdquoEuropean Journal of Immunology vol 26 no 2 pp 409ndash4141996

[47] R Muszligmann L du Pasquier and E Hsu ldquoIs Xenopus IgX ananalog of IgArdquo European Journal of Immunology vol 26 no12 pp 2823ndash2830 1996

[48] B Schaerlinger and J-P Frippiat ldquoIgX antibodies in the urodeleamphibian Ambystoma mexicanumrdquo Developmental and Com-parative Immunology vol 32 no 8 pp 908ndash915 2008

[49] B Schaerlinger M Bascove and J-P Frippiat ldquoA new isotypeof immunoglobulin heavy chain in the urodele amphibianPleurodeles waltl predominantly expressed in larvaerdquoMolecularImmunology vol 45 no 3 pp 776ndash786 2008

[50] S Mashoof A Goodroe C C Du et al ldquoAncient T-independence of mucosal IgXA gut microbiota unaffected bylarval thymectomy in Xenopus laevisrdquo Mucosal Immunologyvol 6 no 2 pp 358ndash368 2013

[51] J P Vaerman J Picard and J F Heremans ldquoStructural dataon chicken IgA and failure to identify the IgA of the tortoiserdquoin Immunologic Phylogeny vol 64 of Advances in ExperimentalMedicine and Biology pp 185ndash195 Springer New York NYUSA 1975

[52] J L Portis and J E Coe ldquoIgM the secretory immunoglobulinof reptiles and amphibiansrdquo Nature vol 258 no 5535 pp 547ndash548 1975

[53] J E Coe D Leong J L Portis and L A Thomas ldquoImmuneresponse in the garter snake (Thamnophis ordinoides)rdquo Immu-nology vol 31 no 3 pp 417ndash424 1976

[54] D Hadge and H Ambrosius ldquoEvolution of low molecularweight immunoglobulinsmdashIV IgY-like immunoglobulins ofbirds reptiles and amphibians precursors of mammalian IgArdquoMolecular Immunology vol 21 no 8 pp 699ndash707 1984

[55] D Hadge and H Ambrosius ldquoEvolution of low molecularweight immunoglobulins V Degree of antigenic relationshipbetween the 7S immunoglobulins ofmammals birds and lowervertebrates to the turkey IgYrdquo Developmental and ComparativeImmunology vol 10 no 3 pp 377ndash385 1986

[56] S Magadan-Mompo C Sanchez-Espinel and F Gambon-Deza ldquoImmunoglobulin genes of the turtlesrdquo Immunogeneticsvol 65 no 3 pp 227ndash237 2013

[57] Z Wei Q Wu L Ren et al ldquoExpression of IgM IgD and IgYin a reptile Anolis carolinensisrdquoThe Journal of Immunology vol183 no 6 pp 3858ndash3864 2009

[58] F Gambon-Deza C Sanchez-Espinel and J V Beneitez ldquoAnovel IgA-like immunoglobulin in the reptile Eublepharis mac-ulariusrdquo Developmental and Comparative Immunology vol 31no 6 pp 596ndash605 2007

[59] G Cheng Y Gao T Wang et al ldquoExtensive diversification ofIgH subclass-encoding genes and IgM subclass switching incrocodiliansrdquo Nature Communications vol 4 article 1337 2013

[60] S Magadan-Mompo C Sanchez-Espinel and F Gambon-Deza ldquoIgH loci of American alligator and saltwater crocodileshed light on IgA evolutionrdquo Immunogenetics vol 65 no 7 pp531ndash541 2013

[61] E Orlans and M E Rose ldquoAn IgA-like immunoglobulin in thefowlrdquo Immunochemistry vol 9 no 8 pp 833ndash838 1972

[62] G A Leslie and L N Martin ldquoStudies on the secretory immu-nologic system of fowl 3 Serum and secretory IgA of thechickenrdquoThe Journal of Immunology vol 110 no 1 pp 1ndash9 1973

[63] J Bienenstock D Y Perey J Gauldie and B J UnderdownldquoChicken 120574A physicochemical and immunochemical charac-teristicsrdquoThe Journal of Immunology vol 110 no 2 pp 524ndash5331973

[64] A M Lebacq-Verheyden J P Vaerman and J F HeremansldquoQuantification and distribution of chicken immunoglobulinsIgA IgM and IgG in serum and secretionsrdquo Immunology vol27 no 4 pp 683ndash692 1974

[65] J Goudswaard A Noordzij R H van Dam J A vanderDonk and J P Vaerman ldquoThe immunoglobulins of the turkey(Meleagris gallopavo) Isolation and characterization of IgGIgM and IgA in body fluids eggs and intraocular tissuesrdquoPoultry science vol 56 no 6 pp 1847ndash1851 1977

[66] D Hadge and H Ambrosius ldquoComparative studies on thestructure of biliary immunoglobulins of some avian speciesII Antigenic properties of the biliary immunoglobulins ofchicken turkey duck and gooserdquo Developmental and Compar-ative Immunology vol 12 no 2 pp 319ndash329 1988

[67] J Goudswaard J P Vaerman and J F Heremans ldquoThreeimmunoglobulin classes in the pigeon (Columbia livia)rdquo Inter-national Archives of Allergy andApplied Immunology vol 53 no5 pp 409ndash419 1977

[68] P L K Ng and D A Higgins ldquoBile immunoglobulin of theduck (Anas platyrhynchos) I Preliminary characterization andontogenyrdquo Immunology vol 58 no 2 pp 323ndash327 1986

[69] K E Magor G W Warr Y Bando D L Middleton and DA Higgins ldquoSecretory immune system of the duck (Anas

ISRN Immunology 17

platyrhynchos) Identification and expression of the genesencoding IgA and IgM heavy chainsrdquo European Journal ofImmunology vol 28 no 3 pp 1063ndash1068 1998

[70] Y Zhao H Rabbani A Shimizu and L Hammarstrom ldquoMap-ping of the chicken immunoglobulin heavy-chain constantregion gene locus reveals an inverted 120572 gene upstream of acondensed 120592 generdquo Immunology vol 101 no 3 pp 348ndash3532000

[71] M L Lundqvist D L Middleton S Hazard and G W WarrldquoThe immunoglobulin heavy chain locus of the duck genomicorganization and expression of D J and C region genesrdquo TheJournal of Biological Chemistry vol 276 no 50 pp 46729ndash46736 2001

[72] T HuangM Zhang ZWei et al ldquoAnalysis of immunoglobulintranscripts in the ostrich Struthio camelus a primitive avianspeciesrdquo PLoS ONE vol 7 no 3 Article ID e34346 2012

[73] K H Roux ldquoImmunoglobulin structure and function asrevealed by electron microscopyrdquo International Archives ofAllergy and Immunology vol 120 no 2 pp 85ndash99 1999

[74] F Gambon-Deza C Sanchez-Espinel and S Magadan-Mompo ldquoThe immunoglobulin heavy chain locus in the platy-pus (Ornithorhynchus anatinus)rdquo Molecular Immunology vol46 no 13 pp 2515ndash2523 2009

[75] Y Zhao H Cui C M Whittington et al ldquoOrnithorhynchusanatinus (platypus) links the evolution of immunoglobulingenes in eutherian mammals and nonmammalian tetrapodsrdquoThe Journal of Immunology vol 183 no 5 pp 3285ndash3293 2009

[76] M Aveskogh and L Hellman ldquoEvidence for an early appear-ance of modern post-switch isotypes in mammalian evolutioncloning of IgE IgG and IgA from the marsupial Monodelphisdomesticardquo European Journal of Immunology vol 28 no 9 pp2738ndash2750 1998

[77] K Belov G A Harrison and DW Cooper ldquoMolecular cloningof the cDNA encoding the constant region of the immunoglob-ulin a heavy chain (C120572) from amarsupialTrichosurus vulpecula(common brushtail possum)rdquo Immunology Letters vol 60 no2-3 pp 165ndash170 1998

[78] K Belov K R Zenger L Hellman and DW Cooper ldquoEchidnaIgA supports mammalian unity and traditional Therian rela-tionshiprdquo Mammalian Genome vol 13 no 11 pp 656ndash6632002

[79] K Belov and L Hellman ldquoImmunoglobulin genetics of Orni-thorhynchus anatinus (platypus) and Tachyglossus aculeatus(short-beaked echidna)rdquo Comparative Biochemistry and Phys-iology vol 136 no 4 pp 811ndash819 2003

[80] M VernerssonM Aveskogh BMunday and L Hellman ldquoEvi-dence for an early appearance of modern post-switch immu-noglobulin isotypes in mammalian evolution (II) cloning ofIgE IgG1 and IgG2 fromamonotreme the duck-billed platypusOrnithorhynchus anatinusrdquo European Journal of Immunologyvol 32 no 8 pp 2145ndash2155 2002

[81] C Auffray R Nageotte and J L Sikorav ldquoMouse immunoglob-ulin A nucleotide sequence of the structural gene for the 120572heavy chain derived from cloned cDNAsrdquo Gene vol 13 no 4pp 365ndash374 1981

[82] T Ukaji D Sumiyama and O Kai ldquoSequence determinationof the heavy-chain constant region in four immunoglobulinclasses of Mongolian gerbils (Meriones unguiculatus)rdquo Experi-mental Animals vol 61 no 2 pp 99ndash107 2012

[83] R C Burnett W C Hanly S K Zhai and K L Knight ldquoTheIgA heavy chain gene family in rabbit cloning and sequence

analysis of 13 C120572 genesrdquo The EMBO Journal vol 8 no 13 pp4041ndash4047 1989

[84] D K Lanning S-K Zhai and K L Knight ldquoAnalysis of the 31015840C120583 region of the rabbit Ig heavy chain locusrdquoGene vol 309 no2 pp 135ndash144 2003

[85] F Ros J Puels N Reichenberger W van Schooten R Buelowand J Platzer ldquoSequence analysis of 05Mb of the rabbitgermline immunoglobulin heavy chain locusrdquo Gene vol 330no 1-2 pp 49ndash59 2004

[86] M Patel D Selinger G E Mark G J Hickey and G FHollis ldquoSequence of the dog immunoglobulin alpha and epsilonconstant region genesrdquo Immunogenetics vol 41 no 5 pp 282ndash286 1995

[87] Z Zhao Y Zhao Q Pan-Hammarstrom et al ldquoPhysical map-ping of the giant panda immunoglobulin heavy chain constantregion genesrdquo Developmental and Comparative Immunologyvol 31 no 10 pp 1034ndash1049 2007

[88] W R Brown and J E Butler ldquoCharacterization of a C120572 gene ofswinerdquoMolecular Immunology vol 31 no 8 pp 633ndash642 1994

[89] W R Brown H Rabbani J E Butler and L HammarstromldquoCharacterization of the bovine C120572 generdquo Immunology vol 91no 1 pp 1ndash6 1997

[90] G PWhite P Roche M R Brandon S E Newton and E N TMeeusen ldquoCloning and characterization of sheep (Ovis aries)immunoglobulin 120572 chainrdquo Immunogenetics vol 48 no 5 pp359ndash362 1998

[91] AMancia T A Romano H A Gefroh et al ldquoCharacterizationof the immunoglobulin A heavy chain gene of the Atlantic bot-tlenose dolphin (Tursiops truncatus)rdquo Veterinary Immunologyand Immunopathology vol 118 no 3-4 pp 304ndash309 2007

[92] B Wagner I Greiser-Wilke and D F Antczak ldquoCharacteriza-tion of the horse [Equus caballus] IGHA generdquo Immunogeneticsvol 55 no 8 pp 552ndash560 2003

[93] N Takahashi S Ueda and M Obata ldquoStructure of humanimmunoglobulin gamma genes implications for evolution of agene familyrdquo Cell vol 29 no 2 pp 671ndash679 1982

[94] J G Flanagan M-P Lefranc and T H Rabbitts ldquoMechanismsof divergence and convergence of the human immunoglobulin1205721 and 1205722 constant region gene sequencesrdquo Cell vol 36 no 3pp 681ndash688 1984

[95] S Kawamura K Omoto and S Ueda ldquoEvolutionary hypervari-ability in the hinge region of the immunoglobulin alpha generdquoJournal of Molecular Biology vol 215 no 2 pp 201ndash206 1990

[96] F Scinicariello F Masseoud L Jayashankar and R AttanasioldquoSooty mangabey (Cercocebus torquatus atys) IGHG and IGHAgenesrdquo Immunogenetics vol 58 no 12 pp 955ndash965 2006

[97] K A Rogers L Jayashankar F Scinicariello and R AttanasioldquoNonhuman primate IgA genetic heterogeneity and interac-tions with CD89rdquoThe Journal of Immunology vol 180 no 7 pp4816ndash4824 2008

[98] S Kawamura N Saitou and S Ueda ldquoConcerted evolution ofthe primate immunoglobulin 120572-gene through gene conversionrdquoThe Journal of Biological Chemistry vol 267 no 11 pp 7359ndash7367 1992

[99] S Kawamura and S Ueda ldquoImmunoglobulin C119867gene family in

hominoids and its evolutionary historyrdquo Genomics vol 13 no1 pp 194ndash200 1992

[100] A Brusco U Cariota A Bottaro et al ldquoStructural andimmunologic analysis of gene triplications in the Ig heavy chainconstant region locusrdquoThe Journal of Immunology vol 152 no1 pp 129ndash135 1994

18 ISRN Immunology

[101] H Rabbani Q Pan N Kondo C I E Smith and L Ham-marstrom ldquoDuplications and deletions of the human IGHClocus evolutionary implicationsrdquo Immunogenetics vol 45 no2 pp 136ndash141 1996

[102] P F Weinheimer J Mestecky and R T Acton ldquoSpecies distri-bution of J chainrdquoThe Journal of Immunology vol 107 no 4 pp1211ndash1212 1971

[103] F P Inman and J Mestecky ldquoThe J chain of polymeric immu-noglobulinsrdquo inContemporary Topics inMolecular Immunologyvol 3 pp 111ndash141 Springer New York NY USA 1974

[104] P Brandtzaeg ldquoPresence of J chain in human immunocytescontaining various immunoglobulin classesrdquo Nature vol 252no 5482 pp 418ndash420 1974

[105] L Tacchi E Larragoite and I Salinas ldquoDiscovery of J chain inAfrican lungfish (Protopterus dolloi Sarcopterygii) using highthroughput transcriptome sequencing implications in mucosalimmunityrdquo PLoS ONE vol 8 no 8 Article ID e70650 2013

[106] I K Zarkadis D Mastellos and J D Lambris ldquoPhylogeneticaspects of the complement systemrdquo Developmental and Com-parative Immunology vol 25 no 8-9 pp 745ndash762 2001

[107] A P West Jr A B Herr and P J Bjorkman ldquoThe chickenyolk sac IgY receptor a functional equivalent of themammalianMHC-related Fc receptor is a phospholipase A

2receptor

homologrdquo Immunity vol 20 no 5 pp 601ndash610 2004[108] D B Tesar E J Cheung and P J Bjorkman ldquoThe chicken

yolk sac IgY receptor a mammalian mannose receptor familymember transcytoses IgY across polarized epithelial cellsrdquoMolecular Biology of the Cell vol 19 no 4 pp 1587ndash1593 2008

[109] A I Taylor R L Beavil B J Sutton and R A Calvert ldquoAmonomeric chicken IgY receptor binds IgY with 21 stoichiom-etryrdquo The Journal of Biological Chemistry vol 284 no 36 pp24168ndash24175 2009

[110] K Baker S-W Qiao T Kuo et al ldquoImmune and non-immunefunctions of the (not so) neonatal Fc receptor FcRnrdquo Seminarsin Immunopathology vol 31 no 2 pp 223ndash236 2009

[111] K Baker R S Blumberg and C S Kaetzel ldquoImmunoglob-ulin transport and immunoglobulin receptorsrdquo in MucosalImmunology J Mestecky W Strober H Cheroutre B KelsallB N Lambrecht andMW Russell Eds chapter 20 AcademicPressElsevier Waltham Mass USA 2014

[112] C S Kaetzel ldquoThepolymeric immunoglobulin receptorrdquo in eLSJohn Wiley amp Sons Chichester UK 2013

[113] N J Mantis N Rol and B Corthesy ldquoSecretory IgArsquos complexroles in immunity andmucosal homeostasis in the gutrdquoMucosalImmunology vol 4 no 6 pp 603ndash611 2011

[114] J V Peppard M E Rose and P Hesketh ldquoA functional homo-logue of mammalian secretory component exists in chickensrdquoEuropean Journal of Immunology vol 13 no 7 pp 566ndash5701983

[115] K E Mostov M Friedlander and G Blobel ldquoThe receptorfor transepithelial transport of IgA and IgM contains multipleimmunoglobulin-like domainsrdquo Nature vol 308 no 5954 pp37ndash43 1984

[116] P Krajci R Solberg M Sandberg O Oyen T Jahnsen and PBrandtzaeg ldquoMolecular cloning of the human transmembranesecretory component (poly-Ig receptor) and its mRNA expres-sion in human tissuesrdquo Biochemical and Biophysical ResearchCommunications vol 158 no 3 pp 783ndash789 1989

[117] P Krajci D Kvale K Tasken and P Brandtzaeg ldquoMolecularcloning and exon-intron mapping of the gene encoding humantransmembrane secretory component (the poly-Ig receptor)rdquo

European Journal of Immunology vol 22 no 9 pp 2309ndash23151992

[118] J F Piskurich J A France C M Tamer C A Willmer CS Kaetzel and D M Kaetzel ldquoInterferon-120574 induces polymericimmunoglobulin receptormRNA in human intestinal epithelialcells by a protein synthesis dependent mechanismrdquo MolecularImmunology vol 30 no 4 pp 413ndash421 1993

[119] J F Piskurich M H Blanchard K R Youngman J A Franceand C S Kaetzel ldquoMolecular cloning of the mouse polymericIg receptor functional regions of the molecule are conservedamong five mammalian speciesrdquo The Journal of Immunologyvol 154 no 4 pp 1735ndash1747 1995

[120] M A Kulseth P Krajci O Myklebost and S RogneldquoCloning and characterization of two forms of bovine polymericimmunoglobulin receptor cDNArdquo DNA and Cell Biology vol14 no 3 pp 251ndash256 1995

[121] K S Koch A S Gleiberman T Aoki et al ldquoDiscordant expres-sion and variable numbers of neighboring GGA- and GAA-richtriplet repeats in the 31015840 untranslated regions of two groups ofmessenger RNAs encoded by the rat polymeric immunoglob-ulin receptor generdquo Nucleic Acids Research vol 23 no 7 pp1098ndash1112 1995

[122] F M Adamski and J Demmer ldquoTwo stages of increased IgAtransfer during lactation in themarsupialTrichosurus vulpecula(brushtail possum)rdquoThe Journal of Immunology vol 162 no 10pp 6009ndash6015 1999

[123] H Kumura T Sone K-I Shimazaki and E KobayashildquoSequence analysis of porcine polymeric immunoglobulinreceptor from mammary epithelial cells present in colostrumrdquoThe Journal of Dairy Research vol 67 no 4 pp 631ndash636 2000

[124] C L Taylor G A Harrison C M Watson and E M DeaneldquocDNA cloning of the polymeric immunoglobulin receptor ofthe marsupial Macropus eugenii (tammar wallaby)rdquo EuropeanJournal of Immunogenetics vol 29 no 2 pp 87ndash93 2002

[125] R Braathen V S Hohman P Brandtzaeg and F-E JohansenldquoSecretory antibody formation conserved binding interactionsbetween J chain and polymeric Ig receptor from humans andamphibiansrdquo The Journal of Immunology vol 178 no 3 pp1589ndash1597 2007

[126] M J Lewis BWagner R M Irvine and J MWoof ldquoIgA in thehorse cloning of equine polymeric Ig receptor and J chain andcharacterization of recombinant forms of equine IgArdquoMucosalImmunology vol 3 no 6 pp 610ndash621 2010

[127] A J Leon D Banner L Xu et al ldquoSequencing annotation andcharacterization of the influenza ferret infectomerdquo Journal ofVirology vol 87 no 4 pp 1957ndash1966 2013

[128] W H Wieland D Orzaez A Lammers H K ParmentierM W A Verstegen and A Schots ldquoA functional polymericimmunoglobulin receptor in chicken (Gallus gallus) indicatesancient role of secretory IgA inmucosal immunityrdquoBiochemicalJournal vol 380 no 3 pp 669ndash676 2004

[129] K Hamuro H Suetake N R Saha K Kikuchi and YSuzuki ldquoA teleost polymeric Ig receptor exhibiting two Ig-likedomains transports tetrameric IgM into the skinrdquo The Journalof Immunology vol 178 no 9 pp 5682ndash5689 2007

[130] J H W M Rombout S J L van der Tuin G Yang et alldquoExpression of the polymeric immunoglobulin receptor (pIgR)in mucosal tissues of common carp (Cyprinus carpio L)rdquo Fishand Shellfish Immunology vol 24 no 5 pp 620ndash628 2008

[131] L-N Feng D-Q Lu J-X Bei et al ldquoMolecular cloning andfunctional analysis of polymeric immunoglobulin receptor gene

ISRN Immunology 19

in orange-spotted grouper (Epinephelus coioides)rdquo ComparativeBiochemistry and Physiology B vol 154 no 3 pp 282ndash289 2009

[132] A E Oslashstergaard S A M Martin T Wang R J M Stet andC J Secombes ldquoRainbow trout (Oncorhynchus mykiss) pos-sessmultiple novel immunoglobulin-like transcripts containingeither an ITAM or ITIMsrdquo Developmental and ComparativeImmunology vol 33 no 4 pp 525ndash532 2009

[133] H Eiffert E Quentin and J Decker ldquoThe primary structureof the human free secretory component and the arrangementof disulfide bondsrdquo Hoppe-Seylerrsquos Zeitschrift fur PhysiologischeChemie vol 365 no 12 pp 1489ndash1495 1984

[134] E Fallgreen-Gebauer W Gebauer A Bastian et al ldquoThe cova-lent linkage of secretory component to IgA Structure of sIgArdquoBiological Chemistry Hoppe-Seyler vol 374 no 11 pp 1023ndash1028 1993

[135] J MWoof ldquoThe structure of IgArdquo inMucosal Immune DefenseImmunoglobulin A C S Kaetzel Ed chapter 1 pp 1ndash24Springer New York NY USA 2007

[136] A Bonner A Almogren P B Furtado M A Kerr and S JPerkins ldquoLocation of secretory component on the Fc edge ofdimeric IgA1 reveals insight into the role of secretory IgA1 inmucosal immunityrdquoMucosal Immunology vol 2 no 1 pp 74ndash84 2009

[137] A Bonner A Almogren P B Furtado M A Kerr and S JPerkins ldquoThe nonplanar secretory IgA2 and near planar secre-tory IgA1 solution structures rationalize their different mucosalimmune responsesrdquo The Journal of Biological Chemistry vol284 no 8 pp 5077ndash5087 2009

[138] J Johansen B Braathen and P Brandtzaeg ldquoRole of J chain insecretory immunoglobulin formationrdquo Scandinavian Journal ofImmunology vol 52 no 3 pp 240ndash248 2000

[139] B A Hendrickson D A Conner D J Ladd et al ldquoAlteredhepatic transport of immunoglobulin A in mice lacking the Jchainrdquo Journal of Experimental Medicine vol 182 no 6 pp1905ndash1911 1995

[140] B A Hendrickson L Rindisbacher B Corthesy et al ldquoLackof association of secretory component with IgA in J chain-deficient micerdquo The Journal of Immunology vol 157 no 2 pp750ndash754 1996

[141] N Lycke L Erlandsson L Ekman K Schon and T Lean-derson ldquoLack of J chain inhibits the transport of gut IgA andabrogates the development of intestinal antitoxic protectionrdquoThe Journal of Immunology vol 163 no 2 pp 913ndash919 1999

[142] F-E Johansen R Braathen and P Brandtzaeg ldquoThe J chainis essential for polymeric Ig receptor-mediated epithelial trans-port of IgArdquoThe Journal of Immunology vol 167 no 9 pp 5185ndash5192 2001

[143] R E Ley D A Peterson and J I Gordon ldquoEcological andevolutionary forces shaping microbial diversity in the humanintestinerdquo Cell vol 124 no 4 pp 837ndash848 2006

[144] M McFall-Ngai ldquoAdaptive immunity care for the communityrdquoNature vol 445 no 7124 p 153 2007

[145] A J Macpherson K D McCoy F-E Johansen and PBrandtzaeg ldquoThe immune geography of IgA induction andfunctionrdquoMucosal Immunology vol 1 no 1 pp 11ndash22 2008

[146] D Kvale and P Brandtzaeg ldquoConstitutive and cytokine inducedexpression of HLA molecules secretory component and inter-cellular adhesion molecule-1 is modulated by butyrate in thecolonic epithelial cell line HT-29rdquo Gut vol 36 no 5 pp 737ndash742 1995

[147] L VHooperMHWong AThelin L Hansson P G Falk andJ I Gordon ldquoMolecular analysis of commensal host-microbialrelationships in the intestinerdquo Science vol 291 no 5505 pp 881ndash884 2001

[148] S Hapfelmeier M A E Lawson E Slack et al ldquoReversiblemicrobial colonization of germ-free mice reveals the dynamicsof IgA immune responsesrdquo Science vol 328 no 5986 pp 1705ndash1709 2010

[149] DH ReikvamMDerrien R Islam et al ldquoEpithelial-microbialcross-talk in polymeric Ig receptor deficient micerdquo EuropeanJournal of Immunology vol 42 no 11 pp 2959ndash2970 2012

[150] EW Rogier A L Frantz M E C Bruno et al ldquoSecretory anti-bodies in breast milk promote long-term intestinal homeostasisby regulating the gut microbiota and host gene expressionrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 111 no 8 pp 3074ndash3079 2014

[151] G M Barton and R Medzhitov ldquoToll-like receptor signalingpathwaysrdquo Science vol 300 no 5625 pp 1524ndash1525 2003

[152] K Takeda and S Akira ldquoToll receptors and pathogen resis-tancerdquo Cellular Microbiology vol 5 no 3 pp 143ndash153 2003

[153] E Cario andD K Podolsky ldquoDifferential alteration in intestinalepithelial cell expression of Toll-like receptor 3 (TLR3) andTLR4 in inflammatory bowel diseaserdquo Infection and Immunityvol 68 no 12 pp 7010ndash7017 2000

[154] M Hausmann S Kiessling S Mestermann et al ldquoToll-likereceptors 2 and 4 are up-regulated during intestinal inflamma-tionrdquo Gastroenterology vol 122 no 7 pp 1987ndash2000 2002

[155] M T Abreu L S Thomas S Y Tesfay et al ldquoRegulation ofTLR4 and MD-2 in the intestinal epithelium evidence for dys-regulated LPS signaling in human inflammatory bowel diseaserdquoin Proceedings of the 90th Annual Meeting of the AmericanAssociation for Immunologists Abstract 3634 Denver ColoUSA 2003

[156] T A Schneeman M E C Bruno H Schjerven F-E JohansenL Chady and C S Kaetzel ldquoRegulation of the polymeric Igreceptor by signaling through TLRs 3 and 4 linking innate andadaptive immune responsesrdquo The Journal of Immunology vol175 no 1 pp 376ndash384 2005

[157] M E C Bruno A L Frantz E W Rogier F-E Johansen andC S Kaetzel ldquoRegulation of the polymeric immunoglobulinreceptor by the classical and alternative NF-120581B pathways inintestinal epithelial cellsrdquoMucosal Immunology vol 4 no 4 pp468ndash478 2011

[158] M E C Bruno E W Rogier A L Frantz A T Stefka SN Thompson and C S Kaetzel ldquoRegulation of the poly-meric immunoglobulin receptor in intestinal epithelial cellsby Enterobacteriaceae implications for mucosal homeostasisrdquoImmunological Investigations vol 39 no 4-5 pp 356ndash382 2010

[159] A L Frantz E W Rogier C R Weber et al ldquoTargeted deletionof MyD88 in intestinal epithelial cells results in compromisedantibacterial immunity associatedwith downregulation of poly-meric immunoglobulin receptor mucin-2 and antibacterialpeptidesrdquoMucosal Immunology vol 5 no 5 pp 501ndash512 2012

[160] E W Rogier A L Frantz M E C Bruno and C S KaetzelldquoSecretory IgA is concentrated in the outer layer of intestinalmucus along with gut bacteriardquo Pathogens In press

[161] M B Geuking K D McCoy and A J Macpherson ldquoThe func-tion of secretory IgA in the context of the intestinal continuumof adaptive immune responses in host-microbial mutualismrdquoSeminars in Immunology vol 24 no 1 pp 36ndash42 2012

20 ISRN Immunology

[162] L VHooper D R Littman andA JMacpherson ldquoInteractionsbetween the microbiota and the immune systemrdquo Science vol336 no 6086 pp 1268ndash1273 2012

[163] A J Macpherson M B Geuking E Slack S Hapfelmeierand K D McCoy ldquoThe habitat double life citizenship andforgetfulness of IgArdquo Immunological Reviews vol 245 no 1 pp132ndash146 2012

Submit your manuscripts athttpwwwhindawicom

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Behavioural Neurology

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Disease Markers

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OncologyJournal of

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The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

8 ISRN Immunology

02

100

Human IgA1Gorilla IgA1

Gorilla IgA281

6164

Human IgA2

Chimpanzee IgA2Chimpanzee IgA1

Gibbon IgA1Gibbon IgA2

Orangutan IgABaboon IgA

Rhesus macaque IgA53 100

98 69Dog IgA

Pig IgA100 Cattle IgA

52

Horse IgARabbit IgA (13 subclasses)

Mouse IgA57

99

Possum IgA

93

Chicken IgAPlatypus IgA1100

5095

Platypus IgA2

Trout IgTFrog IgX

Gecko IgldquoArdquo

(a)

02

Human pIgR

100Chimpanzee pIgRGorilla pIgR

55Gibbon pIgROrangutan pIgR100

100

100 Baboon pIgRRhesus macaque pIgR

Mouse pIgR

66

96

100 Pig pIgRCattle pIgR

85Horse pIgR

Dog pIgR

74

Rabbit pIgRPossum pIgR

Platypus pIgR

Chicken pIgR

10075

5979

Trout pIgRFrog pIgR

Anole pIgR

71

(b)

Figure 5 Coevolution of mucosal Igs and pIgR Simplified neighbor-joining phylogenetic trees of vertebrate (a) Ig and (b) pIgR proteinsequences with human IgA1 and pIgR denoted as outgroups Horizontal distances are proportional to the degree of divergence followinga multiple alignment of amino acid sequences Numbers at nodes denote bootstrap support for each bifurcation after 100 replicationsAccession numbers for mucosal Ig sequences human (Homo sapiens) IgA1 J00220 IgA2 (allotype m1) J00221 gorilla (Gorilla gorilla) IgA1X53703 IgA2 X53707 chimpanzee (Pan troglodytes) IgA1 X53702 IgA2 X53706 gibbon (Hylobates lar) IgA1 X53708 IgA2 X53709 Borneanorangutan (Pongo pygmaeus) IgA X53704 baboon (Papio anubis) IgA DQ868435 rhesus macaque (Macaca mulatta) AY039245 pig (Susscrofa) IgA U12594 cattle (Bos taurus) IgA AF109167 dog (Canis lupus familiaris) IgA L36871 horse (Equus caballus) IgA AY247966mouse (Mus musculus) IgA D11468 rabbit (Oryctolagus cuniculus) IgA1 X51647 brushtail possum (Trichosurus vulpecula) IgA AF027382duck-billed platypus (Ornithorhynchus anatinus) IgA1 AY055778 IgA2 AY055779 chicken (Gallus gallus) IgA AAB226142 leopard gecko(Eublepharis macularius) IgldquoArdquo (so designated because of its uncertain phylogeny with homology to both IgA and IgY) ABG726841African clawed frog (Xenopus laevis) IgX S03186 rainbow trout (Oncorhynchus mykiss) IgT AAW669811 Accession numbers for pIgRsequences with species that vary from those used for the mucosal Ig alignment in panel A noted in parentheses human NM 002644chimpanzee XM 003308710 gorilla XM 004028295 gibbon XM 003272974 Sumatran orangutan (Pongo abelii) NM 001131626 baboonXM 003893189 rhesus macaque XM 001083307 pig NM 214159 cattle NM 174143 dog XM 537133 horse XM 001492298 mouseNM 011082 rabbit NM 001171045 brushtail possum AF091137 duck-billed platypus XM 001508602 chicken NM 001044644 green anole(Anolis carolinensis) XM 003224013 African clawed frog EF079076 rainbow trout FJ940682

ISRN Immunology 9

our knowledge of pIgR-mediated transcytosis of mucosalIgs is derived from studies of mammalian secretory IgA(SIgA) as illustrated in Figure 4 Transcription of the PIGRgene and translation of pIgR mRNA is accompanied byinsertion of the nascent protein into the endoplasmic retic-ulum The pIgR undergoes substantial glycosylation duringtransport through the ER and Golgi apparatus and is thentargeted to the basolateral surface of polarized epithelialcells Membrane-bound pIgR binds pIg and pIg-containingimmune complexes which are internalized along with unoc-cupied pIgR via receptor-mediated endocytosis and thentranscytosed through a series of intracellular vesicles to theapical surface During transcytosis intracellular pIg antibod-ies can neutralize bacteria viruses and other antigens thathave gained access to the interior of the epithelial cell Atthe apical surface proteolytic cleavage of the membrane-spanning region of pIgR leads to the release of its extracellulardomain known as secretory component (SC) either in freeform or covalently bound to pIg Secretory Igs can neutralizepathogens and antigens within the mucosal lumen andfacilitate excretion of antigens that were transported throughthe epithelial cell as IgA immune complexes The SC moietyof SIgA has been shown to protect IgA from degradationby host and bacterial proteases and along with free SCconfers additional innate immune functions that protectthe epithelial surface from microbial invasion and limitpotentially damaging host inflammatory responses (reviewedin [113]) The finding of an SC-like polypeptide associatedwith polymeric IgT in rainbow trout [38] polymeric IgXin Xenopus [50] and polymeric IgA in birds [114] suggeststhat all vertebrate pIgRs share the function of transportingpolymeric Igs into external secretions In many mammalianspecies pIgR mediates epithelial transcytosis of both poly-meric IgM and IgA (reviewed in [111]) Although directevidence is not yet available it is reasonable to assume thatpIgR transports IgM in lower vertebrates It will be interestingto investigate whether the SCmoiety of secretory Igs in lowervertebrates mediates additional innate immune functions ashas been demonstrated for mammalian SC

6 Coevolution of pIgR and Mucosal Igs

Molecular cloning of the PIGR gene was first reportedfor mammalian species including eutherians marsupialsand monotremes [115ndash127] Subsequent elucidation of PIGRsequences from diverse species of jawed vertebrates hasallowed a comprehensive analysis of the evolutionary originsof the PIGR gene [38 128 128ndash132] and additional sequencesavailable in the Genbank database Whereas no ortholog ofthe PIGR gene has been found in any species of cartilaginousfish the PIGR gene has been annotated in all species of teleostfish for which the genome has been sequenced No orthologof the PIGR gene has been reported in lobe-finned bonyfishes but further analyses of whole genome sequences willbe required to determine whether the PIGR gene was lostfollowing the split of the Sarcopterygii It thus appears thatthe PIGR gene emerged in a common ancestor of highervertebrates after the split of cartilaginous fish and prior

to the evolution of modern teleosts likely driven by theselective pressure to provide a mechanism for transport ofpolymeric Igs such as IgM and IgT into mucosal secretionsThis hypothesis is supported by a comparison of phylogenetictrees based on amino acid sequences for IgT IgX and IgAheavy chains and pIgR (Figure 5)The predicted evolutionarydistance between trout IgT and frog IgX is similar to thedistance between trout and frog pIgR suggesting that thetransition from IgT to IgX as the dominantmucosal Ig isotypewas accompanied by adaptations in pIgR structure Similarparallels can be seen in the transition from IgX to IgA inreptiles birds and mammals and the concurrent evolutionof pIgR

Alignments of the amino acid sequences of mucosal Igheavy chains and pIgR from 10 representative vertebratespecies provide further support for the theory of coevolutionof mucosal IGH and PIGR genes (Figure 6) A commonfeature of Ig and pIgR proteins is the presence of repeatingIg-like domains (see Figure 2 for the basic structure of thesedomains) The structure of IgT IgX and IgA heavy chainsfrom fish amphibians reptiles and birds is similar to thatof IgM with 4 constant Ig-like domains In mammalianIgA (and IgG) the exon for the 2nd constant region wastruncated to encode a short ldquohingerdquo region which confersgreater mobility to the antigen-binding region at the N-terminusThus the CH3 domain of IgT IgX and IgA in lowervertebrates is structurally and functionally homologous tothe CH2 domain of mammalian IgA The heavy chains ofIgT IgX and IgA have retained a characteristic feature ofthe IgM heavy chain that is the presence of a conservedcysteine residue in the tailpiece that allows disulfide bondingbetween heavy chains of individual Ig proteins to formhigher molecular weight polymers These large Ig structurescontaining multiple antigen-binding sites are particularlywell suited for immune clearance of large antigens found atmucosal surfaces such as intact microbes and food particlesIn mucosal Igs from most vertebrate orders the J chainprotein initiates this polymerization process by disulfidebonding with 2 Ig heavy chains remaining associated withthe polymeric Ig at a stoichiometric ratio of 1 J chain subunitper 2 3 4 or 5 Ig units Despite the absence of J chainthe predominant form of IgM and IgT in mucus secretionsin rainbow trout was found to be polymeric in contrastto monomeric forms of IgM and IgT in the blood [38] Inmammals IgM is mainly found as a pentamer whereas theshorter heavy chain ofmammalian IgA restricts its polymericforms to dimers trimers and tetramers Further studies willbe required to characterize the polymeric structures of IgMIgT IgX and IgA in lower vertebrates

Alignment of pIgR amino acid sequences from 10 rep-resentative vertebrate species reveals structural changes thatwere evolved in parallel with structural changes in mucosalIgs (Figure 6(b)) All pIgR proteins have an N-terminalhydrophobic leader peptide required for targeting of thenascent protein into the ER The extracellular region ofpIgR protein is characterized by repeating ldquoIg-likerdquo domainssimilar to Ig heavy chains [115 133] Interestingly the num-ber of extracellular Ig-like domains has increased duringvertebrate evolution culminating with a total of 5 domains

10 ISRN Immunology

TailpieceHinge

Tailpiece

Mammalian IgA

VVVVVVVVVV

200121 300 400 4721

Human IgA1Rhesus IgA

Cattle IgAMouse IgA

Possum IgAPlatypus IgAChicken IgA

Frog IgXTrout IgT

Premammalian IgTXA

Gecko IgldquoArdquo

CH1

CH1

CH2

CH2

CH3

CH3

CH4

(a)

Leader 1 2 3 4 5

Ig homology extracellular domains

Linker CytoplasmicTM

1001 200 300 400 500 600 700 764

HumanRhesus

CattleMouse

PossumPlatypusChicken

AnoleFrog

Trout

(b)

Figure 6 Interspecies similarity in mucosal Ig and pIgR protein sequences from 10 representative vertebrate species Alignments in aminoacid sequences correspond to the phylogenetic trees shown in Figure 5 (a) Numbering ofmucosal Ig amino acids corresponds to the sequenceof human IgA1 beginning with the first residue of the variable domain CH heavy chain constant region domain (b) Numbering of pIgRamino acids corresponds to the sequence of human pIgR beginning with the first residue of the leader peptide TM transmembrane Forboth alignments the intensity of shading at each position signifies the degree of similarity amongmucosal Ig or pIgR sequences from differentspecies Gaps in sequence alignments signify regions of limited interspecies homology Approximate boundaries are noted of key structuralelements in mucosal Ig and pIgR proteins

in mammalian pIgR By contrast pIgR from amphibiansreptiles and birds contains 4 extracellular domains lackinga homolog of domain 2 of mammalian pIgR The mostprimitive form of pIgR found in teleost fish contains only2 extracellular domains homologous to domains 1 and 5of mammalian pIgR Interspecies homology is greatest indomain 1 which has been shown to be critical for binding ofmammalian pIgR to polymeric Igs (reviewed in [111]) Highlyconserved internal disulfide bonds are found in all the Ig-like domains of pIgR characteristic of the immunoglobulinfold An additional disulfide bond is found in domain 5 ofpIgR frommammals birds reptiles and amphibians but notfish In human SIgA this ldquoextrardquo disulfide bond in domain 5has been shown to rearrange to form a disulfide bond with

cysteine residues in one of the heavy chains of polymericIgA [134] Although the structure of SIgA has not beenfully characterized for lower vertebrates it is reasonable toassume that similar disulfide bonds form between domain 5of pIgR and polymeric IgA or IgX from birds reptiles andamphibians The linker region connecting domain 5 of pIgRto the transmembrane domain has a random structure that ispoorly conserved across species Proteolytic cleavage of pIgRwithin this domain leads to the release of SC from the apicalsurface of epithelial cells either free or bound to polymericIg The cytoplasmic domain of mammalian pIgR containsa number of intracellular sorting motifs that interact withcytoplasmic proteins to direct pIgR through the transcytoticpathway (reviewed in [111]) These motifs are reasonably

ISRN Immunology 11

Linker

TMCytoplasmic

J chain

Hinge 1

2

34

5

CL

VLVH

C1205721C1205722 C1205723

(a)

Linker

TMCytoplasmic

J chain

1

3 4

5

CL

VL

VH

C1205941205721

C1205941205722C1205941205723 C1205941205724

(b)

11

5

LinkerTM

Cytoplasmic

5

CL

VL

VH

C1205911C1205912

C1205913 C1205914

pIgR Ig-like domain

H chain Ig-like domain

L chain Ig-like domain

J chain

Disulfide bond

(c)

Figure 7 Theoretical model for changes in the structure of secretory Igs during evolution (a) The structure for mammalian SIgA is adaptedfrom the model of Woof and Russell [16] for human SIgA1 with permission from Nature Publishing Group (b) and (c) Theoretical modelsfor the structure of IgXA from amphibians and birds and SIgT from teleost fish respectively are predicted from alignment of Ig heavy chainand pIgR sequences with mammalian homologs

well conserved in pIgR from birds and reptiles but not inpIgR from amphibians and fish suggesting that complexmechanisms of intracellular trafficking of pIgR coevolvedwith the increasing complexity of the mucosal immunesystem

7 Hypothetical Models for Changes inSecretory Ig Structure during Coevolutionof Mucosal Igs and pIgR

A large number of structural and functional analyses overthe past 30 years allowed the development of detailed modelsfor the structure of mammalian SIgA (reviewed in [111 135])(Figure 7(a)) Domains 1 and 5 of pIgR the most highlyconserved Ig-like domains associate with theC1205722 subunits oftwo adjacent IgA heavy chains in a near-planar structure [136137] During transcytosis a disulfide bond forms betweenhighly conserved cysteine residues in domain 5 of pIgRand the C1205722 domain of one of the IgA heavy chains [134]Domains 2 3 and 4 allow mammalian pIgR to assume aflexible extended structure which is thought to wrap aroundthe IgA heavy chains and protect against degradation fromhost and microbial proteases Binding of mammalian pIgRto polymeric IgA or IgM requires the presence of J chain

connecting the Ig subunits (reviewed in [138]) and J chain-deficient mice fail to transport IgA and IgM into externalsecretions [139ndash141] Structure-function studies usingmutantforms of human J chain suggested that J chain binds directlyto pIgR and also maintains polymeric Ig in an optimalconformation for pIgR binding and transcytosis [142] Theunstructured linker region connecting domain 5 of pIgRto the transmembrane (TM) region gives membrane-boundpIgR the flexibility to bind large polymeric Igs (with orwithout associated antigens) and provides an exposed site forproteolytic cleavage of pIgR to SC The C-terminal region ofpIgR extends past the cytoplasmic face of the plasma mem-brane allowing association with cytoplasmic factors thatregulate trafficking of pIgR with or without bound polymericIg

Although detailed structural studies have not yet beenperformed on secretory Igs from lower vertebrates hypo-thetical models can be constructed based on alignmentswith their mammalian homologs A model for secretoryIgXA in birds reptiles and amphibians is illustrated inFigure 7(b) showing the C

1205941205722 domain in place of the hinge

region ofmammalian IgAThenumbering of the extracellulardomains of pIgR corresponds to the homologous domainsin mammalian pIgR noting the absence of domain 2 In

12 ISRN Immunology

this model the C120594120572

3 domains of two adjacent IgXA heavychains (homologous to the C

1205722 domain of mammalian IgA)

bind to the highly conserved domains 1 and 5 of pIgRGiven the conservation of the analogous cysteine residuesin domain 5 of pIgR and the C

1205941205723 domain of IgXA it

is assumed that a disulfide bond forms between pIgR andpolymeric Ig during epithelial transcytosis in birds reptilesand amphibiansThe absence of domain 2 in pIgR from thesevertebrate orders necessitates a more rigid structure thanthat of mammalian pIgR with a corresponding decrease inits ability to wrap around the IgXA heavy chains and pro-vide protection against proteoltyic degradation Despite theshorter length of pIgR in birds reptiles and amphibians theassociation with the J chain subunit of polymeric IgXA stillappears to be required Recombinant pIgR from the Africanfrog (Xenopus laevis) was shown to bind with moderatelyhigh affinity to human polymeric IgA containing J chain butnot to monomeric IgA [125] The affinity of Xenopus pIgRfor human pIgA was improved when Xenopus J chain wassubstituted for human J chain in a chimeric polymeric IgAmolecule The lack of sequence conservation across speciesin the linker region connecting domain 5 of pIgR to the TMregion suggests that it acts as a nonspecific ldquospacerrdquo As statedabove the cytoplasmic region of pIgR appears to have evolvedover time to provide enhanced regulation of pIgR trafficking

The hypothetical structure of secretory IgT from teleostfish in Figure 7(c) illustrates how the most primitive form ofpIgR comprising only extracellular domains 1 and 5 couldassociate with polymeric Ig and mediate epithelial transcy-tosis Association of pIgR domain 1 with the C

1205913 domain of

IgT would preserve the functional homology with secretoryIgs in higher vertebrates The short length of teleost pIgRwould necessitate the association of domain 5 with a C

1205913

domain on one of the heavy chains of the same IgT ratherthan spanning across to the adjaent IgT subunit While thismodel preserves the highly conserved association of pIgRdomain 1 with the orthologous domain of the IgT heavychain it does not explain the selectivity of teleost pIgR forpolymeric rather than monomeric IgT Although there is noexperimental evidence to support this model it could behypothesized that dimerization of two pIgR molecules in theplasmamembrane is required for high affinity binding of IgTas illustrated in the model in Figure 7(c) This hypotheticalmodel would also explain the lack of a necessity for J chainin polymeric IgT since each subunit in the pIgR dimer wouldonly be in contact with one IgT subunit The unstructuredlinker region connecting domain 5 of pIgR to the TM regionwould provide flexibility for association of 2 membrane-bound pIgR molecules with a large polymeric IgT molecule

Taken together the structural models for secretory Igsshown in Figure 7 are consistent with the selection of a morefunctional pIgR molecule over evolutionary time Duplica-tion and diversification of the extracellular Ig-like domainsof pIgR would provide a longer more flexible surface forbinding to polymeric Igs with higher affinity and protectingthe Ig heavy chains against proteolytic attack Expansion ofthe cytoplasmic domain of pIgR and incorporation of motifsfor binding cytoplasmic proteins would allow regulated

trafficking of pIgR and polymeric Igs across mucosal andglandular epithelial cells Importantly these models illustratea potential path for coevolution of IGH and PIGR genesdriven by the common selective pressure to provide antigen-specific humoral immune responses at mucosal surfaces

8 Evidence that the CommensalMicrobiota Provided the Driving Force forCoevolution of Mucosal Igs and pIgR

From the earliest evolution of vertebrate animals mucosal Igshave been an integral part of the emerging adaptive immunesystem Clearly many environmental factors served as driv-ing forces for the evolution of the adaptive immune systemin vertebrates including a longer lifespan thanmany (but notall) invertebrates and amore diverse diet that could introducea broader range of potential gut pathogens However it hasbeen proposed that the most significant force may havebeen the dramatic increase in the numbers and complexityof the resident microbiota in the evolution of vertebratesfrom their invertebrate ancestors [1 143 144] Antibodiesin mucosal secretions contribute to immune homeostasis bylimiting access of microbes and their products to the bodyproper maintaining the integrity of the epithelial barrier andshaping the composition of the commensal microbiota infavor of metabolically beneficial microorganisms [145] Thepredominance of polymeric Igs in these secretions promotesthese functions by providing multiple antigen-binding sitesper Ig complex thus increasing the overall avidity of antigen-antibody interactions Structural and functional refinementsin mucosal Igs culminating with the multifunctional secre-tory IgA molecule in mammals have further enhanced theirability to enhance immune homeostasis

The early emergence of pIgR in vertebrate evolutionprovided a mechanism for efficient transport of mucosal Igsinto external secretions It is well documented that crosstalkbetween mucosal epithelial cells and the resident microbiotamodulates expression of pIgR (reviewed in [17 111 112]) andit is reasonable to assume that these host-microbe interac-tions provided a driving force for evolution of the PIGR genein vertebrates The first demonstration that gut bacteria maymodulate pIgR expression in epithelial cells was the findingthat butyrate a bacterial fermentation product and importantenergy source in the colon upregulated expression of pIgRin the human colonic epithelial cell line HT-29 [146] A rolefor commensal bacteria in pIgR regulation was subsequentlydemonstrated by the observation that pIgR expression wasincreased when germ-free mice were colonized with Bacteri-oides thetaiotaomicron a prominent organism of the normalmouse and human intestinal microbiota [147] Amore recentstudy using a model of reversible colonization of germ-free mice with a nondividing mutant of Escherichia colidemonstrated that a long-lived SIgA response could besustained that specifically recognized the inducing bacteria[148] However exposure of E coli-colonized mice to otherbacteria limited the duration of the SIgA response against theoriginal colonizer suggesting a dynamic equilibriumbetweenmembers of the gut microbial community and host SIgA A

ISRN Immunology 13

study from the laboratory of Finn-Eirik Johansen demon-strated that diversity of the bacterial community in the cecallumen was reduced in pIgR-knockoutmice supporting a rolefor SIgA in limiting overgrowth of selected species [149] Incontrast the community of bacteria adherent to the epithelialsurface was more diverse in pIgR-knockout mice than inwild-typemice and these adherent bacteria caused enhancedexpression of several epithelial antimicrobial peptides Thesefindings suggest that bacteria-specific SIgA anchored in themucus layer restricts adhesion of bacteria to the epithelialsurface and limits bacterial stimulation of host epithelial cellsA recent study from the authorrsquos laboratory employing abreeding scheme in which119875119894119892119903minusminus damswere bred to119875119894119892119903+minusmales and vice versa demonstrated that SIgA antibodiesin breast milk promote long-term intestinal homeostasis byregulating the gut microbiota and gene expression in colonicepithelial cells [150]

A direct role for commensal andor pathogenic bacteriain the regulation of pIgR expression suggests that the innateimmune system may ldquoprimerdquo epithelial cells for transportof polymeric Ig produced during the adaptive immuneresponse Host cells mediate innate immune responses tomicrobial components through toll-like receptor (TLR) sig-naling (reviewed in [151 152]) Intestinal epithelial cells havebeen shown to express a wide variety of TLRs the expressionof which is upregulated during intestinal inflammation [153ndash155] Significantly expression of pIgR was shown to beupregulated in the HT-29 human intestinal epithelial cellline by bacterial LPS a ligand for TLR4 [156 157] Similarinduction of PIGR gene transcription was seen followingdirect binding of bacteria of the family Enterobacteriaceaewhich express a form of LPS that stimulates TLR4 [158]A recent study from the authorrsquos laboratory demonstratedthat shRNA-mediated knockdown of myeloid differentiationprimary response protein 88 (MyD88) a cytoplasmic adapterprotein that transduces signals from cell surface TLR4blocked the induction of PIGR gene transcription by LPS inHT-29 cells [159] The in vivo significance was confirmed bythe finding that mice with a targeted deletion of the Myd88gene only in intestinal epithelial cells had reduced expressionof pIgR compared to wild-type littermates [159] Mice withtargeted depletion of MyD88 in intestinal epithelial cells alsoexhibited reduced expression of mucin-2 the major compo-nent of the intestinal mucus layer and several antimicrobialpeptides and decreased transmucosal electrical resistanceThese alterations in epithelial barrier function were accom-panied by significant changes in the composition of the fecalmicrobiota increased numbers of bacteria adherent to theintestinal mucus layer and a dramatic increase in transloca-tion of gut bacteria into the drainingmesenteric lymphnodesincluding the opportunistic pathogen Klebsiella pneumoniaeThese findings demonstrate that MyD88-mediated crosstalkbetween the gut microbiota and intestinal epithelial cells iscrucial for optimal expression of pIgR production of SIgAdevelopment of a healthy gut microbiota and maintenanceof intestinal homeostasis

A model can be proposed in which continuous stimu-lation of intestinal epithelial cells by gut bacteria regulates

Lumen

Mucus

Epithelium

Lamina

PIGR

TLRs

MyD88

Bacteria

Plasma cells

propria

Polymeric Ig

Polymeric Ig receptor

Secretory component

Figure 8 Crosstalk between the polymeric immunoglobulin recep-tor secretory immunoglobulins and the gut microbiotaThe single-layered epithelium that lines the gastrointestinal tract is coveredwith a thick mucus layer which physically excludes members ofthe resident microbiota but allows diffusion of shed components ofmicrobial cells Stimulation of epithelial toll-like receptors (TLRs)with microbial products engages the cytoplasmic adaptor proteinMyD88 and initiates NF120581B-dependent signaling pathways Translo-cation of activated NF120581B and other transcription factors to thenucleus enhances transcription of thePIGR gene Activation of TLRsmay also stimulate pIgR transcytosis Polymeric Igs secreted bylamina propria plasma cells bind to pIgRon the basolateral surface ofepithelial cells and are transcytosed to the apical surface along withunoccupied pIgR Proteolytic cleavage of pIgR at the apical surfacereleases secretory SIg and free secretory component (SC) Binding ofSIg and SC to luminal bacteria promotes association with themucuslayer and prevents direct access of bacteria to the epithelial surfaceOver time the continuous crosstalk with SIg shapes the compositionof the gut microbiota Modified from [17] under terms of authorrsquoscopyright with Nature Publishing Group

pIgR expression and transport of SIgA and promotes immuneexclusion of resident and pathogenic bacteria (Figure 8) Adense layer of mucus which increases in thickness fromthe proximal to the distal colon serves to separate bacteriafrom direct contact with the epithelial surface Secretionof microbial-associated molecular patterns (MAMPs) bycommensal bacteria stimulates MyD88-dependent TLR sig-naling leading to enhanced expression of pIgR and antimi-crobial peptides and increased mucus production Bindingof pIgA to pIgR and possibly also signaling via MAMPs

14 ISRN Immunology

enhances transcytosis of pIgA pIgA-containing immunecomplexes and unoccupied pIgR which promotes clearanceof antigens and pathogens from the lamina propria intra-cellular neutralization and release of SIgA and SC at theluminal surface SIgA and SC serve to trap bacteria in themucus layer limiting their access to the epithelial surface Inmice with a targeted deletion of the Muc2 gene which havea severely depleted mucus layer in the colon SIgA and SCfail to associate with the surface of colonic epithelial cells[160] The presence of SIgA in the intestinal lumen whetherderived passively frommaternalmilk or actively via epithelialtranscytosis shapes the composition of the gut microbiotaand modulates intestinal epithelial gene expression

9 Concluding Remarks

The first microbes that emerged on Earth almost 4 billionyears ago encountered a hostile world where nutrients werescarce hazards were everywhere and life was short Withthe evolution of multicellular organisms about 3 billion yearslater a select group ofmicrobes chose to sacrifice an indepen-dent existence for the benefits of a mutualistic relationshipwith eukaryotic hosts Prokaryotic-eukaryotic mutualismreached its apex some 500 million years ago with theemergence of primitive vertebrates whose gastrointestinaltracts were populated by an abundant and diverse commensalmicrobiota In humans the large intestine is home to some100 trillion microorganisms 10 times more than the totalnumber of eukaryotic cells in the entire body The microbesthat inhabit the vertebrate GI tract provide many benefitsto the eukaryotic host including digestion of complex foodmolecules synthesis of vitamins and production of solublefactors that enhance the development of the host immunesystem In return the eukaryotic host provides the microbeswith a warm moist place to live abundant food low oxygentension and a soft bed of mucus on which to form biofilmsWhen this mutually beneficial arrangement is challenged bypathogenicmicrobes the eukaryotic host and the commensalmicrobiota join forces to battle the pathogens and protectthe body from invasion The vertebrate immune system isequipped with a well-trained army of immune cells and asophisticated arsenal of weapons (cell surface molecules andsecreted factors) that protect the host from all but the mostvirulent pathogens This immune ldquoarmyrdquo also serves as aconstant reminder to the commensal microbes that whilethey are free to enjoy the amenities of the mucosal surfacesthey are not welcome in the body proper The emergence ofantigen-specific Igs and T-cell receptors in jawed vertebratesbegan a process of immunological diversification that led tothe development of a specialized mucosal immune systemin higher vertebrates in which secretory Igs play a centralrole The relationship between host and microbiota is clearlyreciprocal the mucosal Igs that evolved in response toselective pressure from the commensal microbiota play acentral role throughout life in shaping the compositiongenetics andmetabolic activity of themicrobiota [1 161 162]

The epithelial layer lining mucosal surfaces provides aphysical and innate immune barrier against penetration of

the body proper by microbes undigested food antigens andpotentially noxious environmental substances The evolu-tionary challenge of transporting mucosal Igs into externalsecretions without compromising the epithelial barrier wasmet by the emergence of the PIGR gene in an ancestor ofbony fishes encoding an epithelial-specific transmembraneprotein that actively transports polymeric Igs across mucosaland glandular epithelia (Figure 4) Structural similaritiesbetween Igs and the extracellular Ig-binding domains of pIgR(Figure 6) suggest that duplication and diversification of agene encoding primordial Ig-like domain may have givenrise to the PIGR gene in a primitive vertebrate ancestorParallel refinement of the structures of mucosal Igs andpIgR during tetrapod evolution (Figures 6 and 7) culminatedin the evolution of the multifunctional SIgA molecule inmammals in which the pIgR-derived SC subunit providesinnate immune functions and protects the antigen-bindingIgA polymer from proteolytic degradation In addition toacting as a powerful force during vertebrate evolution thereciprocal relationship between pIgR mucosal Igs and thecommensal microbiota provides benefits throughout thelife of the individual Microbial colonization of newbornvertebrates stimulates development of mucosal B cells andclass switching to mucosal Ig isotypes [1 163] Microbialfactors upregulate expression of pIgR enhancing transportof mucosal Igs into external secretions where they in turnregulate the microbiotaThis beautifully orchestrated processallows us to maintain a healthy relationship with our resi-dent microbiota while providing mutual protection againstpathogens

Conflict of Interests

The author declares that there is no conflict of interestsregarding the publication of this paper

Acknowledgments

This work was supported by Grant no AI069027 from theNational Institutes of Health of the United States of America(and an associatedAmerican Recovery andReinvestmentActsupplement) and a Senior Research Award from the Crohnrsquosand Colitis Foundation of America

References

[1] C L Maynard C O Elson R D Hatton and C T WeaverldquoReciprocal interactions of the intestinal microbiota andimmune systemrdquo Nature vol 489 no 7415 pp 231ndash241 2012

[2] M F Flajnik and M Kasahara ldquoOrigin and evolution of theadaptive immune system genetic events and selective pres-suresrdquo Nature Reviews Genetics vol 11 no 1 pp 47ndash59 2010

[3] M F Flajnik and L du Pasquier ldquoEvolution of the immunesystemrdquo in Fundamental Immunology W E Paul Ed chapter4 pp 67ndash128 Lippincott Williams ampWilkins Philadelphia PaUSA 2012

[4] M Hirano S Das P Guo and M D Cooper ldquoThe evolutionof adaptive immunity in vertebratesrdquo Advances in Immunologyvol 109 pp 125ndash157 2011

ISRN Immunology 15

[5] T BoehmNMcCurley Y SutohM SchorppMKasahara andM D Cooper ldquoVLR-based adaptive immunityrdquo Annual Reviewof Immunology vol 30 pp 203ndash220 2012

[6] T Hunkapiller and L Hood ldquoImmunology the growing immu-noglobulin gene superfamilyrdquoNature vol 323 no 6083 pp 15ndash16 1986

[7] P Bork L Holm and C Sander ldquoThe immunoglobulin foldstructural classification sequence patterns and common corerdquoJournal of Molecular Biology vol 242 no 4 pp 309ndash320 1994

[8] C S Kaetzel and M W Russell ldquoPhylogeny and comparativephysiology of IgArdquo in Mucosal Immunology J Mestecky WStrober H Cheroutre B Kelsall B N Lambrecht and M WRussell Eds chapter 19 Academic PressElsevier WalthamMass USA 2014

[9] Y He and P J Bjorkman ldquoStructure of FcRY an avian immu-noglobulin receptor related to mammalian mannose receptorsand its complex with IgYrdquo Proceedings of the National Academyof Sciences of the United States of America vol 108 no 30 pp12431ndash12436 2011

[10] J M Woof and D R Burton ldquoHuman antibody-Fc receptorinteractions illuminated by crystal structuresrdquo Nature ReviewsImmunology vol 4 no 2 pp 89ndash99 2004

[11] W L Martin A P West Jr L Gan and P J Bjorkman ldquoCrystalstructure at 28 A of an FcRnheterodimeric Fc complexmechanism of pH-dependent bindingrdquo Molecular Cell vol 7no 4 pp 867ndash877 2001

[12] E S Ward ldquoAcquiring maternal immunoglobulin differentreceptors similar functionsrdquo Immunity vol 20 no 5 pp 507ndash508 2004

[13] C S Kaetzel ldquoThe polymeric immunoglobulin receptor bridg-ing innate and adaptive immune responses atmucosal surfacesrdquoImmunological Reviews vol 206 no 1 pp 83ndash99 2005

[14] M Acharya G Borland A L Edkins et al ldquoCD23Fc120576RIImolecular multi-taskingrdquo Clinical and Experimental Immunol-ogy vol 162 no 1 pp 12ndash23 2010

[15] V B Klimovich ldquoIgM and its receptors structural and func-tional aspectsrdquo Biochemistry vol 76 no 5 pp 534ndash549 2011

[16] J MWoof andMW Russell ldquoStructure and function relation-ships in IgArdquo Mucosal Immunology vol 4 no 6 pp 590ndash5972011

[17] F-E Johansen and C S Kaetzel ldquoRegulation of the polymericimmunoglobulin receptor and IgA transport new advances inenvironmental factors that stimulate pIgR expression and itsrole in mucosal immunityrdquo Mucosal Immunology vol 4 no 6pp 598ndash602 2011

[18] F Kokubu K Hinds R Litman M J Shamblott and G WLitman ldquoExtensive families of constant region genes in a phy-logenetically primitive vertebrate indicate an additional levelof immunoglobulin complexityrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 84 no16 pp 5868ndash5872 1987

[19] A S Greenberg A L Hughes J Guo D Avila E CMcKinneyand M F Flajnik ldquoA novel ldquochimericrdquo antibody class in carti-laginous fish IgMmay not be the primordial immunoglobulinrdquoEuropean Journal of Immunology vol 26 no 5 pp 1123ndash11291996

[20] H Dooley and M F Flajnik ldquoShark immunity bites back affin-ity maturation and memory response in the nurse shark Ging-lymostoma cirratumrdquo European Journal of Immunology vol 35no 3 pp 936ndash945 2005

[21] S F Schluter R M Bernstein and J J Marchalonis ldquoMolecularorigins and evolution of immunoglobulin heavy-chain genes ofjawed vertebratesrdquo Immunology Today vol 18 no 11 pp 543ndash549 1997

[22] Y Ohta and M Flajnik ldquoIgD like IgM is a primordial immu-noglobulin class perpetuated in most jawed vertebratesrdquo Pro-ceedings of the National Academy of Sciences of the United Statesof America vol 103 no 28 pp 10723ndash10728 2006

[23] S Fillatreau A Six S Magadan R Castro J O Sunyer andP Boudinot ldquoThe astonishing diversity of Ig classes and B cellrepertoires in teleost fishrdquo Frontiers in Immunology vol 4 no28 2013

[24] W Harriman H Volk N Defranoux and M Wabl ldquoImmu-noglobulin class switch recombinationrdquo Annual Review ofImmunology vol 11 pp 361ndash384 1993

[25] J Stavnezer and C T Amemiya ldquoEvolution of isotype switch-ingrdquo Seminars in Immunology vol 16 no 4 pp 257ndash275 2004

[26] V M Barreto Q Pan-Hammarstrom Y Zhao L Ham-marstrom Z Misulovin and M C Nussenzweig ldquoAID frombony fish catalyzes class switch recombinationrdquo Journal ofExperimental Medicine vol 202 no 6 pp 733ndash738 2005

[27] T C Fletcher and AWhite ldquoAntibody production in the plaice(Pleuronectes platessa L) after oral and parenteral immuniza-tion with Vibrio anguillarum antigensrdquo Aquaculture vol 1 pp417ndash428 1972

[28] J W H M Rombout L J Blok C H J Lamers and E EgbertsldquoImmunization of carp (Cyprinus carpio) with a Vibrio anguil-larum bacterin indications for a common mucosal immunesystemrdquo Developmental and Comparative Immunology vol 10no 3 pp 341ndash351 1986

[29] U Georgopoulou and J-M Vernier ldquoLocal immunologicalresponse in the posterior intestinal segment of the rainbowtrout after oral administration of macromoleculesrdquo Develop-mental andComparative Immunology vol 10 no 4 pp 529ndash5371986

[30] C J Lobb ldquoSecretory immunity induced in catfish Ictaluruspunctatus following bath immunizationrdquo Developmental andComparative Immunology vol 11 no 4 pp 727ndash738 1987

[31] J D Hansen E D Landis and R B Phillips ldquoDiscovery ofa unique Ig heavy-chain (IgT) in rainbow trout implicationsfor a distinctive B cell developmental pathway in teleost fishrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 102 no 19 pp 6919ndash6924 2005

[32] N Danilova J Bussmann K Jekosch and L A Steiner ldquoTheimmunoglobulin heavy-chain locus in zebrafish identificationand expression of a previously unknown isotype immunoglob-ulin Zrdquo Nature Immunology vol 6 no 3 pp 295ndash302 2005

[33] R Savan A Aman K Sato R Yamaguchi and M Sakai ldquoDis-covery of a new class of immunoglobulin heavy chain fromfugurdquo European Journal of Immunology vol 35 no 11 pp 3320ndash3331 2005

[34] R Savan A AmanMNakao HWatanuki andM Sakai ldquoDis-covery of a novel immunoglobulin heavy chain gene chimerafrom common carp (Cyprinus carpio L)rdquo Immunogenetics vol57 no 6 pp 458ndash463 2005

[35] F Gambon-Deza C Sanchez-Espinel and S Magadan-Mompo ldquoPresence of an unique IgT on the IGH locus in three-spined stickleback fish (Gasterosteus aculeatus) and the veryrecent generation of a repertoire of VH genesrdquo Developmentaland Comparative Immunology vol 34 no 2 pp 114ndash122 2010

[36] T M Tadiso K K Lie and I Hordvik ldquoMolecular cloning ofIgT fromAtlantic salmon and analysis of the relative expression

16 ISRN Immunology

of 120591 120583 and 120575 in different tissuesrdquo Veterinary Immunology andImmunopathology vol 139 no 1 pp 17ndash26 2011

[37] S Mashoof C Pohlenz P L Chen et al ldquoExpressed IgH 120583and 120591 transcripts share diversity segment in ranched Thunnusorientalisrdquo Developmental and Comparative Immunology vol43 no 1 pp 76ndash86 2014

[38] Y-A Zhang I Salinas J Li et al ldquoIgT a primitive immunoglob-ulin class specialized in mucosal immunityrdquo Nature Immunol-ogy vol 11 no 9 pp 827ndash835 2010

[39] S Magadan-Mompo C Sanchez-Espinel and F Gambon-Deza ldquoImmunoglobulin heavy chains in medaka (Oryziaslatipes)rdquo BMC Evolutionary Biology vol 11 no 1 article 1652011

[40] C T Amemiya J Alfoldi A P Lee et al ldquoThe African coela-canth genome provides insights into tetrapod evolutionrdquoNature vol 496 no 7445 pp 311ndash316 2013

[41] T Ota J P Rast G W Litman and C T Amemiya ldquoLineage-restricted retention of a primitive immunoglobulin heavy chainisotype within the Dipnoi reveals an evolutionary paradoxrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 100 no 5 pp 2501ndash2506 2003

[42] Y Sun Z Wei N Li and Y Zhao ldquoA comparative overview ofimmunoglobulin genes and the generation of their diversity intetrapodsrdquo Developmental and Comparative Immunology vol39 no 1-2 pp 103ndash109 2013

[43] I Hadji-Azimi ldquoAnuran immunoglobulins a reviewrdquo Develop-mental and Comparative Immunology vol 3 no 2 pp 223ndash2431979

[44] E Hsu M F Flajnik and L du Pasquier ldquoA third immunoglob-ulin class in amphibiansrdquo The Journal of Immunology vol 135no 3 pp 1998ndash2004 1985

[45] C T Amemiya R N Haire and G W Litman ldquoNucleotidesequence of a cDNA encoding a third distinct Xenopusimmunoglobulin heavy chain isotyperdquo Nucleic Acids Researchvol 17 no 13 p 5388 1989

[46] R Muszligmann M Wilson A Marcuz M Courtet and L duPasquier ldquoMembrane exon sequences of the three Xenopus Igclasses explain the evolutionary origin of mammalian isotypesrdquoEuropean Journal of Immunology vol 26 no 2 pp 409ndash4141996

[47] R Muszligmann L du Pasquier and E Hsu ldquoIs Xenopus IgX ananalog of IgArdquo European Journal of Immunology vol 26 no12 pp 2823ndash2830 1996

[48] B Schaerlinger and J-P Frippiat ldquoIgX antibodies in the urodeleamphibian Ambystoma mexicanumrdquo Developmental and Com-parative Immunology vol 32 no 8 pp 908ndash915 2008

[49] B Schaerlinger M Bascove and J-P Frippiat ldquoA new isotypeof immunoglobulin heavy chain in the urodele amphibianPleurodeles waltl predominantly expressed in larvaerdquoMolecularImmunology vol 45 no 3 pp 776ndash786 2008

[50] S Mashoof A Goodroe C C Du et al ldquoAncient T-independence of mucosal IgXA gut microbiota unaffected bylarval thymectomy in Xenopus laevisrdquo Mucosal Immunologyvol 6 no 2 pp 358ndash368 2013

[51] J P Vaerman J Picard and J F Heremans ldquoStructural dataon chicken IgA and failure to identify the IgA of the tortoiserdquoin Immunologic Phylogeny vol 64 of Advances in ExperimentalMedicine and Biology pp 185ndash195 Springer New York NYUSA 1975

[52] J L Portis and J E Coe ldquoIgM the secretory immunoglobulinof reptiles and amphibiansrdquo Nature vol 258 no 5535 pp 547ndash548 1975

[53] J E Coe D Leong J L Portis and L A Thomas ldquoImmuneresponse in the garter snake (Thamnophis ordinoides)rdquo Immu-nology vol 31 no 3 pp 417ndash424 1976

[54] D Hadge and H Ambrosius ldquoEvolution of low molecularweight immunoglobulinsmdashIV IgY-like immunoglobulins ofbirds reptiles and amphibians precursors of mammalian IgArdquoMolecular Immunology vol 21 no 8 pp 699ndash707 1984

[55] D Hadge and H Ambrosius ldquoEvolution of low molecularweight immunoglobulins V Degree of antigenic relationshipbetween the 7S immunoglobulins ofmammals birds and lowervertebrates to the turkey IgYrdquo Developmental and ComparativeImmunology vol 10 no 3 pp 377ndash385 1986

[56] S Magadan-Mompo C Sanchez-Espinel and F Gambon-Deza ldquoImmunoglobulin genes of the turtlesrdquo Immunogeneticsvol 65 no 3 pp 227ndash237 2013

[57] Z Wei Q Wu L Ren et al ldquoExpression of IgM IgD and IgYin a reptile Anolis carolinensisrdquoThe Journal of Immunology vol183 no 6 pp 3858ndash3864 2009

[58] F Gambon-Deza C Sanchez-Espinel and J V Beneitez ldquoAnovel IgA-like immunoglobulin in the reptile Eublepharis mac-ulariusrdquo Developmental and Comparative Immunology vol 31no 6 pp 596ndash605 2007

[59] G Cheng Y Gao T Wang et al ldquoExtensive diversification ofIgH subclass-encoding genes and IgM subclass switching incrocodiliansrdquo Nature Communications vol 4 article 1337 2013

[60] S Magadan-Mompo C Sanchez-Espinel and F Gambon-Deza ldquoIgH loci of American alligator and saltwater crocodileshed light on IgA evolutionrdquo Immunogenetics vol 65 no 7 pp531ndash541 2013

[61] E Orlans and M E Rose ldquoAn IgA-like immunoglobulin in thefowlrdquo Immunochemistry vol 9 no 8 pp 833ndash838 1972

[62] G A Leslie and L N Martin ldquoStudies on the secretory immu-nologic system of fowl 3 Serum and secretory IgA of thechickenrdquoThe Journal of Immunology vol 110 no 1 pp 1ndash9 1973

[63] J Bienenstock D Y Perey J Gauldie and B J UnderdownldquoChicken 120574A physicochemical and immunochemical charac-teristicsrdquoThe Journal of Immunology vol 110 no 2 pp 524ndash5331973

[64] A M Lebacq-Verheyden J P Vaerman and J F HeremansldquoQuantification and distribution of chicken immunoglobulinsIgA IgM and IgG in serum and secretionsrdquo Immunology vol27 no 4 pp 683ndash692 1974

[65] J Goudswaard A Noordzij R H van Dam J A vanderDonk and J P Vaerman ldquoThe immunoglobulins of the turkey(Meleagris gallopavo) Isolation and characterization of IgGIgM and IgA in body fluids eggs and intraocular tissuesrdquoPoultry science vol 56 no 6 pp 1847ndash1851 1977

[66] D Hadge and H Ambrosius ldquoComparative studies on thestructure of biliary immunoglobulins of some avian speciesII Antigenic properties of the biliary immunoglobulins ofchicken turkey duck and gooserdquo Developmental and Compar-ative Immunology vol 12 no 2 pp 319ndash329 1988

[67] J Goudswaard J P Vaerman and J F Heremans ldquoThreeimmunoglobulin classes in the pigeon (Columbia livia)rdquo Inter-national Archives of Allergy andApplied Immunology vol 53 no5 pp 409ndash419 1977

[68] P L K Ng and D A Higgins ldquoBile immunoglobulin of theduck (Anas platyrhynchos) I Preliminary characterization andontogenyrdquo Immunology vol 58 no 2 pp 323ndash327 1986

[69] K E Magor G W Warr Y Bando D L Middleton and DA Higgins ldquoSecretory immune system of the duck (Anas

ISRN Immunology 17

platyrhynchos) Identification and expression of the genesencoding IgA and IgM heavy chainsrdquo European Journal ofImmunology vol 28 no 3 pp 1063ndash1068 1998

[70] Y Zhao H Rabbani A Shimizu and L Hammarstrom ldquoMap-ping of the chicken immunoglobulin heavy-chain constantregion gene locus reveals an inverted 120572 gene upstream of acondensed 120592 generdquo Immunology vol 101 no 3 pp 348ndash3532000

[71] M L Lundqvist D L Middleton S Hazard and G W WarrldquoThe immunoglobulin heavy chain locus of the duck genomicorganization and expression of D J and C region genesrdquo TheJournal of Biological Chemistry vol 276 no 50 pp 46729ndash46736 2001

[72] T HuangM Zhang ZWei et al ldquoAnalysis of immunoglobulintranscripts in the ostrich Struthio camelus a primitive avianspeciesrdquo PLoS ONE vol 7 no 3 Article ID e34346 2012

[73] K H Roux ldquoImmunoglobulin structure and function asrevealed by electron microscopyrdquo International Archives ofAllergy and Immunology vol 120 no 2 pp 85ndash99 1999

[74] F Gambon-Deza C Sanchez-Espinel and S Magadan-Mompo ldquoThe immunoglobulin heavy chain locus in the platy-pus (Ornithorhynchus anatinus)rdquo Molecular Immunology vol46 no 13 pp 2515ndash2523 2009

[75] Y Zhao H Cui C M Whittington et al ldquoOrnithorhynchusanatinus (platypus) links the evolution of immunoglobulingenes in eutherian mammals and nonmammalian tetrapodsrdquoThe Journal of Immunology vol 183 no 5 pp 3285ndash3293 2009

[76] M Aveskogh and L Hellman ldquoEvidence for an early appear-ance of modern post-switch isotypes in mammalian evolutioncloning of IgE IgG and IgA from the marsupial Monodelphisdomesticardquo European Journal of Immunology vol 28 no 9 pp2738ndash2750 1998

[77] K Belov G A Harrison and DW Cooper ldquoMolecular cloningof the cDNA encoding the constant region of the immunoglob-ulin a heavy chain (C120572) from amarsupialTrichosurus vulpecula(common brushtail possum)rdquo Immunology Letters vol 60 no2-3 pp 165ndash170 1998

[78] K Belov K R Zenger L Hellman and DW Cooper ldquoEchidnaIgA supports mammalian unity and traditional Therian rela-tionshiprdquo Mammalian Genome vol 13 no 11 pp 656ndash6632002

[79] K Belov and L Hellman ldquoImmunoglobulin genetics of Orni-thorhynchus anatinus (platypus) and Tachyglossus aculeatus(short-beaked echidna)rdquo Comparative Biochemistry and Phys-iology vol 136 no 4 pp 811ndash819 2003

[80] M VernerssonM Aveskogh BMunday and L Hellman ldquoEvi-dence for an early appearance of modern post-switch immu-noglobulin isotypes in mammalian evolution (II) cloning ofIgE IgG1 and IgG2 fromamonotreme the duck-billed platypusOrnithorhynchus anatinusrdquo European Journal of Immunologyvol 32 no 8 pp 2145ndash2155 2002

[81] C Auffray R Nageotte and J L Sikorav ldquoMouse immunoglob-ulin A nucleotide sequence of the structural gene for the 120572heavy chain derived from cloned cDNAsrdquo Gene vol 13 no 4pp 365ndash374 1981

[82] T Ukaji D Sumiyama and O Kai ldquoSequence determinationof the heavy-chain constant region in four immunoglobulinclasses of Mongolian gerbils (Meriones unguiculatus)rdquo Experi-mental Animals vol 61 no 2 pp 99ndash107 2012

[83] R C Burnett W C Hanly S K Zhai and K L Knight ldquoTheIgA heavy chain gene family in rabbit cloning and sequence

analysis of 13 C120572 genesrdquo The EMBO Journal vol 8 no 13 pp4041ndash4047 1989

[84] D K Lanning S-K Zhai and K L Knight ldquoAnalysis of the 31015840C120583 region of the rabbit Ig heavy chain locusrdquoGene vol 309 no2 pp 135ndash144 2003

[85] F Ros J Puels N Reichenberger W van Schooten R Buelowand J Platzer ldquoSequence analysis of 05Mb of the rabbitgermline immunoglobulin heavy chain locusrdquo Gene vol 330no 1-2 pp 49ndash59 2004

[86] M Patel D Selinger G E Mark G J Hickey and G FHollis ldquoSequence of the dog immunoglobulin alpha and epsilonconstant region genesrdquo Immunogenetics vol 41 no 5 pp 282ndash286 1995

[87] Z Zhao Y Zhao Q Pan-Hammarstrom et al ldquoPhysical map-ping of the giant panda immunoglobulin heavy chain constantregion genesrdquo Developmental and Comparative Immunologyvol 31 no 10 pp 1034ndash1049 2007

[88] W R Brown and J E Butler ldquoCharacterization of a C120572 gene ofswinerdquoMolecular Immunology vol 31 no 8 pp 633ndash642 1994

[89] W R Brown H Rabbani J E Butler and L HammarstromldquoCharacterization of the bovine C120572 generdquo Immunology vol 91no 1 pp 1ndash6 1997

[90] G PWhite P Roche M R Brandon S E Newton and E N TMeeusen ldquoCloning and characterization of sheep (Ovis aries)immunoglobulin 120572 chainrdquo Immunogenetics vol 48 no 5 pp359ndash362 1998

[91] AMancia T A Romano H A Gefroh et al ldquoCharacterizationof the immunoglobulin A heavy chain gene of the Atlantic bot-tlenose dolphin (Tursiops truncatus)rdquo Veterinary Immunologyand Immunopathology vol 118 no 3-4 pp 304ndash309 2007

[92] B Wagner I Greiser-Wilke and D F Antczak ldquoCharacteriza-tion of the horse [Equus caballus] IGHA generdquo Immunogeneticsvol 55 no 8 pp 552ndash560 2003

[93] N Takahashi S Ueda and M Obata ldquoStructure of humanimmunoglobulin gamma genes implications for evolution of agene familyrdquo Cell vol 29 no 2 pp 671ndash679 1982

[94] J G Flanagan M-P Lefranc and T H Rabbitts ldquoMechanismsof divergence and convergence of the human immunoglobulin1205721 and 1205722 constant region gene sequencesrdquo Cell vol 36 no 3pp 681ndash688 1984

[95] S Kawamura K Omoto and S Ueda ldquoEvolutionary hypervari-ability in the hinge region of the immunoglobulin alpha generdquoJournal of Molecular Biology vol 215 no 2 pp 201ndash206 1990

[96] F Scinicariello F Masseoud L Jayashankar and R AttanasioldquoSooty mangabey (Cercocebus torquatus atys) IGHG and IGHAgenesrdquo Immunogenetics vol 58 no 12 pp 955ndash965 2006

[97] K A Rogers L Jayashankar F Scinicariello and R AttanasioldquoNonhuman primate IgA genetic heterogeneity and interac-tions with CD89rdquoThe Journal of Immunology vol 180 no 7 pp4816ndash4824 2008

[98] S Kawamura N Saitou and S Ueda ldquoConcerted evolution ofthe primate immunoglobulin 120572-gene through gene conversionrdquoThe Journal of Biological Chemistry vol 267 no 11 pp 7359ndash7367 1992

[99] S Kawamura and S Ueda ldquoImmunoglobulin C119867gene family in

hominoids and its evolutionary historyrdquo Genomics vol 13 no1 pp 194ndash200 1992

[100] A Brusco U Cariota A Bottaro et al ldquoStructural andimmunologic analysis of gene triplications in the Ig heavy chainconstant region locusrdquoThe Journal of Immunology vol 152 no1 pp 129ndash135 1994

18 ISRN Immunology

[101] H Rabbani Q Pan N Kondo C I E Smith and L Ham-marstrom ldquoDuplications and deletions of the human IGHClocus evolutionary implicationsrdquo Immunogenetics vol 45 no2 pp 136ndash141 1996

[102] P F Weinheimer J Mestecky and R T Acton ldquoSpecies distri-bution of J chainrdquoThe Journal of Immunology vol 107 no 4 pp1211ndash1212 1971

[103] F P Inman and J Mestecky ldquoThe J chain of polymeric immu-noglobulinsrdquo inContemporary Topics inMolecular Immunologyvol 3 pp 111ndash141 Springer New York NY USA 1974

[104] P Brandtzaeg ldquoPresence of J chain in human immunocytescontaining various immunoglobulin classesrdquo Nature vol 252no 5482 pp 418ndash420 1974

[105] L Tacchi E Larragoite and I Salinas ldquoDiscovery of J chain inAfrican lungfish (Protopterus dolloi Sarcopterygii) using highthroughput transcriptome sequencing implications in mucosalimmunityrdquo PLoS ONE vol 8 no 8 Article ID e70650 2013

[106] I K Zarkadis D Mastellos and J D Lambris ldquoPhylogeneticaspects of the complement systemrdquo Developmental and Com-parative Immunology vol 25 no 8-9 pp 745ndash762 2001

[107] A P West Jr A B Herr and P J Bjorkman ldquoThe chickenyolk sac IgY receptor a functional equivalent of themammalianMHC-related Fc receptor is a phospholipase A

2receptor

homologrdquo Immunity vol 20 no 5 pp 601ndash610 2004[108] D B Tesar E J Cheung and P J Bjorkman ldquoThe chicken

yolk sac IgY receptor a mammalian mannose receptor familymember transcytoses IgY across polarized epithelial cellsrdquoMolecular Biology of the Cell vol 19 no 4 pp 1587ndash1593 2008

[109] A I Taylor R L Beavil B J Sutton and R A Calvert ldquoAmonomeric chicken IgY receptor binds IgY with 21 stoichiom-etryrdquo The Journal of Biological Chemistry vol 284 no 36 pp24168ndash24175 2009

[110] K Baker S-W Qiao T Kuo et al ldquoImmune and non-immunefunctions of the (not so) neonatal Fc receptor FcRnrdquo Seminarsin Immunopathology vol 31 no 2 pp 223ndash236 2009

[111] K Baker R S Blumberg and C S Kaetzel ldquoImmunoglob-ulin transport and immunoglobulin receptorsrdquo in MucosalImmunology J Mestecky W Strober H Cheroutre B KelsallB N Lambrecht andMW Russell Eds chapter 20 AcademicPressElsevier Waltham Mass USA 2014

[112] C S Kaetzel ldquoThepolymeric immunoglobulin receptorrdquo in eLSJohn Wiley amp Sons Chichester UK 2013

[113] N J Mantis N Rol and B Corthesy ldquoSecretory IgArsquos complexroles in immunity andmucosal homeostasis in the gutrdquoMucosalImmunology vol 4 no 6 pp 603ndash611 2011

[114] J V Peppard M E Rose and P Hesketh ldquoA functional homo-logue of mammalian secretory component exists in chickensrdquoEuropean Journal of Immunology vol 13 no 7 pp 566ndash5701983

[115] K E Mostov M Friedlander and G Blobel ldquoThe receptorfor transepithelial transport of IgA and IgM contains multipleimmunoglobulin-like domainsrdquo Nature vol 308 no 5954 pp37ndash43 1984

[116] P Krajci R Solberg M Sandberg O Oyen T Jahnsen and PBrandtzaeg ldquoMolecular cloning of the human transmembranesecretory component (poly-Ig receptor) and its mRNA expres-sion in human tissuesrdquo Biochemical and Biophysical ResearchCommunications vol 158 no 3 pp 783ndash789 1989

[117] P Krajci D Kvale K Tasken and P Brandtzaeg ldquoMolecularcloning and exon-intron mapping of the gene encoding humantransmembrane secretory component (the poly-Ig receptor)rdquo

European Journal of Immunology vol 22 no 9 pp 2309ndash23151992

[118] J F Piskurich J A France C M Tamer C A Willmer CS Kaetzel and D M Kaetzel ldquoInterferon-120574 induces polymericimmunoglobulin receptormRNA in human intestinal epithelialcells by a protein synthesis dependent mechanismrdquo MolecularImmunology vol 30 no 4 pp 413ndash421 1993

[119] J F Piskurich M H Blanchard K R Youngman J A Franceand C S Kaetzel ldquoMolecular cloning of the mouse polymericIg receptor functional regions of the molecule are conservedamong five mammalian speciesrdquo The Journal of Immunologyvol 154 no 4 pp 1735ndash1747 1995

[120] M A Kulseth P Krajci O Myklebost and S RogneldquoCloning and characterization of two forms of bovine polymericimmunoglobulin receptor cDNArdquo DNA and Cell Biology vol14 no 3 pp 251ndash256 1995

[121] K S Koch A S Gleiberman T Aoki et al ldquoDiscordant expres-sion and variable numbers of neighboring GGA- and GAA-richtriplet repeats in the 31015840 untranslated regions of two groups ofmessenger RNAs encoded by the rat polymeric immunoglob-ulin receptor generdquo Nucleic Acids Research vol 23 no 7 pp1098ndash1112 1995

[122] F M Adamski and J Demmer ldquoTwo stages of increased IgAtransfer during lactation in themarsupialTrichosurus vulpecula(brushtail possum)rdquoThe Journal of Immunology vol 162 no 10pp 6009ndash6015 1999

[123] H Kumura T Sone K-I Shimazaki and E KobayashildquoSequence analysis of porcine polymeric immunoglobulinreceptor from mammary epithelial cells present in colostrumrdquoThe Journal of Dairy Research vol 67 no 4 pp 631ndash636 2000

[124] C L Taylor G A Harrison C M Watson and E M DeaneldquocDNA cloning of the polymeric immunoglobulin receptor ofthe marsupial Macropus eugenii (tammar wallaby)rdquo EuropeanJournal of Immunogenetics vol 29 no 2 pp 87ndash93 2002

[125] R Braathen V S Hohman P Brandtzaeg and F-E JohansenldquoSecretory antibody formation conserved binding interactionsbetween J chain and polymeric Ig receptor from humans andamphibiansrdquo The Journal of Immunology vol 178 no 3 pp1589ndash1597 2007

[126] M J Lewis BWagner R M Irvine and J MWoof ldquoIgA in thehorse cloning of equine polymeric Ig receptor and J chain andcharacterization of recombinant forms of equine IgArdquoMucosalImmunology vol 3 no 6 pp 610ndash621 2010

[127] A J Leon D Banner L Xu et al ldquoSequencing annotation andcharacterization of the influenza ferret infectomerdquo Journal ofVirology vol 87 no 4 pp 1957ndash1966 2013

[128] W H Wieland D Orzaez A Lammers H K ParmentierM W A Verstegen and A Schots ldquoA functional polymericimmunoglobulin receptor in chicken (Gallus gallus) indicatesancient role of secretory IgA inmucosal immunityrdquoBiochemicalJournal vol 380 no 3 pp 669ndash676 2004

[129] K Hamuro H Suetake N R Saha K Kikuchi and YSuzuki ldquoA teleost polymeric Ig receptor exhibiting two Ig-likedomains transports tetrameric IgM into the skinrdquo The Journalof Immunology vol 178 no 9 pp 5682ndash5689 2007

[130] J H W M Rombout S J L van der Tuin G Yang et alldquoExpression of the polymeric immunoglobulin receptor (pIgR)in mucosal tissues of common carp (Cyprinus carpio L)rdquo Fishand Shellfish Immunology vol 24 no 5 pp 620ndash628 2008

[131] L-N Feng D-Q Lu J-X Bei et al ldquoMolecular cloning andfunctional analysis of polymeric immunoglobulin receptor gene

ISRN Immunology 19

in orange-spotted grouper (Epinephelus coioides)rdquo ComparativeBiochemistry and Physiology B vol 154 no 3 pp 282ndash289 2009

[132] A E Oslashstergaard S A M Martin T Wang R J M Stet andC J Secombes ldquoRainbow trout (Oncorhynchus mykiss) pos-sessmultiple novel immunoglobulin-like transcripts containingeither an ITAM or ITIMsrdquo Developmental and ComparativeImmunology vol 33 no 4 pp 525ndash532 2009

[133] H Eiffert E Quentin and J Decker ldquoThe primary structureof the human free secretory component and the arrangementof disulfide bondsrdquo Hoppe-Seylerrsquos Zeitschrift fur PhysiologischeChemie vol 365 no 12 pp 1489ndash1495 1984

[134] E Fallgreen-Gebauer W Gebauer A Bastian et al ldquoThe cova-lent linkage of secretory component to IgA Structure of sIgArdquoBiological Chemistry Hoppe-Seyler vol 374 no 11 pp 1023ndash1028 1993

[135] J MWoof ldquoThe structure of IgArdquo inMucosal Immune DefenseImmunoglobulin A C S Kaetzel Ed chapter 1 pp 1ndash24Springer New York NY USA 2007

[136] A Bonner A Almogren P B Furtado M A Kerr and S JPerkins ldquoLocation of secretory component on the Fc edge ofdimeric IgA1 reveals insight into the role of secretory IgA1 inmucosal immunityrdquoMucosal Immunology vol 2 no 1 pp 74ndash84 2009

[137] A Bonner A Almogren P B Furtado M A Kerr and S JPerkins ldquoThe nonplanar secretory IgA2 and near planar secre-tory IgA1 solution structures rationalize their different mucosalimmune responsesrdquo The Journal of Biological Chemistry vol284 no 8 pp 5077ndash5087 2009

[138] J Johansen B Braathen and P Brandtzaeg ldquoRole of J chain insecretory immunoglobulin formationrdquo Scandinavian Journal ofImmunology vol 52 no 3 pp 240ndash248 2000

[139] B A Hendrickson D A Conner D J Ladd et al ldquoAlteredhepatic transport of immunoglobulin A in mice lacking the Jchainrdquo Journal of Experimental Medicine vol 182 no 6 pp1905ndash1911 1995

[140] B A Hendrickson L Rindisbacher B Corthesy et al ldquoLackof association of secretory component with IgA in J chain-deficient micerdquo The Journal of Immunology vol 157 no 2 pp750ndash754 1996

[141] N Lycke L Erlandsson L Ekman K Schon and T Lean-derson ldquoLack of J chain inhibits the transport of gut IgA andabrogates the development of intestinal antitoxic protectionrdquoThe Journal of Immunology vol 163 no 2 pp 913ndash919 1999

[142] F-E Johansen R Braathen and P Brandtzaeg ldquoThe J chainis essential for polymeric Ig receptor-mediated epithelial trans-port of IgArdquoThe Journal of Immunology vol 167 no 9 pp 5185ndash5192 2001

[143] R E Ley D A Peterson and J I Gordon ldquoEcological andevolutionary forces shaping microbial diversity in the humanintestinerdquo Cell vol 124 no 4 pp 837ndash848 2006

[144] M McFall-Ngai ldquoAdaptive immunity care for the communityrdquoNature vol 445 no 7124 p 153 2007

[145] A J Macpherson K D McCoy F-E Johansen and PBrandtzaeg ldquoThe immune geography of IgA induction andfunctionrdquoMucosal Immunology vol 1 no 1 pp 11ndash22 2008

[146] D Kvale and P Brandtzaeg ldquoConstitutive and cytokine inducedexpression of HLA molecules secretory component and inter-cellular adhesion molecule-1 is modulated by butyrate in thecolonic epithelial cell line HT-29rdquo Gut vol 36 no 5 pp 737ndash742 1995

[147] L VHooperMHWong AThelin L Hansson P G Falk andJ I Gordon ldquoMolecular analysis of commensal host-microbialrelationships in the intestinerdquo Science vol 291 no 5505 pp 881ndash884 2001

[148] S Hapfelmeier M A E Lawson E Slack et al ldquoReversiblemicrobial colonization of germ-free mice reveals the dynamicsof IgA immune responsesrdquo Science vol 328 no 5986 pp 1705ndash1709 2010

[149] DH ReikvamMDerrien R Islam et al ldquoEpithelial-microbialcross-talk in polymeric Ig receptor deficient micerdquo EuropeanJournal of Immunology vol 42 no 11 pp 2959ndash2970 2012

[150] EW Rogier A L Frantz M E C Bruno et al ldquoSecretory anti-bodies in breast milk promote long-term intestinal homeostasisby regulating the gut microbiota and host gene expressionrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 111 no 8 pp 3074ndash3079 2014

[151] G M Barton and R Medzhitov ldquoToll-like receptor signalingpathwaysrdquo Science vol 300 no 5625 pp 1524ndash1525 2003

[152] K Takeda and S Akira ldquoToll receptors and pathogen resis-tancerdquo Cellular Microbiology vol 5 no 3 pp 143ndash153 2003

[153] E Cario andD K Podolsky ldquoDifferential alteration in intestinalepithelial cell expression of Toll-like receptor 3 (TLR3) andTLR4 in inflammatory bowel diseaserdquo Infection and Immunityvol 68 no 12 pp 7010ndash7017 2000

[154] M Hausmann S Kiessling S Mestermann et al ldquoToll-likereceptors 2 and 4 are up-regulated during intestinal inflamma-tionrdquo Gastroenterology vol 122 no 7 pp 1987ndash2000 2002

[155] M T Abreu L S Thomas S Y Tesfay et al ldquoRegulation ofTLR4 and MD-2 in the intestinal epithelium evidence for dys-regulated LPS signaling in human inflammatory bowel diseaserdquoin Proceedings of the 90th Annual Meeting of the AmericanAssociation for Immunologists Abstract 3634 Denver ColoUSA 2003

[156] T A Schneeman M E C Bruno H Schjerven F-E JohansenL Chady and C S Kaetzel ldquoRegulation of the polymeric Igreceptor by signaling through TLRs 3 and 4 linking innate andadaptive immune responsesrdquo The Journal of Immunology vol175 no 1 pp 376ndash384 2005

[157] M E C Bruno A L Frantz E W Rogier F-E Johansen andC S Kaetzel ldquoRegulation of the polymeric immunoglobulinreceptor by the classical and alternative NF-120581B pathways inintestinal epithelial cellsrdquoMucosal Immunology vol 4 no 4 pp468ndash478 2011

[158] M E C Bruno E W Rogier A L Frantz A T Stefka SN Thompson and C S Kaetzel ldquoRegulation of the poly-meric immunoglobulin receptor in intestinal epithelial cellsby Enterobacteriaceae implications for mucosal homeostasisrdquoImmunological Investigations vol 39 no 4-5 pp 356ndash382 2010

[159] A L Frantz E W Rogier C R Weber et al ldquoTargeted deletionof MyD88 in intestinal epithelial cells results in compromisedantibacterial immunity associatedwith downregulation of poly-meric immunoglobulin receptor mucin-2 and antibacterialpeptidesrdquoMucosal Immunology vol 5 no 5 pp 501ndash512 2012

[160] E W Rogier A L Frantz M E C Bruno and C S KaetzelldquoSecretory IgA is concentrated in the outer layer of intestinalmucus along with gut bacteriardquo Pathogens In press

[161] M B Geuking K D McCoy and A J Macpherson ldquoThe func-tion of secretory IgA in the context of the intestinal continuumof adaptive immune responses in host-microbial mutualismrdquoSeminars in Immunology vol 24 no 1 pp 36ndash42 2012

20 ISRN Immunology

[162] L VHooper D R Littman andA JMacpherson ldquoInteractionsbetween the microbiota and the immune systemrdquo Science vol336 no 6086 pp 1268ndash1273 2012

[163] A J Macpherson M B Geuking E Slack S Hapfelmeierand K D McCoy ldquoThe habitat double life citizenship andforgetfulness of IgArdquo Immunological Reviews vol 245 no 1 pp132ndash146 2012

Submit your manuscripts athttpwwwhindawicom

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Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

ISRN Immunology 9

our knowledge of pIgR-mediated transcytosis of mucosalIgs is derived from studies of mammalian secretory IgA(SIgA) as illustrated in Figure 4 Transcription of the PIGRgene and translation of pIgR mRNA is accompanied byinsertion of the nascent protein into the endoplasmic retic-ulum The pIgR undergoes substantial glycosylation duringtransport through the ER and Golgi apparatus and is thentargeted to the basolateral surface of polarized epithelialcells Membrane-bound pIgR binds pIg and pIg-containingimmune complexes which are internalized along with unoc-cupied pIgR via receptor-mediated endocytosis and thentranscytosed through a series of intracellular vesicles to theapical surface During transcytosis intracellular pIg antibod-ies can neutralize bacteria viruses and other antigens thathave gained access to the interior of the epithelial cell Atthe apical surface proteolytic cleavage of the membrane-spanning region of pIgR leads to the release of its extracellulardomain known as secretory component (SC) either in freeform or covalently bound to pIg Secretory Igs can neutralizepathogens and antigens within the mucosal lumen andfacilitate excretion of antigens that were transported throughthe epithelial cell as IgA immune complexes The SC moietyof SIgA has been shown to protect IgA from degradationby host and bacterial proteases and along with free SCconfers additional innate immune functions that protectthe epithelial surface from microbial invasion and limitpotentially damaging host inflammatory responses (reviewedin [113]) The finding of an SC-like polypeptide associatedwith polymeric IgT in rainbow trout [38] polymeric IgXin Xenopus [50] and polymeric IgA in birds [114] suggeststhat all vertebrate pIgRs share the function of transportingpolymeric Igs into external secretions In many mammalianspecies pIgR mediates epithelial transcytosis of both poly-meric IgM and IgA (reviewed in [111]) Although directevidence is not yet available it is reasonable to assume thatpIgR transports IgM in lower vertebrates It will be interestingto investigate whether the SCmoiety of secretory Igs in lowervertebrates mediates additional innate immune functions ashas been demonstrated for mammalian SC

6 Coevolution of pIgR and Mucosal Igs

Molecular cloning of the PIGR gene was first reportedfor mammalian species including eutherians marsupialsand monotremes [115ndash127] Subsequent elucidation of PIGRsequences from diverse species of jawed vertebrates hasallowed a comprehensive analysis of the evolutionary originsof the PIGR gene [38 128 128ndash132] and additional sequencesavailable in the Genbank database Whereas no ortholog ofthe PIGR gene has been found in any species of cartilaginousfish the PIGR gene has been annotated in all species of teleostfish for which the genome has been sequenced No orthologof the PIGR gene has been reported in lobe-finned bonyfishes but further analyses of whole genome sequences willbe required to determine whether the PIGR gene was lostfollowing the split of the Sarcopterygii It thus appears thatthe PIGR gene emerged in a common ancestor of highervertebrates after the split of cartilaginous fish and prior

to the evolution of modern teleosts likely driven by theselective pressure to provide a mechanism for transport ofpolymeric Igs such as IgM and IgT into mucosal secretionsThis hypothesis is supported by a comparison of phylogenetictrees based on amino acid sequences for IgT IgX and IgAheavy chains and pIgR (Figure 5)The predicted evolutionarydistance between trout IgT and frog IgX is similar to thedistance between trout and frog pIgR suggesting that thetransition from IgT to IgX as the dominantmucosal Ig isotypewas accompanied by adaptations in pIgR structure Similarparallels can be seen in the transition from IgX to IgA inreptiles birds and mammals and the concurrent evolutionof pIgR

Alignments of the amino acid sequences of mucosal Igheavy chains and pIgR from 10 representative vertebratespecies provide further support for the theory of coevolutionof mucosal IGH and PIGR genes (Figure 6) A commonfeature of Ig and pIgR proteins is the presence of repeatingIg-like domains (see Figure 2 for the basic structure of thesedomains) The structure of IgT IgX and IgA heavy chainsfrom fish amphibians reptiles and birds is similar to thatof IgM with 4 constant Ig-like domains In mammalianIgA (and IgG) the exon for the 2nd constant region wastruncated to encode a short ldquohingerdquo region which confersgreater mobility to the antigen-binding region at the N-terminusThus the CH3 domain of IgT IgX and IgA in lowervertebrates is structurally and functionally homologous tothe CH2 domain of mammalian IgA The heavy chains ofIgT IgX and IgA have retained a characteristic feature ofthe IgM heavy chain that is the presence of a conservedcysteine residue in the tailpiece that allows disulfide bondingbetween heavy chains of individual Ig proteins to formhigher molecular weight polymers These large Ig structurescontaining multiple antigen-binding sites are particularlywell suited for immune clearance of large antigens found atmucosal surfaces such as intact microbes and food particlesIn mucosal Igs from most vertebrate orders the J chainprotein initiates this polymerization process by disulfidebonding with 2 Ig heavy chains remaining associated withthe polymeric Ig at a stoichiometric ratio of 1 J chain subunitper 2 3 4 or 5 Ig units Despite the absence of J chainthe predominant form of IgM and IgT in mucus secretionsin rainbow trout was found to be polymeric in contrastto monomeric forms of IgM and IgT in the blood [38] Inmammals IgM is mainly found as a pentamer whereas theshorter heavy chain ofmammalian IgA restricts its polymericforms to dimers trimers and tetramers Further studies willbe required to characterize the polymeric structures of IgMIgT IgX and IgA in lower vertebrates

Alignment of pIgR amino acid sequences from 10 rep-resentative vertebrate species reveals structural changes thatwere evolved in parallel with structural changes in mucosalIgs (Figure 6(b)) All pIgR proteins have an N-terminalhydrophobic leader peptide required for targeting of thenascent protein into the ER The extracellular region ofpIgR protein is characterized by repeating ldquoIg-likerdquo domainssimilar to Ig heavy chains [115 133] Interestingly the num-ber of extracellular Ig-like domains has increased duringvertebrate evolution culminating with a total of 5 domains

10 ISRN Immunology

TailpieceHinge

Tailpiece

Mammalian IgA

VVVVVVVVVV

200121 300 400 4721

Human IgA1Rhesus IgA

Cattle IgAMouse IgA

Possum IgAPlatypus IgAChicken IgA

Frog IgXTrout IgT

Premammalian IgTXA

Gecko IgldquoArdquo

CH1

CH1

CH2

CH2

CH3

CH3

CH4

(a)

Leader 1 2 3 4 5

Ig homology extracellular domains

Linker CytoplasmicTM

1001 200 300 400 500 600 700 764

HumanRhesus

CattleMouse

PossumPlatypusChicken

AnoleFrog

Trout

(b)

Figure 6 Interspecies similarity in mucosal Ig and pIgR protein sequences from 10 representative vertebrate species Alignments in aminoacid sequences correspond to the phylogenetic trees shown in Figure 5 (a) Numbering ofmucosal Ig amino acids corresponds to the sequenceof human IgA1 beginning with the first residue of the variable domain CH heavy chain constant region domain (b) Numbering of pIgRamino acids corresponds to the sequence of human pIgR beginning with the first residue of the leader peptide TM transmembrane Forboth alignments the intensity of shading at each position signifies the degree of similarity amongmucosal Ig or pIgR sequences from differentspecies Gaps in sequence alignments signify regions of limited interspecies homology Approximate boundaries are noted of key structuralelements in mucosal Ig and pIgR proteins

in mammalian pIgR By contrast pIgR from amphibiansreptiles and birds contains 4 extracellular domains lackinga homolog of domain 2 of mammalian pIgR The mostprimitive form of pIgR found in teleost fish contains only2 extracellular domains homologous to domains 1 and 5of mammalian pIgR Interspecies homology is greatest indomain 1 which has been shown to be critical for binding ofmammalian pIgR to polymeric Igs (reviewed in [111]) Highlyconserved internal disulfide bonds are found in all the Ig-like domains of pIgR characteristic of the immunoglobulinfold An additional disulfide bond is found in domain 5 ofpIgR frommammals birds reptiles and amphibians but notfish In human SIgA this ldquoextrardquo disulfide bond in domain 5has been shown to rearrange to form a disulfide bond with

cysteine residues in one of the heavy chains of polymericIgA [134] Although the structure of SIgA has not beenfully characterized for lower vertebrates it is reasonable toassume that similar disulfide bonds form between domain 5of pIgR and polymeric IgA or IgX from birds reptiles andamphibians The linker region connecting domain 5 of pIgRto the transmembrane domain has a random structure that ispoorly conserved across species Proteolytic cleavage of pIgRwithin this domain leads to the release of SC from the apicalsurface of epithelial cells either free or bound to polymericIg The cytoplasmic domain of mammalian pIgR containsa number of intracellular sorting motifs that interact withcytoplasmic proteins to direct pIgR through the transcytoticpathway (reviewed in [111]) These motifs are reasonably

ISRN Immunology 11

Linker

TMCytoplasmic

J chain

Hinge 1

2

34

5

CL

VLVH

C1205721C1205722 C1205723

(a)

Linker

TMCytoplasmic

J chain

1

3 4

5

CL

VL

VH

C1205941205721

C1205941205722C1205941205723 C1205941205724

(b)

11

5

LinkerTM

Cytoplasmic

5

CL

VL

VH

C1205911C1205912

C1205913 C1205914

pIgR Ig-like domain

H chain Ig-like domain

L chain Ig-like domain

J chain

Disulfide bond

(c)

Figure 7 Theoretical model for changes in the structure of secretory Igs during evolution (a) The structure for mammalian SIgA is adaptedfrom the model of Woof and Russell [16] for human SIgA1 with permission from Nature Publishing Group (b) and (c) Theoretical modelsfor the structure of IgXA from amphibians and birds and SIgT from teleost fish respectively are predicted from alignment of Ig heavy chainand pIgR sequences with mammalian homologs

well conserved in pIgR from birds and reptiles but not inpIgR from amphibians and fish suggesting that complexmechanisms of intracellular trafficking of pIgR coevolvedwith the increasing complexity of the mucosal immunesystem

7 Hypothetical Models for Changes inSecretory Ig Structure during Coevolutionof Mucosal Igs and pIgR

A large number of structural and functional analyses overthe past 30 years allowed the development of detailed modelsfor the structure of mammalian SIgA (reviewed in [111 135])(Figure 7(a)) Domains 1 and 5 of pIgR the most highlyconserved Ig-like domains associate with theC1205722 subunits oftwo adjacent IgA heavy chains in a near-planar structure [136137] During transcytosis a disulfide bond forms betweenhighly conserved cysteine residues in domain 5 of pIgRand the C1205722 domain of one of the IgA heavy chains [134]Domains 2 3 and 4 allow mammalian pIgR to assume aflexible extended structure which is thought to wrap aroundthe IgA heavy chains and protect against degradation fromhost and microbial proteases Binding of mammalian pIgRto polymeric IgA or IgM requires the presence of J chain

connecting the Ig subunits (reviewed in [138]) and J chain-deficient mice fail to transport IgA and IgM into externalsecretions [139ndash141] Structure-function studies usingmutantforms of human J chain suggested that J chain binds directlyto pIgR and also maintains polymeric Ig in an optimalconformation for pIgR binding and transcytosis [142] Theunstructured linker region connecting domain 5 of pIgRto the transmembrane (TM) region gives membrane-boundpIgR the flexibility to bind large polymeric Igs (with orwithout associated antigens) and provides an exposed site forproteolytic cleavage of pIgR to SC The C-terminal region ofpIgR extends past the cytoplasmic face of the plasma mem-brane allowing association with cytoplasmic factors thatregulate trafficking of pIgR with or without bound polymericIg

Although detailed structural studies have not yet beenperformed on secretory Igs from lower vertebrates hypo-thetical models can be constructed based on alignmentswith their mammalian homologs A model for secretoryIgXA in birds reptiles and amphibians is illustrated inFigure 7(b) showing the C

1205941205722 domain in place of the hinge

region ofmammalian IgAThenumbering of the extracellulardomains of pIgR corresponds to the homologous domainsin mammalian pIgR noting the absence of domain 2 In

12 ISRN Immunology

this model the C120594120572

3 domains of two adjacent IgXA heavychains (homologous to the C

1205722 domain of mammalian IgA)

bind to the highly conserved domains 1 and 5 of pIgRGiven the conservation of the analogous cysteine residuesin domain 5 of pIgR and the C

1205941205723 domain of IgXA it

is assumed that a disulfide bond forms between pIgR andpolymeric Ig during epithelial transcytosis in birds reptilesand amphibiansThe absence of domain 2 in pIgR from thesevertebrate orders necessitates a more rigid structure thanthat of mammalian pIgR with a corresponding decrease inits ability to wrap around the IgXA heavy chains and pro-vide protection against proteoltyic degradation Despite theshorter length of pIgR in birds reptiles and amphibians theassociation with the J chain subunit of polymeric IgXA stillappears to be required Recombinant pIgR from the Africanfrog (Xenopus laevis) was shown to bind with moderatelyhigh affinity to human polymeric IgA containing J chain butnot to monomeric IgA [125] The affinity of Xenopus pIgRfor human pIgA was improved when Xenopus J chain wassubstituted for human J chain in a chimeric polymeric IgAmolecule The lack of sequence conservation across speciesin the linker region connecting domain 5 of pIgR to the TMregion suggests that it acts as a nonspecific ldquospacerrdquo As statedabove the cytoplasmic region of pIgR appears to have evolvedover time to provide enhanced regulation of pIgR trafficking

The hypothetical structure of secretory IgT from teleostfish in Figure 7(c) illustrates how the most primitive form ofpIgR comprising only extracellular domains 1 and 5 couldassociate with polymeric Ig and mediate epithelial transcy-tosis Association of pIgR domain 1 with the C

1205913 domain of

IgT would preserve the functional homology with secretoryIgs in higher vertebrates The short length of teleost pIgRwould necessitate the association of domain 5 with a C

1205913

domain on one of the heavy chains of the same IgT ratherthan spanning across to the adjaent IgT subunit While thismodel preserves the highly conserved association of pIgRdomain 1 with the orthologous domain of the IgT heavychain it does not explain the selectivity of teleost pIgR forpolymeric rather than monomeric IgT Although there is noexperimental evidence to support this model it could behypothesized that dimerization of two pIgR molecules in theplasmamembrane is required for high affinity binding of IgTas illustrated in the model in Figure 7(c) This hypotheticalmodel would also explain the lack of a necessity for J chainin polymeric IgT since each subunit in the pIgR dimer wouldonly be in contact with one IgT subunit The unstructuredlinker region connecting domain 5 of pIgR to the TM regionwould provide flexibility for association of 2 membrane-bound pIgR molecules with a large polymeric IgT molecule

Taken together the structural models for secretory Igsshown in Figure 7 are consistent with the selection of a morefunctional pIgR molecule over evolutionary time Duplica-tion and diversification of the extracellular Ig-like domainsof pIgR would provide a longer more flexible surface forbinding to polymeric Igs with higher affinity and protectingthe Ig heavy chains against proteolytic attack Expansion ofthe cytoplasmic domain of pIgR and incorporation of motifsfor binding cytoplasmic proteins would allow regulated

trafficking of pIgR and polymeric Igs across mucosal andglandular epithelial cells Importantly these models illustratea potential path for coevolution of IGH and PIGR genesdriven by the common selective pressure to provide antigen-specific humoral immune responses at mucosal surfaces

8 Evidence that the CommensalMicrobiota Provided the Driving Force forCoevolution of Mucosal Igs and pIgR

From the earliest evolution of vertebrate animals mucosal Igshave been an integral part of the emerging adaptive immunesystem Clearly many environmental factors served as driv-ing forces for the evolution of the adaptive immune systemin vertebrates including a longer lifespan thanmany (but notall) invertebrates and amore diverse diet that could introducea broader range of potential gut pathogens However it hasbeen proposed that the most significant force may havebeen the dramatic increase in the numbers and complexityof the resident microbiota in the evolution of vertebratesfrom their invertebrate ancestors [1 143 144] Antibodiesin mucosal secretions contribute to immune homeostasis bylimiting access of microbes and their products to the bodyproper maintaining the integrity of the epithelial barrier andshaping the composition of the commensal microbiota infavor of metabolically beneficial microorganisms [145] Thepredominance of polymeric Igs in these secretions promotesthese functions by providing multiple antigen-binding sitesper Ig complex thus increasing the overall avidity of antigen-antibody interactions Structural and functional refinementsin mucosal Igs culminating with the multifunctional secre-tory IgA molecule in mammals have further enhanced theirability to enhance immune homeostasis

The early emergence of pIgR in vertebrate evolutionprovided a mechanism for efficient transport of mucosal Igsinto external secretions It is well documented that crosstalkbetween mucosal epithelial cells and the resident microbiotamodulates expression of pIgR (reviewed in [17 111 112]) andit is reasonable to assume that these host-microbe interac-tions provided a driving force for evolution of the PIGR genein vertebrates The first demonstration that gut bacteria maymodulate pIgR expression in epithelial cells was the findingthat butyrate a bacterial fermentation product and importantenergy source in the colon upregulated expression of pIgRin the human colonic epithelial cell line HT-29 [146] A rolefor commensal bacteria in pIgR regulation was subsequentlydemonstrated by the observation that pIgR expression wasincreased when germ-free mice were colonized with Bacteri-oides thetaiotaomicron a prominent organism of the normalmouse and human intestinal microbiota [147] Amore recentstudy using a model of reversible colonization of germ-free mice with a nondividing mutant of Escherichia colidemonstrated that a long-lived SIgA response could besustained that specifically recognized the inducing bacteria[148] However exposure of E coli-colonized mice to otherbacteria limited the duration of the SIgA response against theoriginal colonizer suggesting a dynamic equilibriumbetweenmembers of the gut microbial community and host SIgA A

ISRN Immunology 13

study from the laboratory of Finn-Eirik Johansen demon-strated that diversity of the bacterial community in the cecallumen was reduced in pIgR-knockoutmice supporting a rolefor SIgA in limiting overgrowth of selected species [149] Incontrast the community of bacteria adherent to the epithelialsurface was more diverse in pIgR-knockout mice than inwild-typemice and these adherent bacteria caused enhancedexpression of several epithelial antimicrobial peptides Thesefindings suggest that bacteria-specific SIgA anchored in themucus layer restricts adhesion of bacteria to the epithelialsurface and limits bacterial stimulation of host epithelial cellsA recent study from the authorrsquos laboratory employing abreeding scheme in which119875119894119892119903minusminus damswere bred to119875119894119892119903+minusmales and vice versa demonstrated that SIgA antibodiesin breast milk promote long-term intestinal homeostasis byregulating the gut microbiota and gene expression in colonicepithelial cells [150]

A direct role for commensal andor pathogenic bacteriain the regulation of pIgR expression suggests that the innateimmune system may ldquoprimerdquo epithelial cells for transportof polymeric Ig produced during the adaptive immuneresponse Host cells mediate innate immune responses tomicrobial components through toll-like receptor (TLR) sig-naling (reviewed in [151 152]) Intestinal epithelial cells havebeen shown to express a wide variety of TLRs the expressionof which is upregulated during intestinal inflammation [153ndash155] Significantly expression of pIgR was shown to beupregulated in the HT-29 human intestinal epithelial cellline by bacterial LPS a ligand for TLR4 [156 157] Similarinduction of PIGR gene transcription was seen followingdirect binding of bacteria of the family Enterobacteriaceaewhich express a form of LPS that stimulates TLR4 [158]A recent study from the authorrsquos laboratory demonstratedthat shRNA-mediated knockdown of myeloid differentiationprimary response protein 88 (MyD88) a cytoplasmic adapterprotein that transduces signals from cell surface TLR4blocked the induction of PIGR gene transcription by LPS inHT-29 cells [159] The in vivo significance was confirmed bythe finding that mice with a targeted deletion of the Myd88gene only in intestinal epithelial cells had reduced expressionof pIgR compared to wild-type littermates [159] Mice withtargeted depletion of MyD88 in intestinal epithelial cells alsoexhibited reduced expression of mucin-2 the major compo-nent of the intestinal mucus layer and several antimicrobialpeptides and decreased transmucosal electrical resistanceThese alterations in epithelial barrier function were accom-panied by significant changes in the composition of the fecalmicrobiota increased numbers of bacteria adherent to theintestinal mucus layer and a dramatic increase in transloca-tion of gut bacteria into the drainingmesenteric lymphnodesincluding the opportunistic pathogen Klebsiella pneumoniaeThese findings demonstrate that MyD88-mediated crosstalkbetween the gut microbiota and intestinal epithelial cells iscrucial for optimal expression of pIgR production of SIgAdevelopment of a healthy gut microbiota and maintenanceof intestinal homeostasis

A model can be proposed in which continuous stimu-lation of intestinal epithelial cells by gut bacteria regulates

Lumen

Mucus

Epithelium

Lamina

PIGR

TLRs

MyD88

Bacteria

Plasma cells

propria

Polymeric Ig

Polymeric Ig receptor

Secretory component

Figure 8 Crosstalk between the polymeric immunoglobulin recep-tor secretory immunoglobulins and the gut microbiotaThe single-layered epithelium that lines the gastrointestinal tract is coveredwith a thick mucus layer which physically excludes members ofthe resident microbiota but allows diffusion of shed components ofmicrobial cells Stimulation of epithelial toll-like receptors (TLRs)with microbial products engages the cytoplasmic adaptor proteinMyD88 and initiates NF120581B-dependent signaling pathways Translo-cation of activated NF120581B and other transcription factors to thenucleus enhances transcription of thePIGR gene Activation of TLRsmay also stimulate pIgR transcytosis Polymeric Igs secreted bylamina propria plasma cells bind to pIgRon the basolateral surface ofepithelial cells and are transcytosed to the apical surface along withunoccupied pIgR Proteolytic cleavage of pIgR at the apical surfacereleases secretory SIg and free secretory component (SC) Binding ofSIg and SC to luminal bacteria promotes association with themucuslayer and prevents direct access of bacteria to the epithelial surfaceOver time the continuous crosstalk with SIg shapes the compositionof the gut microbiota Modified from [17] under terms of authorrsquoscopyright with Nature Publishing Group

pIgR expression and transport of SIgA and promotes immuneexclusion of resident and pathogenic bacteria (Figure 8) Adense layer of mucus which increases in thickness fromthe proximal to the distal colon serves to separate bacteriafrom direct contact with the epithelial surface Secretionof microbial-associated molecular patterns (MAMPs) bycommensal bacteria stimulates MyD88-dependent TLR sig-naling leading to enhanced expression of pIgR and antimi-crobial peptides and increased mucus production Bindingof pIgA to pIgR and possibly also signaling via MAMPs

14 ISRN Immunology

enhances transcytosis of pIgA pIgA-containing immunecomplexes and unoccupied pIgR which promotes clearanceof antigens and pathogens from the lamina propria intra-cellular neutralization and release of SIgA and SC at theluminal surface SIgA and SC serve to trap bacteria in themucus layer limiting their access to the epithelial surface Inmice with a targeted deletion of the Muc2 gene which havea severely depleted mucus layer in the colon SIgA and SCfail to associate with the surface of colonic epithelial cells[160] The presence of SIgA in the intestinal lumen whetherderived passively frommaternalmilk or actively via epithelialtranscytosis shapes the composition of the gut microbiotaand modulates intestinal epithelial gene expression

9 Concluding Remarks

The first microbes that emerged on Earth almost 4 billionyears ago encountered a hostile world where nutrients werescarce hazards were everywhere and life was short Withthe evolution of multicellular organisms about 3 billion yearslater a select group ofmicrobes chose to sacrifice an indepen-dent existence for the benefits of a mutualistic relationshipwith eukaryotic hosts Prokaryotic-eukaryotic mutualismreached its apex some 500 million years ago with theemergence of primitive vertebrates whose gastrointestinaltracts were populated by an abundant and diverse commensalmicrobiota In humans the large intestine is home to some100 trillion microorganisms 10 times more than the totalnumber of eukaryotic cells in the entire body The microbesthat inhabit the vertebrate GI tract provide many benefitsto the eukaryotic host including digestion of complex foodmolecules synthesis of vitamins and production of solublefactors that enhance the development of the host immunesystem In return the eukaryotic host provides the microbeswith a warm moist place to live abundant food low oxygentension and a soft bed of mucus on which to form biofilmsWhen this mutually beneficial arrangement is challenged bypathogenicmicrobes the eukaryotic host and the commensalmicrobiota join forces to battle the pathogens and protectthe body from invasion The vertebrate immune system isequipped with a well-trained army of immune cells and asophisticated arsenal of weapons (cell surface molecules andsecreted factors) that protect the host from all but the mostvirulent pathogens This immune ldquoarmyrdquo also serves as aconstant reminder to the commensal microbes that whilethey are free to enjoy the amenities of the mucosal surfacesthey are not welcome in the body proper The emergence ofantigen-specific Igs and T-cell receptors in jawed vertebratesbegan a process of immunological diversification that led tothe development of a specialized mucosal immune systemin higher vertebrates in which secretory Igs play a centralrole The relationship between host and microbiota is clearlyreciprocal the mucosal Igs that evolved in response toselective pressure from the commensal microbiota play acentral role throughout life in shaping the compositiongenetics andmetabolic activity of themicrobiota [1 161 162]

The epithelial layer lining mucosal surfaces provides aphysical and innate immune barrier against penetration of

the body proper by microbes undigested food antigens andpotentially noxious environmental substances The evolu-tionary challenge of transporting mucosal Igs into externalsecretions without compromising the epithelial barrier wasmet by the emergence of the PIGR gene in an ancestor ofbony fishes encoding an epithelial-specific transmembraneprotein that actively transports polymeric Igs across mucosaland glandular epithelia (Figure 4) Structural similaritiesbetween Igs and the extracellular Ig-binding domains of pIgR(Figure 6) suggest that duplication and diversification of agene encoding primordial Ig-like domain may have givenrise to the PIGR gene in a primitive vertebrate ancestorParallel refinement of the structures of mucosal Igs andpIgR during tetrapod evolution (Figures 6 and 7) culminatedin the evolution of the multifunctional SIgA molecule inmammals in which the pIgR-derived SC subunit providesinnate immune functions and protects the antigen-bindingIgA polymer from proteolytic degradation In addition toacting as a powerful force during vertebrate evolution thereciprocal relationship between pIgR mucosal Igs and thecommensal microbiota provides benefits throughout thelife of the individual Microbial colonization of newbornvertebrates stimulates development of mucosal B cells andclass switching to mucosal Ig isotypes [1 163] Microbialfactors upregulate expression of pIgR enhancing transportof mucosal Igs into external secretions where they in turnregulate the microbiotaThis beautifully orchestrated processallows us to maintain a healthy relationship with our resi-dent microbiota while providing mutual protection againstpathogens

Conflict of Interests

The author declares that there is no conflict of interestsregarding the publication of this paper

Acknowledgments

This work was supported by Grant no AI069027 from theNational Institutes of Health of the United States of America(and an associatedAmerican Recovery andReinvestmentActsupplement) and a Senior Research Award from the Crohnrsquosand Colitis Foundation of America

References

[1] C L Maynard C O Elson R D Hatton and C T WeaverldquoReciprocal interactions of the intestinal microbiota andimmune systemrdquo Nature vol 489 no 7415 pp 231ndash241 2012

[2] M F Flajnik and M Kasahara ldquoOrigin and evolution of theadaptive immune system genetic events and selective pres-suresrdquo Nature Reviews Genetics vol 11 no 1 pp 47ndash59 2010

[3] M F Flajnik and L du Pasquier ldquoEvolution of the immunesystemrdquo in Fundamental Immunology W E Paul Ed chapter4 pp 67ndash128 Lippincott Williams ampWilkins Philadelphia PaUSA 2012

[4] M Hirano S Das P Guo and M D Cooper ldquoThe evolutionof adaptive immunity in vertebratesrdquo Advances in Immunologyvol 109 pp 125ndash157 2011

ISRN Immunology 15

[5] T BoehmNMcCurley Y SutohM SchorppMKasahara andM D Cooper ldquoVLR-based adaptive immunityrdquo Annual Reviewof Immunology vol 30 pp 203ndash220 2012

[6] T Hunkapiller and L Hood ldquoImmunology the growing immu-noglobulin gene superfamilyrdquoNature vol 323 no 6083 pp 15ndash16 1986

[7] P Bork L Holm and C Sander ldquoThe immunoglobulin foldstructural classification sequence patterns and common corerdquoJournal of Molecular Biology vol 242 no 4 pp 309ndash320 1994

[8] C S Kaetzel and M W Russell ldquoPhylogeny and comparativephysiology of IgArdquo in Mucosal Immunology J Mestecky WStrober H Cheroutre B Kelsall B N Lambrecht and M WRussell Eds chapter 19 Academic PressElsevier WalthamMass USA 2014

[9] Y He and P J Bjorkman ldquoStructure of FcRY an avian immu-noglobulin receptor related to mammalian mannose receptorsand its complex with IgYrdquo Proceedings of the National Academyof Sciences of the United States of America vol 108 no 30 pp12431ndash12436 2011

[10] J M Woof and D R Burton ldquoHuman antibody-Fc receptorinteractions illuminated by crystal structuresrdquo Nature ReviewsImmunology vol 4 no 2 pp 89ndash99 2004

[11] W L Martin A P West Jr L Gan and P J Bjorkman ldquoCrystalstructure at 28 A of an FcRnheterodimeric Fc complexmechanism of pH-dependent bindingrdquo Molecular Cell vol 7no 4 pp 867ndash877 2001

[12] E S Ward ldquoAcquiring maternal immunoglobulin differentreceptors similar functionsrdquo Immunity vol 20 no 5 pp 507ndash508 2004

[13] C S Kaetzel ldquoThe polymeric immunoglobulin receptor bridg-ing innate and adaptive immune responses atmucosal surfacesrdquoImmunological Reviews vol 206 no 1 pp 83ndash99 2005

[14] M Acharya G Borland A L Edkins et al ldquoCD23Fc120576RIImolecular multi-taskingrdquo Clinical and Experimental Immunol-ogy vol 162 no 1 pp 12ndash23 2010

[15] V B Klimovich ldquoIgM and its receptors structural and func-tional aspectsrdquo Biochemistry vol 76 no 5 pp 534ndash549 2011

[16] J MWoof andMW Russell ldquoStructure and function relation-ships in IgArdquo Mucosal Immunology vol 4 no 6 pp 590ndash5972011

[17] F-E Johansen and C S Kaetzel ldquoRegulation of the polymericimmunoglobulin receptor and IgA transport new advances inenvironmental factors that stimulate pIgR expression and itsrole in mucosal immunityrdquo Mucosal Immunology vol 4 no 6pp 598ndash602 2011

[18] F Kokubu K Hinds R Litman M J Shamblott and G WLitman ldquoExtensive families of constant region genes in a phy-logenetically primitive vertebrate indicate an additional levelof immunoglobulin complexityrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 84 no16 pp 5868ndash5872 1987

[19] A S Greenberg A L Hughes J Guo D Avila E CMcKinneyand M F Flajnik ldquoA novel ldquochimericrdquo antibody class in carti-laginous fish IgMmay not be the primordial immunoglobulinrdquoEuropean Journal of Immunology vol 26 no 5 pp 1123ndash11291996

[20] H Dooley and M F Flajnik ldquoShark immunity bites back affin-ity maturation and memory response in the nurse shark Ging-lymostoma cirratumrdquo European Journal of Immunology vol 35no 3 pp 936ndash945 2005

[21] S F Schluter R M Bernstein and J J Marchalonis ldquoMolecularorigins and evolution of immunoglobulin heavy-chain genes ofjawed vertebratesrdquo Immunology Today vol 18 no 11 pp 543ndash549 1997

[22] Y Ohta and M Flajnik ldquoIgD like IgM is a primordial immu-noglobulin class perpetuated in most jawed vertebratesrdquo Pro-ceedings of the National Academy of Sciences of the United Statesof America vol 103 no 28 pp 10723ndash10728 2006

[23] S Fillatreau A Six S Magadan R Castro J O Sunyer andP Boudinot ldquoThe astonishing diversity of Ig classes and B cellrepertoires in teleost fishrdquo Frontiers in Immunology vol 4 no28 2013

[24] W Harriman H Volk N Defranoux and M Wabl ldquoImmu-noglobulin class switch recombinationrdquo Annual Review ofImmunology vol 11 pp 361ndash384 1993

[25] J Stavnezer and C T Amemiya ldquoEvolution of isotype switch-ingrdquo Seminars in Immunology vol 16 no 4 pp 257ndash275 2004

[26] V M Barreto Q Pan-Hammarstrom Y Zhao L Ham-marstrom Z Misulovin and M C Nussenzweig ldquoAID frombony fish catalyzes class switch recombinationrdquo Journal ofExperimental Medicine vol 202 no 6 pp 733ndash738 2005

[27] T C Fletcher and AWhite ldquoAntibody production in the plaice(Pleuronectes platessa L) after oral and parenteral immuniza-tion with Vibrio anguillarum antigensrdquo Aquaculture vol 1 pp417ndash428 1972

[28] J W H M Rombout L J Blok C H J Lamers and E EgbertsldquoImmunization of carp (Cyprinus carpio) with a Vibrio anguil-larum bacterin indications for a common mucosal immunesystemrdquo Developmental and Comparative Immunology vol 10no 3 pp 341ndash351 1986

[29] U Georgopoulou and J-M Vernier ldquoLocal immunologicalresponse in the posterior intestinal segment of the rainbowtrout after oral administration of macromoleculesrdquo Develop-mental andComparative Immunology vol 10 no 4 pp 529ndash5371986

[30] C J Lobb ldquoSecretory immunity induced in catfish Ictaluruspunctatus following bath immunizationrdquo Developmental andComparative Immunology vol 11 no 4 pp 727ndash738 1987

[31] J D Hansen E D Landis and R B Phillips ldquoDiscovery ofa unique Ig heavy-chain (IgT) in rainbow trout implicationsfor a distinctive B cell developmental pathway in teleost fishrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 102 no 19 pp 6919ndash6924 2005

[32] N Danilova J Bussmann K Jekosch and L A Steiner ldquoTheimmunoglobulin heavy-chain locus in zebrafish identificationand expression of a previously unknown isotype immunoglob-ulin Zrdquo Nature Immunology vol 6 no 3 pp 295ndash302 2005

[33] R Savan A Aman K Sato R Yamaguchi and M Sakai ldquoDis-covery of a new class of immunoglobulin heavy chain fromfugurdquo European Journal of Immunology vol 35 no 11 pp 3320ndash3331 2005

[34] R Savan A AmanMNakao HWatanuki andM Sakai ldquoDis-covery of a novel immunoglobulin heavy chain gene chimerafrom common carp (Cyprinus carpio L)rdquo Immunogenetics vol57 no 6 pp 458ndash463 2005

[35] F Gambon-Deza C Sanchez-Espinel and S Magadan-Mompo ldquoPresence of an unique IgT on the IGH locus in three-spined stickleback fish (Gasterosteus aculeatus) and the veryrecent generation of a repertoire of VH genesrdquo Developmentaland Comparative Immunology vol 34 no 2 pp 114ndash122 2010

[36] T M Tadiso K K Lie and I Hordvik ldquoMolecular cloning ofIgT fromAtlantic salmon and analysis of the relative expression

16 ISRN Immunology

of 120591 120583 and 120575 in different tissuesrdquo Veterinary Immunology andImmunopathology vol 139 no 1 pp 17ndash26 2011

[37] S Mashoof C Pohlenz P L Chen et al ldquoExpressed IgH 120583and 120591 transcripts share diversity segment in ranched Thunnusorientalisrdquo Developmental and Comparative Immunology vol43 no 1 pp 76ndash86 2014

[38] Y-A Zhang I Salinas J Li et al ldquoIgT a primitive immunoglob-ulin class specialized in mucosal immunityrdquo Nature Immunol-ogy vol 11 no 9 pp 827ndash835 2010

[39] S Magadan-Mompo C Sanchez-Espinel and F Gambon-Deza ldquoImmunoglobulin heavy chains in medaka (Oryziaslatipes)rdquo BMC Evolutionary Biology vol 11 no 1 article 1652011

[40] C T Amemiya J Alfoldi A P Lee et al ldquoThe African coela-canth genome provides insights into tetrapod evolutionrdquoNature vol 496 no 7445 pp 311ndash316 2013

[41] T Ota J P Rast G W Litman and C T Amemiya ldquoLineage-restricted retention of a primitive immunoglobulin heavy chainisotype within the Dipnoi reveals an evolutionary paradoxrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 100 no 5 pp 2501ndash2506 2003

[42] Y Sun Z Wei N Li and Y Zhao ldquoA comparative overview ofimmunoglobulin genes and the generation of their diversity intetrapodsrdquo Developmental and Comparative Immunology vol39 no 1-2 pp 103ndash109 2013

[43] I Hadji-Azimi ldquoAnuran immunoglobulins a reviewrdquo Develop-mental and Comparative Immunology vol 3 no 2 pp 223ndash2431979

[44] E Hsu M F Flajnik and L du Pasquier ldquoA third immunoglob-ulin class in amphibiansrdquo The Journal of Immunology vol 135no 3 pp 1998ndash2004 1985

[45] C T Amemiya R N Haire and G W Litman ldquoNucleotidesequence of a cDNA encoding a third distinct Xenopusimmunoglobulin heavy chain isotyperdquo Nucleic Acids Researchvol 17 no 13 p 5388 1989

[46] R Muszligmann M Wilson A Marcuz M Courtet and L duPasquier ldquoMembrane exon sequences of the three Xenopus Igclasses explain the evolutionary origin of mammalian isotypesrdquoEuropean Journal of Immunology vol 26 no 2 pp 409ndash4141996

[47] R Muszligmann L du Pasquier and E Hsu ldquoIs Xenopus IgX ananalog of IgArdquo European Journal of Immunology vol 26 no12 pp 2823ndash2830 1996

[48] B Schaerlinger and J-P Frippiat ldquoIgX antibodies in the urodeleamphibian Ambystoma mexicanumrdquo Developmental and Com-parative Immunology vol 32 no 8 pp 908ndash915 2008

[49] B Schaerlinger M Bascove and J-P Frippiat ldquoA new isotypeof immunoglobulin heavy chain in the urodele amphibianPleurodeles waltl predominantly expressed in larvaerdquoMolecularImmunology vol 45 no 3 pp 776ndash786 2008

[50] S Mashoof A Goodroe C C Du et al ldquoAncient T-independence of mucosal IgXA gut microbiota unaffected bylarval thymectomy in Xenopus laevisrdquo Mucosal Immunologyvol 6 no 2 pp 358ndash368 2013

[51] J P Vaerman J Picard and J F Heremans ldquoStructural dataon chicken IgA and failure to identify the IgA of the tortoiserdquoin Immunologic Phylogeny vol 64 of Advances in ExperimentalMedicine and Biology pp 185ndash195 Springer New York NYUSA 1975

[52] J L Portis and J E Coe ldquoIgM the secretory immunoglobulinof reptiles and amphibiansrdquo Nature vol 258 no 5535 pp 547ndash548 1975

[53] J E Coe D Leong J L Portis and L A Thomas ldquoImmuneresponse in the garter snake (Thamnophis ordinoides)rdquo Immu-nology vol 31 no 3 pp 417ndash424 1976

[54] D Hadge and H Ambrosius ldquoEvolution of low molecularweight immunoglobulinsmdashIV IgY-like immunoglobulins ofbirds reptiles and amphibians precursors of mammalian IgArdquoMolecular Immunology vol 21 no 8 pp 699ndash707 1984

[55] D Hadge and H Ambrosius ldquoEvolution of low molecularweight immunoglobulins V Degree of antigenic relationshipbetween the 7S immunoglobulins ofmammals birds and lowervertebrates to the turkey IgYrdquo Developmental and ComparativeImmunology vol 10 no 3 pp 377ndash385 1986

[56] S Magadan-Mompo C Sanchez-Espinel and F Gambon-Deza ldquoImmunoglobulin genes of the turtlesrdquo Immunogeneticsvol 65 no 3 pp 227ndash237 2013

[57] Z Wei Q Wu L Ren et al ldquoExpression of IgM IgD and IgYin a reptile Anolis carolinensisrdquoThe Journal of Immunology vol183 no 6 pp 3858ndash3864 2009

[58] F Gambon-Deza C Sanchez-Espinel and J V Beneitez ldquoAnovel IgA-like immunoglobulin in the reptile Eublepharis mac-ulariusrdquo Developmental and Comparative Immunology vol 31no 6 pp 596ndash605 2007

[59] G Cheng Y Gao T Wang et al ldquoExtensive diversification ofIgH subclass-encoding genes and IgM subclass switching incrocodiliansrdquo Nature Communications vol 4 article 1337 2013

[60] S Magadan-Mompo C Sanchez-Espinel and F Gambon-Deza ldquoIgH loci of American alligator and saltwater crocodileshed light on IgA evolutionrdquo Immunogenetics vol 65 no 7 pp531ndash541 2013

[61] E Orlans and M E Rose ldquoAn IgA-like immunoglobulin in thefowlrdquo Immunochemistry vol 9 no 8 pp 833ndash838 1972

[62] G A Leslie and L N Martin ldquoStudies on the secretory immu-nologic system of fowl 3 Serum and secretory IgA of thechickenrdquoThe Journal of Immunology vol 110 no 1 pp 1ndash9 1973

[63] J Bienenstock D Y Perey J Gauldie and B J UnderdownldquoChicken 120574A physicochemical and immunochemical charac-teristicsrdquoThe Journal of Immunology vol 110 no 2 pp 524ndash5331973

[64] A M Lebacq-Verheyden J P Vaerman and J F HeremansldquoQuantification and distribution of chicken immunoglobulinsIgA IgM and IgG in serum and secretionsrdquo Immunology vol27 no 4 pp 683ndash692 1974

[65] J Goudswaard A Noordzij R H van Dam J A vanderDonk and J P Vaerman ldquoThe immunoglobulins of the turkey(Meleagris gallopavo) Isolation and characterization of IgGIgM and IgA in body fluids eggs and intraocular tissuesrdquoPoultry science vol 56 no 6 pp 1847ndash1851 1977

[66] D Hadge and H Ambrosius ldquoComparative studies on thestructure of biliary immunoglobulins of some avian speciesII Antigenic properties of the biliary immunoglobulins ofchicken turkey duck and gooserdquo Developmental and Compar-ative Immunology vol 12 no 2 pp 319ndash329 1988

[67] J Goudswaard J P Vaerman and J F Heremans ldquoThreeimmunoglobulin classes in the pigeon (Columbia livia)rdquo Inter-national Archives of Allergy andApplied Immunology vol 53 no5 pp 409ndash419 1977

[68] P L K Ng and D A Higgins ldquoBile immunoglobulin of theduck (Anas platyrhynchos) I Preliminary characterization andontogenyrdquo Immunology vol 58 no 2 pp 323ndash327 1986

[69] K E Magor G W Warr Y Bando D L Middleton and DA Higgins ldquoSecretory immune system of the duck (Anas

ISRN Immunology 17

platyrhynchos) Identification and expression of the genesencoding IgA and IgM heavy chainsrdquo European Journal ofImmunology vol 28 no 3 pp 1063ndash1068 1998

[70] Y Zhao H Rabbani A Shimizu and L Hammarstrom ldquoMap-ping of the chicken immunoglobulin heavy-chain constantregion gene locus reveals an inverted 120572 gene upstream of acondensed 120592 generdquo Immunology vol 101 no 3 pp 348ndash3532000

[71] M L Lundqvist D L Middleton S Hazard and G W WarrldquoThe immunoglobulin heavy chain locus of the duck genomicorganization and expression of D J and C region genesrdquo TheJournal of Biological Chemistry vol 276 no 50 pp 46729ndash46736 2001

[72] T HuangM Zhang ZWei et al ldquoAnalysis of immunoglobulintranscripts in the ostrich Struthio camelus a primitive avianspeciesrdquo PLoS ONE vol 7 no 3 Article ID e34346 2012

[73] K H Roux ldquoImmunoglobulin structure and function asrevealed by electron microscopyrdquo International Archives ofAllergy and Immunology vol 120 no 2 pp 85ndash99 1999

[74] F Gambon-Deza C Sanchez-Espinel and S Magadan-Mompo ldquoThe immunoglobulin heavy chain locus in the platy-pus (Ornithorhynchus anatinus)rdquo Molecular Immunology vol46 no 13 pp 2515ndash2523 2009

[75] Y Zhao H Cui C M Whittington et al ldquoOrnithorhynchusanatinus (platypus) links the evolution of immunoglobulingenes in eutherian mammals and nonmammalian tetrapodsrdquoThe Journal of Immunology vol 183 no 5 pp 3285ndash3293 2009

[76] M Aveskogh and L Hellman ldquoEvidence for an early appear-ance of modern post-switch isotypes in mammalian evolutioncloning of IgE IgG and IgA from the marsupial Monodelphisdomesticardquo European Journal of Immunology vol 28 no 9 pp2738ndash2750 1998

[77] K Belov G A Harrison and DW Cooper ldquoMolecular cloningof the cDNA encoding the constant region of the immunoglob-ulin a heavy chain (C120572) from amarsupialTrichosurus vulpecula(common brushtail possum)rdquo Immunology Letters vol 60 no2-3 pp 165ndash170 1998

[78] K Belov K R Zenger L Hellman and DW Cooper ldquoEchidnaIgA supports mammalian unity and traditional Therian rela-tionshiprdquo Mammalian Genome vol 13 no 11 pp 656ndash6632002

[79] K Belov and L Hellman ldquoImmunoglobulin genetics of Orni-thorhynchus anatinus (platypus) and Tachyglossus aculeatus(short-beaked echidna)rdquo Comparative Biochemistry and Phys-iology vol 136 no 4 pp 811ndash819 2003

[80] M VernerssonM Aveskogh BMunday and L Hellman ldquoEvi-dence for an early appearance of modern post-switch immu-noglobulin isotypes in mammalian evolution (II) cloning ofIgE IgG1 and IgG2 fromamonotreme the duck-billed platypusOrnithorhynchus anatinusrdquo European Journal of Immunologyvol 32 no 8 pp 2145ndash2155 2002

[81] C Auffray R Nageotte and J L Sikorav ldquoMouse immunoglob-ulin A nucleotide sequence of the structural gene for the 120572heavy chain derived from cloned cDNAsrdquo Gene vol 13 no 4pp 365ndash374 1981

[82] T Ukaji D Sumiyama and O Kai ldquoSequence determinationof the heavy-chain constant region in four immunoglobulinclasses of Mongolian gerbils (Meriones unguiculatus)rdquo Experi-mental Animals vol 61 no 2 pp 99ndash107 2012

[83] R C Burnett W C Hanly S K Zhai and K L Knight ldquoTheIgA heavy chain gene family in rabbit cloning and sequence

analysis of 13 C120572 genesrdquo The EMBO Journal vol 8 no 13 pp4041ndash4047 1989

[84] D K Lanning S-K Zhai and K L Knight ldquoAnalysis of the 31015840C120583 region of the rabbit Ig heavy chain locusrdquoGene vol 309 no2 pp 135ndash144 2003

[85] F Ros J Puels N Reichenberger W van Schooten R Buelowand J Platzer ldquoSequence analysis of 05Mb of the rabbitgermline immunoglobulin heavy chain locusrdquo Gene vol 330no 1-2 pp 49ndash59 2004

[86] M Patel D Selinger G E Mark G J Hickey and G FHollis ldquoSequence of the dog immunoglobulin alpha and epsilonconstant region genesrdquo Immunogenetics vol 41 no 5 pp 282ndash286 1995

[87] Z Zhao Y Zhao Q Pan-Hammarstrom et al ldquoPhysical map-ping of the giant panda immunoglobulin heavy chain constantregion genesrdquo Developmental and Comparative Immunologyvol 31 no 10 pp 1034ndash1049 2007

[88] W R Brown and J E Butler ldquoCharacterization of a C120572 gene ofswinerdquoMolecular Immunology vol 31 no 8 pp 633ndash642 1994

[89] W R Brown H Rabbani J E Butler and L HammarstromldquoCharacterization of the bovine C120572 generdquo Immunology vol 91no 1 pp 1ndash6 1997

[90] G PWhite P Roche M R Brandon S E Newton and E N TMeeusen ldquoCloning and characterization of sheep (Ovis aries)immunoglobulin 120572 chainrdquo Immunogenetics vol 48 no 5 pp359ndash362 1998

[91] AMancia T A Romano H A Gefroh et al ldquoCharacterizationof the immunoglobulin A heavy chain gene of the Atlantic bot-tlenose dolphin (Tursiops truncatus)rdquo Veterinary Immunologyand Immunopathology vol 118 no 3-4 pp 304ndash309 2007

[92] B Wagner I Greiser-Wilke and D F Antczak ldquoCharacteriza-tion of the horse [Equus caballus] IGHA generdquo Immunogeneticsvol 55 no 8 pp 552ndash560 2003

[93] N Takahashi S Ueda and M Obata ldquoStructure of humanimmunoglobulin gamma genes implications for evolution of agene familyrdquo Cell vol 29 no 2 pp 671ndash679 1982

[94] J G Flanagan M-P Lefranc and T H Rabbitts ldquoMechanismsof divergence and convergence of the human immunoglobulin1205721 and 1205722 constant region gene sequencesrdquo Cell vol 36 no 3pp 681ndash688 1984

[95] S Kawamura K Omoto and S Ueda ldquoEvolutionary hypervari-ability in the hinge region of the immunoglobulin alpha generdquoJournal of Molecular Biology vol 215 no 2 pp 201ndash206 1990

[96] F Scinicariello F Masseoud L Jayashankar and R AttanasioldquoSooty mangabey (Cercocebus torquatus atys) IGHG and IGHAgenesrdquo Immunogenetics vol 58 no 12 pp 955ndash965 2006

[97] K A Rogers L Jayashankar F Scinicariello and R AttanasioldquoNonhuman primate IgA genetic heterogeneity and interac-tions with CD89rdquoThe Journal of Immunology vol 180 no 7 pp4816ndash4824 2008

[98] S Kawamura N Saitou and S Ueda ldquoConcerted evolution ofthe primate immunoglobulin 120572-gene through gene conversionrdquoThe Journal of Biological Chemistry vol 267 no 11 pp 7359ndash7367 1992

[99] S Kawamura and S Ueda ldquoImmunoglobulin C119867gene family in

hominoids and its evolutionary historyrdquo Genomics vol 13 no1 pp 194ndash200 1992

[100] A Brusco U Cariota A Bottaro et al ldquoStructural andimmunologic analysis of gene triplications in the Ig heavy chainconstant region locusrdquoThe Journal of Immunology vol 152 no1 pp 129ndash135 1994

18 ISRN Immunology

[101] H Rabbani Q Pan N Kondo C I E Smith and L Ham-marstrom ldquoDuplications and deletions of the human IGHClocus evolutionary implicationsrdquo Immunogenetics vol 45 no2 pp 136ndash141 1996

[102] P F Weinheimer J Mestecky and R T Acton ldquoSpecies distri-bution of J chainrdquoThe Journal of Immunology vol 107 no 4 pp1211ndash1212 1971

[103] F P Inman and J Mestecky ldquoThe J chain of polymeric immu-noglobulinsrdquo inContemporary Topics inMolecular Immunologyvol 3 pp 111ndash141 Springer New York NY USA 1974

[104] P Brandtzaeg ldquoPresence of J chain in human immunocytescontaining various immunoglobulin classesrdquo Nature vol 252no 5482 pp 418ndash420 1974

[105] L Tacchi E Larragoite and I Salinas ldquoDiscovery of J chain inAfrican lungfish (Protopterus dolloi Sarcopterygii) using highthroughput transcriptome sequencing implications in mucosalimmunityrdquo PLoS ONE vol 8 no 8 Article ID e70650 2013

[106] I K Zarkadis D Mastellos and J D Lambris ldquoPhylogeneticaspects of the complement systemrdquo Developmental and Com-parative Immunology vol 25 no 8-9 pp 745ndash762 2001

[107] A P West Jr A B Herr and P J Bjorkman ldquoThe chickenyolk sac IgY receptor a functional equivalent of themammalianMHC-related Fc receptor is a phospholipase A

2receptor

homologrdquo Immunity vol 20 no 5 pp 601ndash610 2004[108] D B Tesar E J Cheung and P J Bjorkman ldquoThe chicken

yolk sac IgY receptor a mammalian mannose receptor familymember transcytoses IgY across polarized epithelial cellsrdquoMolecular Biology of the Cell vol 19 no 4 pp 1587ndash1593 2008

[109] A I Taylor R L Beavil B J Sutton and R A Calvert ldquoAmonomeric chicken IgY receptor binds IgY with 21 stoichiom-etryrdquo The Journal of Biological Chemistry vol 284 no 36 pp24168ndash24175 2009

[110] K Baker S-W Qiao T Kuo et al ldquoImmune and non-immunefunctions of the (not so) neonatal Fc receptor FcRnrdquo Seminarsin Immunopathology vol 31 no 2 pp 223ndash236 2009

[111] K Baker R S Blumberg and C S Kaetzel ldquoImmunoglob-ulin transport and immunoglobulin receptorsrdquo in MucosalImmunology J Mestecky W Strober H Cheroutre B KelsallB N Lambrecht andMW Russell Eds chapter 20 AcademicPressElsevier Waltham Mass USA 2014

[112] C S Kaetzel ldquoThepolymeric immunoglobulin receptorrdquo in eLSJohn Wiley amp Sons Chichester UK 2013

[113] N J Mantis N Rol and B Corthesy ldquoSecretory IgArsquos complexroles in immunity andmucosal homeostasis in the gutrdquoMucosalImmunology vol 4 no 6 pp 603ndash611 2011

[114] J V Peppard M E Rose and P Hesketh ldquoA functional homo-logue of mammalian secretory component exists in chickensrdquoEuropean Journal of Immunology vol 13 no 7 pp 566ndash5701983

[115] K E Mostov M Friedlander and G Blobel ldquoThe receptorfor transepithelial transport of IgA and IgM contains multipleimmunoglobulin-like domainsrdquo Nature vol 308 no 5954 pp37ndash43 1984

[116] P Krajci R Solberg M Sandberg O Oyen T Jahnsen and PBrandtzaeg ldquoMolecular cloning of the human transmembranesecretory component (poly-Ig receptor) and its mRNA expres-sion in human tissuesrdquo Biochemical and Biophysical ResearchCommunications vol 158 no 3 pp 783ndash789 1989

[117] P Krajci D Kvale K Tasken and P Brandtzaeg ldquoMolecularcloning and exon-intron mapping of the gene encoding humantransmembrane secretory component (the poly-Ig receptor)rdquo

European Journal of Immunology vol 22 no 9 pp 2309ndash23151992

[118] J F Piskurich J A France C M Tamer C A Willmer CS Kaetzel and D M Kaetzel ldquoInterferon-120574 induces polymericimmunoglobulin receptormRNA in human intestinal epithelialcells by a protein synthesis dependent mechanismrdquo MolecularImmunology vol 30 no 4 pp 413ndash421 1993

[119] J F Piskurich M H Blanchard K R Youngman J A Franceand C S Kaetzel ldquoMolecular cloning of the mouse polymericIg receptor functional regions of the molecule are conservedamong five mammalian speciesrdquo The Journal of Immunologyvol 154 no 4 pp 1735ndash1747 1995

[120] M A Kulseth P Krajci O Myklebost and S RogneldquoCloning and characterization of two forms of bovine polymericimmunoglobulin receptor cDNArdquo DNA and Cell Biology vol14 no 3 pp 251ndash256 1995

[121] K S Koch A S Gleiberman T Aoki et al ldquoDiscordant expres-sion and variable numbers of neighboring GGA- and GAA-richtriplet repeats in the 31015840 untranslated regions of two groups ofmessenger RNAs encoded by the rat polymeric immunoglob-ulin receptor generdquo Nucleic Acids Research vol 23 no 7 pp1098ndash1112 1995

[122] F M Adamski and J Demmer ldquoTwo stages of increased IgAtransfer during lactation in themarsupialTrichosurus vulpecula(brushtail possum)rdquoThe Journal of Immunology vol 162 no 10pp 6009ndash6015 1999

[123] H Kumura T Sone K-I Shimazaki and E KobayashildquoSequence analysis of porcine polymeric immunoglobulinreceptor from mammary epithelial cells present in colostrumrdquoThe Journal of Dairy Research vol 67 no 4 pp 631ndash636 2000

[124] C L Taylor G A Harrison C M Watson and E M DeaneldquocDNA cloning of the polymeric immunoglobulin receptor ofthe marsupial Macropus eugenii (tammar wallaby)rdquo EuropeanJournal of Immunogenetics vol 29 no 2 pp 87ndash93 2002

[125] R Braathen V S Hohman P Brandtzaeg and F-E JohansenldquoSecretory antibody formation conserved binding interactionsbetween J chain and polymeric Ig receptor from humans andamphibiansrdquo The Journal of Immunology vol 178 no 3 pp1589ndash1597 2007

[126] M J Lewis BWagner R M Irvine and J MWoof ldquoIgA in thehorse cloning of equine polymeric Ig receptor and J chain andcharacterization of recombinant forms of equine IgArdquoMucosalImmunology vol 3 no 6 pp 610ndash621 2010

[127] A J Leon D Banner L Xu et al ldquoSequencing annotation andcharacterization of the influenza ferret infectomerdquo Journal ofVirology vol 87 no 4 pp 1957ndash1966 2013

[128] W H Wieland D Orzaez A Lammers H K ParmentierM W A Verstegen and A Schots ldquoA functional polymericimmunoglobulin receptor in chicken (Gallus gallus) indicatesancient role of secretory IgA inmucosal immunityrdquoBiochemicalJournal vol 380 no 3 pp 669ndash676 2004

[129] K Hamuro H Suetake N R Saha K Kikuchi and YSuzuki ldquoA teleost polymeric Ig receptor exhibiting two Ig-likedomains transports tetrameric IgM into the skinrdquo The Journalof Immunology vol 178 no 9 pp 5682ndash5689 2007

[130] J H W M Rombout S J L van der Tuin G Yang et alldquoExpression of the polymeric immunoglobulin receptor (pIgR)in mucosal tissues of common carp (Cyprinus carpio L)rdquo Fishand Shellfish Immunology vol 24 no 5 pp 620ndash628 2008

[131] L-N Feng D-Q Lu J-X Bei et al ldquoMolecular cloning andfunctional analysis of polymeric immunoglobulin receptor gene

ISRN Immunology 19

in orange-spotted grouper (Epinephelus coioides)rdquo ComparativeBiochemistry and Physiology B vol 154 no 3 pp 282ndash289 2009

[132] A E Oslashstergaard S A M Martin T Wang R J M Stet andC J Secombes ldquoRainbow trout (Oncorhynchus mykiss) pos-sessmultiple novel immunoglobulin-like transcripts containingeither an ITAM or ITIMsrdquo Developmental and ComparativeImmunology vol 33 no 4 pp 525ndash532 2009

[133] H Eiffert E Quentin and J Decker ldquoThe primary structureof the human free secretory component and the arrangementof disulfide bondsrdquo Hoppe-Seylerrsquos Zeitschrift fur PhysiologischeChemie vol 365 no 12 pp 1489ndash1495 1984

[134] E Fallgreen-Gebauer W Gebauer A Bastian et al ldquoThe cova-lent linkage of secretory component to IgA Structure of sIgArdquoBiological Chemistry Hoppe-Seyler vol 374 no 11 pp 1023ndash1028 1993

[135] J MWoof ldquoThe structure of IgArdquo inMucosal Immune DefenseImmunoglobulin A C S Kaetzel Ed chapter 1 pp 1ndash24Springer New York NY USA 2007

[136] A Bonner A Almogren P B Furtado M A Kerr and S JPerkins ldquoLocation of secretory component on the Fc edge ofdimeric IgA1 reveals insight into the role of secretory IgA1 inmucosal immunityrdquoMucosal Immunology vol 2 no 1 pp 74ndash84 2009

[137] A Bonner A Almogren P B Furtado M A Kerr and S JPerkins ldquoThe nonplanar secretory IgA2 and near planar secre-tory IgA1 solution structures rationalize their different mucosalimmune responsesrdquo The Journal of Biological Chemistry vol284 no 8 pp 5077ndash5087 2009

[138] J Johansen B Braathen and P Brandtzaeg ldquoRole of J chain insecretory immunoglobulin formationrdquo Scandinavian Journal ofImmunology vol 52 no 3 pp 240ndash248 2000

[139] B A Hendrickson D A Conner D J Ladd et al ldquoAlteredhepatic transport of immunoglobulin A in mice lacking the Jchainrdquo Journal of Experimental Medicine vol 182 no 6 pp1905ndash1911 1995

[140] B A Hendrickson L Rindisbacher B Corthesy et al ldquoLackof association of secretory component with IgA in J chain-deficient micerdquo The Journal of Immunology vol 157 no 2 pp750ndash754 1996

[141] N Lycke L Erlandsson L Ekman K Schon and T Lean-derson ldquoLack of J chain inhibits the transport of gut IgA andabrogates the development of intestinal antitoxic protectionrdquoThe Journal of Immunology vol 163 no 2 pp 913ndash919 1999

[142] F-E Johansen R Braathen and P Brandtzaeg ldquoThe J chainis essential for polymeric Ig receptor-mediated epithelial trans-port of IgArdquoThe Journal of Immunology vol 167 no 9 pp 5185ndash5192 2001

[143] R E Ley D A Peterson and J I Gordon ldquoEcological andevolutionary forces shaping microbial diversity in the humanintestinerdquo Cell vol 124 no 4 pp 837ndash848 2006

[144] M McFall-Ngai ldquoAdaptive immunity care for the communityrdquoNature vol 445 no 7124 p 153 2007

[145] A J Macpherson K D McCoy F-E Johansen and PBrandtzaeg ldquoThe immune geography of IgA induction andfunctionrdquoMucosal Immunology vol 1 no 1 pp 11ndash22 2008

[146] D Kvale and P Brandtzaeg ldquoConstitutive and cytokine inducedexpression of HLA molecules secretory component and inter-cellular adhesion molecule-1 is modulated by butyrate in thecolonic epithelial cell line HT-29rdquo Gut vol 36 no 5 pp 737ndash742 1995

[147] L VHooperMHWong AThelin L Hansson P G Falk andJ I Gordon ldquoMolecular analysis of commensal host-microbialrelationships in the intestinerdquo Science vol 291 no 5505 pp 881ndash884 2001

[148] S Hapfelmeier M A E Lawson E Slack et al ldquoReversiblemicrobial colonization of germ-free mice reveals the dynamicsof IgA immune responsesrdquo Science vol 328 no 5986 pp 1705ndash1709 2010

[149] DH ReikvamMDerrien R Islam et al ldquoEpithelial-microbialcross-talk in polymeric Ig receptor deficient micerdquo EuropeanJournal of Immunology vol 42 no 11 pp 2959ndash2970 2012

[150] EW Rogier A L Frantz M E C Bruno et al ldquoSecretory anti-bodies in breast milk promote long-term intestinal homeostasisby regulating the gut microbiota and host gene expressionrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 111 no 8 pp 3074ndash3079 2014

[151] G M Barton and R Medzhitov ldquoToll-like receptor signalingpathwaysrdquo Science vol 300 no 5625 pp 1524ndash1525 2003

[152] K Takeda and S Akira ldquoToll receptors and pathogen resis-tancerdquo Cellular Microbiology vol 5 no 3 pp 143ndash153 2003

[153] E Cario andD K Podolsky ldquoDifferential alteration in intestinalepithelial cell expression of Toll-like receptor 3 (TLR3) andTLR4 in inflammatory bowel diseaserdquo Infection and Immunityvol 68 no 12 pp 7010ndash7017 2000

[154] M Hausmann S Kiessling S Mestermann et al ldquoToll-likereceptors 2 and 4 are up-regulated during intestinal inflamma-tionrdquo Gastroenterology vol 122 no 7 pp 1987ndash2000 2002

[155] M T Abreu L S Thomas S Y Tesfay et al ldquoRegulation ofTLR4 and MD-2 in the intestinal epithelium evidence for dys-regulated LPS signaling in human inflammatory bowel diseaserdquoin Proceedings of the 90th Annual Meeting of the AmericanAssociation for Immunologists Abstract 3634 Denver ColoUSA 2003

[156] T A Schneeman M E C Bruno H Schjerven F-E JohansenL Chady and C S Kaetzel ldquoRegulation of the polymeric Igreceptor by signaling through TLRs 3 and 4 linking innate andadaptive immune responsesrdquo The Journal of Immunology vol175 no 1 pp 376ndash384 2005

[157] M E C Bruno A L Frantz E W Rogier F-E Johansen andC S Kaetzel ldquoRegulation of the polymeric immunoglobulinreceptor by the classical and alternative NF-120581B pathways inintestinal epithelial cellsrdquoMucosal Immunology vol 4 no 4 pp468ndash478 2011

[158] M E C Bruno E W Rogier A L Frantz A T Stefka SN Thompson and C S Kaetzel ldquoRegulation of the poly-meric immunoglobulin receptor in intestinal epithelial cellsby Enterobacteriaceae implications for mucosal homeostasisrdquoImmunological Investigations vol 39 no 4-5 pp 356ndash382 2010

[159] A L Frantz E W Rogier C R Weber et al ldquoTargeted deletionof MyD88 in intestinal epithelial cells results in compromisedantibacterial immunity associatedwith downregulation of poly-meric immunoglobulin receptor mucin-2 and antibacterialpeptidesrdquoMucosal Immunology vol 5 no 5 pp 501ndash512 2012

[160] E W Rogier A L Frantz M E C Bruno and C S KaetzelldquoSecretory IgA is concentrated in the outer layer of intestinalmucus along with gut bacteriardquo Pathogens In press

[161] M B Geuking K D McCoy and A J Macpherson ldquoThe func-tion of secretory IgA in the context of the intestinal continuumof adaptive immune responses in host-microbial mutualismrdquoSeminars in Immunology vol 24 no 1 pp 36ndash42 2012

20 ISRN Immunology

[162] L VHooper D R Littman andA JMacpherson ldquoInteractionsbetween the microbiota and the immune systemrdquo Science vol336 no 6086 pp 1268ndash1273 2012

[163] A J Macpherson M B Geuking E Slack S Hapfelmeierand K D McCoy ldquoThe habitat double life citizenship andforgetfulness of IgArdquo Immunological Reviews vol 245 no 1 pp132ndash146 2012

Submit your manuscripts athttpwwwhindawicom

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

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Disease Markers

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OncologyJournal of

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Oxidative Medicine and Cellular Longevity

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PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

10 ISRN Immunology

TailpieceHinge

Tailpiece

Mammalian IgA

VVVVVVVVVV

200121 300 400 4721

Human IgA1Rhesus IgA

Cattle IgAMouse IgA

Possum IgAPlatypus IgAChicken IgA

Frog IgXTrout IgT

Premammalian IgTXA

Gecko IgldquoArdquo

CH1

CH1

CH2

CH2

CH3

CH3

CH4

(a)

Leader 1 2 3 4 5

Ig homology extracellular domains

Linker CytoplasmicTM

1001 200 300 400 500 600 700 764

HumanRhesus

CattleMouse

PossumPlatypusChicken

AnoleFrog

Trout

(b)

Figure 6 Interspecies similarity in mucosal Ig and pIgR protein sequences from 10 representative vertebrate species Alignments in aminoacid sequences correspond to the phylogenetic trees shown in Figure 5 (a) Numbering ofmucosal Ig amino acids corresponds to the sequenceof human IgA1 beginning with the first residue of the variable domain CH heavy chain constant region domain (b) Numbering of pIgRamino acids corresponds to the sequence of human pIgR beginning with the first residue of the leader peptide TM transmembrane Forboth alignments the intensity of shading at each position signifies the degree of similarity amongmucosal Ig or pIgR sequences from differentspecies Gaps in sequence alignments signify regions of limited interspecies homology Approximate boundaries are noted of key structuralelements in mucosal Ig and pIgR proteins

in mammalian pIgR By contrast pIgR from amphibiansreptiles and birds contains 4 extracellular domains lackinga homolog of domain 2 of mammalian pIgR The mostprimitive form of pIgR found in teleost fish contains only2 extracellular domains homologous to domains 1 and 5of mammalian pIgR Interspecies homology is greatest indomain 1 which has been shown to be critical for binding ofmammalian pIgR to polymeric Igs (reviewed in [111]) Highlyconserved internal disulfide bonds are found in all the Ig-like domains of pIgR characteristic of the immunoglobulinfold An additional disulfide bond is found in domain 5 ofpIgR frommammals birds reptiles and amphibians but notfish In human SIgA this ldquoextrardquo disulfide bond in domain 5has been shown to rearrange to form a disulfide bond with

cysteine residues in one of the heavy chains of polymericIgA [134] Although the structure of SIgA has not beenfully characterized for lower vertebrates it is reasonable toassume that similar disulfide bonds form between domain 5of pIgR and polymeric IgA or IgX from birds reptiles andamphibians The linker region connecting domain 5 of pIgRto the transmembrane domain has a random structure that ispoorly conserved across species Proteolytic cleavage of pIgRwithin this domain leads to the release of SC from the apicalsurface of epithelial cells either free or bound to polymericIg The cytoplasmic domain of mammalian pIgR containsa number of intracellular sorting motifs that interact withcytoplasmic proteins to direct pIgR through the transcytoticpathway (reviewed in [111]) These motifs are reasonably

ISRN Immunology 11

Linker

TMCytoplasmic

J chain

Hinge 1

2

34

5

CL

VLVH

C1205721C1205722 C1205723

(a)

Linker

TMCytoplasmic

J chain

1

3 4

5

CL

VL

VH

C1205941205721

C1205941205722C1205941205723 C1205941205724

(b)

11

5

LinkerTM

Cytoplasmic

5

CL

VL

VH

C1205911C1205912

C1205913 C1205914

pIgR Ig-like domain

H chain Ig-like domain

L chain Ig-like domain

J chain

Disulfide bond

(c)

Figure 7 Theoretical model for changes in the structure of secretory Igs during evolution (a) The structure for mammalian SIgA is adaptedfrom the model of Woof and Russell [16] for human SIgA1 with permission from Nature Publishing Group (b) and (c) Theoretical modelsfor the structure of IgXA from amphibians and birds and SIgT from teleost fish respectively are predicted from alignment of Ig heavy chainand pIgR sequences with mammalian homologs

well conserved in pIgR from birds and reptiles but not inpIgR from amphibians and fish suggesting that complexmechanisms of intracellular trafficking of pIgR coevolvedwith the increasing complexity of the mucosal immunesystem

7 Hypothetical Models for Changes inSecretory Ig Structure during Coevolutionof Mucosal Igs and pIgR

A large number of structural and functional analyses overthe past 30 years allowed the development of detailed modelsfor the structure of mammalian SIgA (reviewed in [111 135])(Figure 7(a)) Domains 1 and 5 of pIgR the most highlyconserved Ig-like domains associate with theC1205722 subunits oftwo adjacent IgA heavy chains in a near-planar structure [136137] During transcytosis a disulfide bond forms betweenhighly conserved cysteine residues in domain 5 of pIgRand the C1205722 domain of one of the IgA heavy chains [134]Domains 2 3 and 4 allow mammalian pIgR to assume aflexible extended structure which is thought to wrap aroundthe IgA heavy chains and protect against degradation fromhost and microbial proteases Binding of mammalian pIgRto polymeric IgA or IgM requires the presence of J chain

connecting the Ig subunits (reviewed in [138]) and J chain-deficient mice fail to transport IgA and IgM into externalsecretions [139ndash141] Structure-function studies usingmutantforms of human J chain suggested that J chain binds directlyto pIgR and also maintains polymeric Ig in an optimalconformation for pIgR binding and transcytosis [142] Theunstructured linker region connecting domain 5 of pIgRto the transmembrane (TM) region gives membrane-boundpIgR the flexibility to bind large polymeric Igs (with orwithout associated antigens) and provides an exposed site forproteolytic cleavage of pIgR to SC The C-terminal region ofpIgR extends past the cytoplasmic face of the plasma mem-brane allowing association with cytoplasmic factors thatregulate trafficking of pIgR with or without bound polymericIg

Although detailed structural studies have not yet beenperformed on secretory Igs from lower vertebrates hypo-thetical models can be constructed based on alignmentswith their mammalian homologs A model for secretoryIgXA in birds reptiles and amphibians is illustrated inFigure 7(b) showing the C

1205941205722 domain in place of the hinge

region ofmammalian IgAThenumbering of the extracellulardomains of pIgR corresponds to the homologous domainsin mammalian pIgR noting the absence of domain 2 In

12 ISRN Immunology

this model the C120594120572

3 domains of two adjacent IgXA heavychains (homologous to the C

1205722 domain of mammalian IgA)

bind to the highly conserved domains 1 and 5 of pIgRGiven the conservation of the analogous cysteine residuesin domain 5 of pIgR and the C

1205941205723 domain of IgXA it

is assumed that a disulfide bond forms between pIgR andpolymeric Ig during epithelial transcytosis in birds reptilesand amphibiansThe absence of domain 2 in pIgR from thesevertebrate orders necessitates a more rigid structure thanthat of mammalian pIgR with a corresponding decrease inits ability to wrap around the IgXA heavy chains and pro-vide protection against proteoltyic degradation Despite theshorter length of pIgR in birds reptiles and amphibians theassociation with the J chain subunit of polymeric IgXA stillappears to be required Recombinant pIgR from the Africanfrog (Xenopus laevis) was shown to bind with moderatelyhigh affinity to human polymeric IgA containing J chain butnot to monomeric IgA [125] The affinity of Xenopus pIgRfor human pIgA was improved when Xenopus J chain wassubstituted for human J chain in a chimeric polymeric IgAmolecule The lack of sequence conservation across speciesin the linker region connecting domain 5 of pIgR to the TMregion suggests that it acts as a nonspecific ldquospacerrdquo As statedabove the cytoplasmic region of pIgR appears to have evolvedover time to provide enhanced regulation of pIgR trafficking

The hypothetical structure of secretory IgT from teleostfish in Figure 7(c) illustrates how the most primitive form ofpIgR comprising only extracellular domains 1 and 5 couldassociate with polymeric Ig and mediate epithelial transcy-tosis Association of pIgR domain 1 with the C

1205913 domain of

IgT would preserve the functional homology with secretoryIgs in higher vertebrates The short length of teleost pIgRwould necessitate the association of domain 5 with a C

1205913

domain on one of the heavy chains of the same IgT ratherthan spanning across to the adjaent IgT subunit While thismodel preserves the highly conserved association of pIgRdomain 1 with the orthologous domain of the IgT heavychain it does not explain the selectivity of teleost pIgR forpolymeric rather than monomeric IgT Although there is noexperimental evidence to support this model it could behypothesized that dimerization of two pIgR molecules in theplasmamembrane is required for high affinity binding of IgTas illustrated in the model in Figure 7(c) This hypotheticalmodel would also explain the lack of a necessity for J chainin polymeric IgT since each subunit in the pIgR dimer wouldonly be in contact with one IgT subunit The unstructuredlinker region connecting domain 5 of pIgR to the TM regionwould provide flexibility for association of 2 membrane-bound pIgR molecules with a large polymeric IgT molecule

Taken together the structural models for secretory Igsshown in Figure 7 are consistent with the selection of a morefunctional pIgR molecule over evolutionary time Duplica-tion and diversification of the extracellular Ig-like domainsof pIgR would provide a longer more flexible surface forbinding to polymeric Igs with higher affinity and protectingthe Ig heavy chains against proteolytic attack Expansion ofthe cytoplasmic domain of pIgR and incorporation of motifsfor binding cytoplasmic proteins would allow regulated

trafficking of pIgR and polymeric Igs across mucosal andglandular epithelial cells Importantly these models illustratea potential path for coevolution of IGH and PIGR genesdriven by the common selective pressure to provide antigen-specific humoral immune responses at mucosal surfaces

8 Evidence that the CommensalMicrobiota Provided the Driving Force forCoevolution of Mucosal Igs and pIgR

From the earliest evolution of vertebrate animals mucosal Igshave been an integral part of the emerging adaptive immunesystem Clearly many environmental factors served as driv-ing forces for the evolution of the adaptive immune systemin vertebrates including a longer lifespan thanmany (but notall) invertebrates and amore diverse diet that could introducea broader range of potential gut pathogens However it hasbeen proposed that the most significant force may havebeen the dramatic increase in the numbers and complexityof the resident microbiota in the evolution of vertebratesfrom their invertebrate ancestors [1 143 144] Antibodiesin mucosal secretions contribute to immune homeostasis bylimiting access of microbes and their products to the bodyproper maintaining the integrity of the epithelial barrier andshaping the composition of the commensal microbiota infavor of metabolically beneficial microorganisms [145] Thepredominance of polymeric Igs in these secretions promotesthese functions by providing multiple antigen-binding sitesper Ig complex thus increasing the overall avidity of antigen-antibody interactions Structural and functional refinementsin mucosal Igs culminating with the multifunctional secre-tory IgA molecule in mammals have further enhanced theirability to enhance immune homeostasis

The early emergence of pIgR in vertebrate evolutionprovided a mechanism for efficient transport of mucosal Igsinto external secretions It is well documented that crosstalkbetween mucosal epithelial cells and the resident microbiotamodulates expression of pIgR (reviewed in [17 111 112]) andit is reasonable to assume that these host-microbe interac-tions provided a driving force for evolution of the PIGR genein vertebrates The first demonstration that gut bacteria maymodulate pIgR expression in epithelial cells was the findingthat butyrate a bacterial fermentation product and importantenergy source in the colon upregulated expression of pIgRin the human colonic epithelial cell line HT-29 [146] A rolefor commensal bacteria in pIgR regulation was subsequentlydemonstrated by the observation that pIgR expression wasincreased when germ-free mice were colonized with Bacteri-oides thetaiotaomicron a prominent organism of the normalmouse and human intestinal microbiota [147] Amore recentstudy using a model of reversible colonization of germ-free mice with a nondividing mutant of Escherichia colidemonstrated that a long-lived SIgA response could besustained that specifically recognized the inducing bacteria[148] However exposure of E coli-colonized mice to otherbacteria limited the duration of the SIgA response against theoriginal colonizer suggesting a dynamic equilibriumbetweenmembers of the gut microbial community and host SIgA A

ISRN Immunology 13

study from the laboratory of Finn-Eirik Johansen demon-strated that diversity of the bacterial community in the cecallumen was reduced in pIgR-knockoutmice supporting a rolefor SIgA in limiting overgrowth of selected species [149] Incontrast the community of bacteria adherent to the epithelialsurface was more diverse in pIgR-knockout mice than inwild-typemice and these adherent bacteria caused enhancedexpression of several epithelial antimicrobial peptides Thesefindings suggest that bacteria-specific SIgA anchored in themucus layer restricts adhesion of bacteria to the epithelialsurface and limits bacterial stimulation of host epithelial cellsA recent study from the authorrsquos laboratory employing abreeding scheme in which119875119894119892119903minusminus damswere bred to119875119894119892119903+minusmales and vice versa demonstrated that SIgA antibodiesin breast milk promote long-term intestinal homeostasis byregulating the gut microbiota and gene expression in colonicepithelial cells [150]

A direct role for commensal andor pathogenic bacteriain the regulation of pIgR expression suggests that the innateimmune system may ldquoprimerdquo epithelial cells for transportof polymeric Ig produced during the adaptive immuneresponse Host cells mediate innate immune responses tomicrobial components through toll-like receptor (TLR) sig-naling (reviewed in [151 152]) Intestinal epithelial cells havebeen shown to express a wide variety of TLRs the expressionof which is upregulated during intestinal inflammation [153ndash155] Significantly expression of pIgR was shown to beupregulated in the HT-29 human intestinal epithelial cellline by bacterial LPS a ligand for TLR4 [156 157] Similarinduction of PIGR gene transcription was seen followingdirect binding of bacteria of the family Enterobacteriaceaewhich express a form of LPS that stimulates TLR4 [158]A recent study from the authorrsquos laboratory demonstratedthat shRNA-mediated knockdown of myeloid differentiationprimary response protein 88 (MyD88) a cytoplasmic adapterprotein that transduces signals from cell surface TLR4blocked the induction of PIGR gene transcription by LPS inHT-29 cells [159] The in vivo significance was confirmed bythe finding that mice with a targeted deletion of the Myd88gene only in intestinal epithelial cells had reduced expressionof pIgR compared to wild-type littermates [159] Mice withtargeted depletion of MyD88 in intestinal epithelial cells alsoexhibited reduced expression of mucin-2 the major compo-nent of the intestinal mucus layer and several antimicrobialpeptides and decreased transmucosal electrical resistanceThese alterations in epithelial barrier function were accom-panied by significant changes in the composition of the fecalmicrobiota increased numbers of bacteria adherent to theintestinal mucus layer and a dramatic increase in transloca-tion of gut bacteria into the drainingmesenteric lymphnodesincluding the opportunistic pathogen Klebsiella pneumoniaeThese findings demonstrate that MyD88-mediated crosstalkbetween the gut microbiota and intestinal epithelial cells iscrucial for optimal expression of pIgR production of SIgAdevelopment of a healthy gut microbiota and maintenanceof intestinal homeostasis

A model can be proposed in which continuous stimu-lation of intestinal epithelial cells by gut bacteria regulates

Lumen

Mucus

Epithelium

Lamina

PIGR

TLRs

MyD88

Bacteria

Plasma cells

propria

Polymeric Ig

Polymeric Ig receptor

Secretory component

Figure 8 Crosstalk between the polymeric immunoglobulin recep-tor secretory immunoglobulins and the gut microbiotaThe single-layered epithelium that lines the gastrointestinal tract is coveredwith a thick mucus layer which physically excludes members ofthe resident microbiota but allows diffusion of shed components ofmicrobial cells Stimulation of epithelial toll-like receptors (TLRs)with microbial products engages the cytoplasmic adaptor proteinMyD88 and initiates NF120581B-dependent signaling pathways Translo-cation of activated NF120581B and other transcription factors to thenucleus enhances transcription of thePIGR gene Activation of TLRsmay also stimulate pIgR transcytosis Polymeric Igs secreted bylamina propria plasma cells bind to pIgRon the basolateral surface ofepithelial cells and are transcytosed to the apical surface along withunoccupied pIgR Proteolytic cleavage of pIgR at the apical surfacereleases secretory SIg and free secretory component (SC) Binding ofSIg and SC to luminal bacteria promotes association with themucuslayer and prevents direct access of bacteria to the epithelial surfaceOver time the continuous crosstalk with SIg shapes the compositionof the gut microbiota Modified from [17] under terms of authorrsquoscopyright with Nature Publishing Group

pIgR expression and transport of SIgA and promotes immuneexclusion of resident and pathogenic bacteria (Figure 8) Adense layer of mucus which increases in thickness fromthe proximal to the distal colon serves to separate bacteriafrom direct contact with the epithelial surface Secretionof microbial-associated molecular patterns (MAMPs) bycommensal bacteria stimulates MyD88-dependent TLR sig-naling leading to enhanced expression of pIgR and antimi-crobial peptides and increased mucus production Bindingof pIgA to pIgR and possibly also signaling via MAMPs

14 ISRN Immunology

enhances transcytosis of pIgA pIgA-containing immunecomplexes and unoccupied pIgR which promotes clearanceof antigens and pathogens from the lamina propria intra-cellular neutralization and release of SIgA and SC at theluminal surface SIgA and SC serve to trap bacteria in themucus layer limiting their access to the epithelial surface Inmice with a targeted deletion of the Muc2 gene which havea severely depleted mucus layer in the colon SIgA and SCfail to associate with the surface of colonic epithelial cells[160] The presence of SIgA in the intestinal lumen whetherderived passively frommaternalmilk or actively via epithelialtranscytosis shapes the composition of the gut microbiotaand modulates intestinal epithelial gene expression

9 Concluding Remarks

The first microbes that emerged on Earth almost 4 billionyears ago encountered a hostile world where nutrients werescarce hazards were everywhere and life was short Withthe evolution of multicellular organisms about 3 billion yearslater a select group ofmicrobes chose to sacrifice an indepen-dent existence for the benefits of a mutualistic relationshipwith eukaryotic hosts Prokaryotic-eukaryotic mutualismreached its apex some 500 million years ago with theemergence of primitive vertebrates whose gastrointestinaltracts were populated by an abundant and diverse commensalmicrobiota In humans the large intestine is home to some100 trillion microorganisms 10 times more than the totalnumber of eukaryotic cells in the entire body The microbesthat inhabit the vertebrate GI tract provide many benefitsto the eukaryotic host including digestion of complex foodmolecules synthesis of vitamins and production of solublefactors that enhance the development of the host immunesystem In return the eukaryotic host provides the microbeswith a warm moist place to live abundant food low oxygentension and a soft bed of mucus on which to form biofilmsWhen this mutually beneficial arrangement is challenged bypathogenicmicrobes the eukaryotic host and the commensalmicrobiota join forces to battle the pathogens and protectthe body from invasion The vertebrate immune system isequipped with a well-trained army of immune cells and asophisticated arsenal of weapons (cell surface molecules andsecreted factors) that protect the host from all but the mostvirulent pathogens This immune ldquoarmyrdquo also serves as aconstant reminder to the commensal microbes that whilethey are free to enjoy the amenities of the mucosal surfacesthey are not welcome in the body proper The emergence ofantigen-specific Igs and T-cell receptors in jawed vertebratesbegan a process of immunological diversification that led tothe development of a specialized mucosal immune systemin higher vertebrates in which secretory Igs play a centralrole The relationship between host and microbiota is clearlyreciprocal the mucosal Igs that evolved in response toselective pressure from the commensal microbiota play acentral role throughout life in shaping the compositiongenetics andmetabolic activity of themicrobiota [1 161 162]

The epithelial layer lining mucosal surfaces provides aphysical and innate immune barrier against penetration of

the body proper by microbes undigested food antigens andpotentially noxious environmental substances The evolu-tionary challenge of transporting mucosal Igs into externalsecretions without compromising the epithelial barrier wasmet by the emergence of the PIGR gene in an ancestor ofbony fishes encoding an epithelial-specific transmembraneprotein that actively transports polymeric Igs across mucosaland glandular epithelia (Figure 4) Structural similaritiesbetween Igs and the extracellular Ig-binding domains of pIgR(Figure 6) suggest that duplication and diversification of agene encoding primordial Ig-like domain may have givenrise to the PIGR gene in a primitive vertebrate ancestorParallel refinement of the structures of mucosal Igs andpIgR during tetrapod evolution (Figures 6 and 7) culminatedin the evolution of the multifunctional SIgA molecule inmammals in which the pIgR-derived SC subunit providesinnate immune functions and protects the antigen-bindingIgA polymer from proteolytic degradation In addition toacting as a powerful force during vertebrate evolution thereciprocal relationship between pIgR mucosal Igs and thecommensal microbiota provides benefits throughout thelife of the individual Microbial colonization of newbornvertebrates stimulates development of mucosal B cells andclass switching to mucosal Ig isotypes [1 163] Microbialfactors upregulate expression of pIgR enhancing transportof mucosal Igs into external secretions where they in turnregulate the microbiotaThis beautifully orchestrated processallows us to maintain a healthy relationship with our resi-dent microbiota while providing mutual protection againstpathogens

Conflict of Interests

The author declares that there is no conflict of interestsregarding the publication of this paper

Acknowledgments

This work was supported by Grant no AI069027 from theNational Institutes of Health of the United States of America(and an associatedAmerican Recovery andReinvestmentActsupplement) and a Senior Research Award from the Crohnrsquosand Colitis Foundation of America

References

[1] C L Maynard C O Elson R D Hatton and C T WeaverldquoReciprocal interactions of the intestinal microbiota andimmune systemrdquo Nature vol 489 no 7415 pp 231ndash241 2012

[2] M F Flajnik and M Kasahara ldquoOrigin and evolution of theadaptive immune system genetic events and selective pres-suresrdquo Nature Reviews Genetics vol 11 no 1 pp 47ndash59 2010

[3] M F Flajnik and L du Pasquier ldquoEvolution of the immunesystemrdquo in Fundamental Immunology W E Paul Ed chapter4 pp 67ndash128 Lippincott Williams ampWilkins Philadelphia PaUSA 2012

[4] M Hirano S Das P Guo and M D Cooper ldquoThe evolutionof adaptive immunity in vertebratesrdquo Advances in Immunologyvol 109 pp 125ndash157 2011

ISRN Immunology 15

[5] T BoehmNMcCurley Y SutohM SchorppMKasahara andM D Cooper ldquoVLR-based adaptive immunityrdquo Annual Reviewof Immunology vol 30 pp 203ndash220 2012

[6] T Hunkapiller and L Hood ldquoImmunology the growing immu-noglobulin gene superfamilyrdquoNature vol 323 no 6083 pp 15ndash16 1986

[7] P Bork L Holm and C Sander ldquoThe immunoglobulin foldstructural classification sequence patterns and common corerdquoJournal of Molecular Biology vol 242 no 4 pp 309ndash320 1994

[8] C S Kaetzel and M W Russell ldquoPhylogeny and comparativephysiology of IgArdquo in Mucosal Immunology J Mestecky WStrober H Cheroutre B Kelsall B N Lambrecht and M WRussell Eds chapter 19 Academic PressElsevier WalthamMass USA 2014

[9] Y He and P J Bjorkman ldquoStructure of FcRY an avian immu-noglobulin receptor related to mammalian mannose receptorsand its complex with IgYrdquo Proceedings of the National Academyof Sciences of the United States of America vol 108 no 30 pp12431ndash12436 2011

[10] J M Woof and D R Burton ldquoHuman antibody-Fc receptorinteractions illuminated by crystal structuresrdquo Nature ReviewsImmunology vol 4 no 2 pp 89ndash99 2004

[11] W L Martin A P West Jr L Gan and P J Bjorkman ldquoCrystalstructure at 28 A of an FcRnheterodimeric Fc complexmechanism of pH-dependent bindingrdquo Molecular Cell vol 7no 4 pp 867ndash877 2001

[12] E S Ward ldquoAcquiring maternal immunoglobulin differentreceptors similar functionsrdquo Immunity vol 20 no 5 pp 507ndash508 2004

[13] C S Kaetzel ldquoThe polymeric immunoglobulin receptor bridg-ing innate and adaptive immune responses atmucosal surfacesrdquoImmunological Reviews vol 206 no 1 pp 83ndash99 2005

[14] M Acharya G Borland A L Edkins et al ldquoCD23Fc120576RIImolecular multi-taskingrdquo Clinical and Experimental Immunol-ogy vol 162 no 1 pp 12ndash23 2010

[15] V B Klimovich ldquoIgM and its receptors structural and func-tional aspectsrdquo Biochemistry vol 76 no 5 pp 534ndash549 2011

[16] J MWoof andMW Russell ldquoStructure and function relation-ships in IgArdquo Mucosal Immunology vol 4 no 6 pp 590ndash5972011

[17] F-E Johansen and C S Kaetzel ldquoRegulation of the polymericimmunoglobulin receptor and IgA transport new advances inenvironmental factors that stimulate pIgR expression and itsrole in mucosal immunityrdquo Mucosal Immunology vol 4 no 6pp 598ndash602 2011

[18] F Kokubu K Hinds R Litman M J Shamblott and G WLitman ldquoExtensive families of constant region genes in a phy-logenetically primitive vertebrate indicate an additional levelof immunoglobulin complexityrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 84 no16 pp 5868ndash5872 1987

[19] A S Greenberg A L Hughes J Guo D Avila E CMcKinneyand M F Flajnik ldquoA novel ldquochimericrdquo antibody class in carti-laginous fish IgMmay not be the primordial immunoglobulinrdquoEuropean Journal of Immunology vol 26 no 5 pp 1123ndash11291996

[20] H Dooley and M F Flajnik ldquoShark immunity bites back affin-ity maturation and memory response in the nurse shark Ging-lymostoma cirratumrdquo European Journal of Immunology vol 35no 3 pp 936ndash945 2005

[21] S F Schluter R M Bernstein and J J Marchalonis ldquoMolecularorigins and evolution of immunoglobulin heavy-chain genes ofjawed vertebratesrdquo Immunology Today vol 18 no 11 pp 543ndash549 1997

[22] Y Ohta and M Flajnik ldquoIgD like IgM is a primordial immu-noglobulin class perpetuated in most jawed vertebratesrdquo Pro-ceedings of the National Academy of Sciences of the United Statesof America vol 103 no 28 pp 10723ndash10728 2006

[23] S Fillatreau A Six S Magadan R Castro J O Sunyer andP Boudinot ldquoThe astonishing diversity of Ig classes and B cellrepertoires in teleost fishrdquo Frontiers in Immunology vol 4 no28 2013

[24] W Harriman H Volk N Defranoux and M Wabl ldquoImmu-noglobulin class switch recombinationrdquo Annual Review ofImmunology vol 11 pp 361ndash384 1993

[25] J Stavnezer and C T Amemiya ldquoEvolution of isotype switch-ingrdquo Seminars in Immunology vol 16 no 4 pp 257ndash275 2004

[26] V M Barreto Q Pan-Hammarstrom Y Zhao L Ham-marstrom Z Misulovin and M C Nussenzweig ldquoAID frombony fish catalyzes class switch recombinationrdquo Journal ofExperimental Medicine vol 202 no 6 pp 733ndash738 2005

[27] T C Fletcher and AWhite ldquoAntibody production in the plaice(Pleuronectes platessa L) after oral and parenteral immuniza-tion with Vibrio anguillarum antigensrdquo Aquaculture vol 1 pp417ndash428 1972

[28] J W H M Rombout L J Blok C H J Lamers and E EgbertsldquoImmunization of carp (Cyprinus carpio) with a Vibrio anguil-larum bacterin indications for a common mucosal immunesystemrdquo Developmental and Comparative Immunology vol 10no 3 pp 341ndash351 1986

[29] U Georgopoulou and J-M Vernier ldquoLocal immunologicalresponse in the posterior intestinal segment of the rainbowtrout after oral administration of macromoleculesrdquo Develop-mental andComparative Immunology vol 10 no 4 pp 529ndash5371986

[30] C J Lobb ldquoSecretory immunity induced in catfish Ictaluruspunctatus following bath immunizationrdquo Developmental andComparative Immunology vol 11 no 4 pp 727ndash738 1987

[31] J D Hansen E D Landis and R B Phillips ldquoDiscovery ofa unique Ig heavy-chain (IgT) in rainbow trout implicationsfor a distinctive B cell developmental pathway in teleost fishrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 102 no 19 pp 6919ndash6924 2005

[32] N Danilova J Bussmann K Jekosch and L A Steiner ldquoTheimmunoglobulin heavy-chain locus in zebrafish identificationand expression of a previously unknown isotype immunoglob-ulin Zrdquo Nature Immunology vol 6 no 3 pp 295ndash302 2005

[33] R Savan A Aman K Sato R Yamaguchi and M Sakai ldquoDis-covery of a new class of immunoglobulin heavy chain fromfugurdquo European Journal of Immunology vol 35 no 11 pp 3320ndash3331 2005

[34] R Savan A AmanMNakao HWatanuki andM Sakai ldquoDis-covery of a novel immunoglobulin heavy chain gene chimerafrom common carp (Cyprinus carpio L)rdquo Immunogenetics vol57 no 6 pp 458ndash463 2005

[35] F Gambon-Deza C Sanchez-Espinel and S Magadan-Mompo ldquoPresence of an unique IgT on the IGH locus in three-spined stickleback fish (Gasterosteus aculeatus) and the veryrecent generation of a repertoire of VH genesrdquo Developmentaland Comparative Immunology vol 34 no 2 pp 114ndash122 2010

[36] T M Tadiso K K Lie and I Hordvik ldquoMolecular cloning ofIgT fromAtlantic salmon and analysis of the relative expression

16 ISRN Immunology

of 120591 120583 and 120575 in different tissuesrdquo Veterinary Immunology andImmunopathology vol 139 no 1 pp 17ndash26 2011

[37] S Mashoof C Pohlenz P L Chen et al ldquoExpressed IgH 120583and 120591 transcripts share diversity segment in ranched Thunnusorientalisrdquo Developmental and Comparative Immunology vol43 no 1 pp 76ndash86 2014

[38] Y-A Zhang I Salinas J Li et al ldquoIgT a primitive immunoglob-ulin class specialized in mucosal immunityrdquo Nature Immunol-ogy vol 11 no 9 pp 827ndash835 2010

[39] S Magadan-Mompo C Sanchez-Espinel and F Gambon-Deza ldquoImmunoglobulin heavy chains in medaka (Oryziaslatipes)rdquo BMC Evolutionary Biology vol 11 no 1 article 1652011

[40] C T Amemiya J Alfoldi A P Lee et al ldquoThe African coela-canth genome provides insights into tetrapod evolutionrdquoNature vol 496 no 7445 pp 311ndash316 2013

[41] T Ota J P Rast G W Litman and C T Amemiya ldquoLineage-restricted retention of a primitive immunoglobulin heavy chainisotype within the Dipnoi reveals an evolutionary paradoxrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 100 no 5 pp 2501ndash2506 2003

[42] Y Sun Z Wei N Li and Y Zhao ldquoA comparative overview ofimmunoglobulin genes and the generation of their diversity intetrapodsrdquo Developmental and Comparative Immunology vol39 no 1-2 pp 103ndash109 2013

[43] I Hadji-Azimi ldquoAnuran immunoglobulins a reviewrdquo Develop-mental and Comparative Immunology vol 3 no 2 pp 223ndash2431979

[44] E Hsu M F Flajnik and L du Pasquier ldquoA third immunoglob-ulin class in amphibiansrdquo The Journal of Immunology vol 135no 3 pp 1998ndash2004 1985

[45] C T Amemiya R N Haire and G W Litman ldquoNucleotidesequence of a cDNA encoding a third distinct Xenopusimmunoglobulin heavy chain isotyperdquo Nucleic Acids Researchvol 17 no 13 p 5388 1989

[46] R Muszligmann M Wilson A Marcuz M Courtet and L duPasquier ldquoMembrane exon sequences of the three Xenopus Igclasses explain the evolutionary origin of mammalian isotypesrdquoEuropean Journal of Immunology vol 26 no 2 pp 409ndash4141996

[47] R Muszligmann L du Pasquier and E Hsu ldquoIs Xenopus IgX ananalog of IgArdquo European Journal of Immunology vol 26 no12 pp 2823ndash2830 1996

[48] B Schaerlinger and J-P Frippiat ldquoIgX antibodies in the urodeleamphibian Ambystoma mexicanumrdquo Developmental and Com-parative Immunology vol 32 no 8 pp 908ndash915 2008

[49] B Schaerlinger M Bascove and J-P Frippiat ldquoA new isotypeof immunoglobulin heavy chain in the urodele amphibianPleurodeles waltl predominantly expressed in larvaerdquoMolecularImmunology vol 45 no 3 pp 776ndash786 2008

[50] S Mashoof A Goodroe C C Du et al ldquoAncient T-independence of mucosal IgXA gut microbiota unaffected bylarval thymectomy in Xenopus laevisrdquo Mucosal Immunologyvol 6 no 2 pp 358ndash368 2013

[51] J P Vaerman J Picard and J F Heremans ldquoStructural dataon chicken IgA and failure to identify the IgA of the tortoiserdquoin Immunologic Phylogeny vol 64 of Advances in ExperimentalMedicine and Biology pp 185ndash195 Springer New York NYUSA 1975

[52] J L Portis and J E Coe ldquoIgM the secretory immunoglobulinof reptiles and amphibiansrdquo Nature vol 258 no 5535 pp 547ndash548 1975

[53] J E Coe D Leong J L Portis and L A Thomas ldquoImmuneresponse in the garter snake (Thamnophis ordinoides)rdquo Immu-nology vol 31 no 3 pp 417ndash424 1976

[54] D Hadge and H Ambrosius ldquoEvolution of low molecularweight immunoglobulinsmdashIV IgY-like immunoglobulins ofbirds reptiles and amphibians precursors of mammalian IgArdquoMolecular Immunology vol 21 no 8 pp 699ndash707 1984

[55] D Hadge and H Ambrosius ldquoEvolution of low molecularweight immunoglobulins V Degree of antigenic relationshipbetween the 7S immunoglobulins ofmammals birds and lowervertebrates to the turkey IgYrdquo Developmental and ComparativeImmunology vol 10 no 3 pp 377ndash385 1986

[56] S Magadan-Mompo C Sanchez-Espinel and F Gambon-Deza ldquoImmunoglobulin genes of the turtlesrdquo Immunogeneticsvol 65 no 3 pp 227ndash237 2013

[57] Z Wei Q Wu L Ren et al ldquoExpression of IgM IgD and IgYin a reptile Anolis carolinensisrdquoThe Journal of Immunology vol183 no 6 pp 3858ndash3864 2009

[58] F Gambon-Deza C Sanchez-Espinel and J V Beneitez ldquoAnovel IgA-like immunoglobulin in the reptile Eublepharis mac-ulariusrdquo Developmental and Comparative Immunology vol 31no 6 pp 596ndash605 2007

[59] G Cheng Y Gao T Wang et al ldquoExtensive diversification ofIgH subclass-encoding genes and IgM subclass switching incrocodiliansrdquo Nature Communications vol 4 article 1337 2013

[60] S Magadan-Mompo C Sanchez-Espinel and F Gambon-Deza ldquoIgH loci of American alligator and saltwater crocodileshed light on IgA evolutionrdquo Immunogenetics vol 65 no 7 pp531ndash541 2013

[61] E Orlans and M E Rose ldquoAn IgA-like immunoglobulin in thefowlrdquo Immunochemistry vol 9 no 8 pp 833ndash838 1972

[62] G A Leslie and L N Martin ldquoStudies on the secretory immu-nologic system of fowl 3 Serum and secretory IgA of thechickenrdquoThe Journal of Immunology vol 110 no 1 pp 1ndash9 1973

[63] J Bienenstock D Y Perey J Gauldie and B J UnderdownldquoChicken 120574A physicochemical and immunochemical charac-teristicsrdquoThe Journal of Immunology vol 110 no 2 pp 524ndash5331973

[64] A M Lebacq-Verheyden J P Vaerman and J F HeremansldquoQuantification and distribution of chicken immunoglobulinsIgA IgM and IgG in serum and secretionsrdquo Immunology vol27 no 4 pp 683ndash692 1974

[65] J Goudswaard A Noordzij R H van Dam J A vanderDonk and J P Vaerman ldquoThe immunoglobulins of the turkey(Meleagris gallopavo) Isolation and characterization of IgGIgM and IgA in body fluids eggs and intraocular tissuesrdquoPoultry science vol 56 no 6 pp 1847ndash1851 1977

[66] D Hadge and H Ambrosius ldquoComparative studies on thestructure of biliary immunoglobulins of some avian speciesII Antigenic properties of the biliary immunoglobulins ofchicken turkey duck and gooserdquo Developmental and Compar-ative Immunology vol 12 no 2 pp 319ndash329 1988

[67] J Goudswaard J P Vaerman and J F Heremans ldquoThreeimmunoglobulin classes in the pigeon (Columbia livia)rdquo Inter-national Archives of Allergy andApplied Immunology vol 53 no5 pp 409ndash419 1977

[68] P L K Ng and D A Higgins ldquoBile immunoglobulin of theduck (Anas platyrhynchos) I Preliminary characterization andontogenyrdquo Immunology vol 58 no 2 pp 323ndash327 1986

[69] K E Magor G W Warr Y Bando D L Middleton and DA Higgins ldquoSecretory immune system of the duck (Anas

ISRN Immunology 17

platyrhynchos) Identification and expression of the genesencoding IgA and IgM heavy chainsrdquo European Journal ofImmunology vol 28 no 3 pp 1063ndash1068 1998

[70] Y Zhao H Rabbani A Shimizu and L Hammarstrom ldquoMap-ping of the chicken immunoglobulin heavy-chain constantregion gene locus reveals an inverted 120572 gene upstream of acondensed 120592 generdquo Immunology vol 101 no 3 pp 348ndash3532000

[71] M L Lundqvist D L Middleton S Hazard and G W WarrldquoThe immunoglobulin heavy chain locus of the duck genomicorganization and expression of D J and C region genesrdquo TheJournal of Biological Chemistry vol 276 no 50 pp 46729ndash46736 2001

[72] T HuangM Zhang ZWei et al ldquoAnalysis of immunoglobulintranscripts in the ostrich Struthio camelus a primitive avianspeciesrdquo PLoS ONE vol 7 no 3 Article ID e34346 2012

[73] K H Roux ldquoImmunoglobulin structure and function asrevealed by electron microscopyrdquo International Archives ofAllergy and Immunology vol 120 no 2 pp 85ndash99 1999

[74] F Gambon-Deza C Sanchez-Espinel and S Magadan-Mompo ldquoThe immunoglobulin heavy chain locus in the platy-pus (Ornithorhynchus anatinus)rdquo Molecular Immunology vol46 no 13 pp 2515ndash2523 2009

[75] Y Zhao H Cui C M Whittington et al ldquoOrnithorhynchusanatinus (platypus) links the evolution of immunoglobulingenes in eutherian mammals and nonmammalian tetrapodsrdquoThe Journal of Immunology vol 183 no 5 pp 3285ndash3293 2009

[76] M Aveskogh and L Hellman ldquoEvidence for an early appear-ance of modern post-switch isotypes in mammalian evolutioncloning of IgE IgG and IgA from the marsupial Monodelphisdomesticardquo European Journal of Immunology vol 28 no 9 pp2738ndash2750 1998

[77] K Belov G A Harrison and DW Cooper ldquoMolecular cloningof the cDNA encoding the constant region of the immunoglob-ulin a heavy chain (C120572) from amarsupialTrichosurus vulpecula(common brushtail possum)rdquo Immunology Letters vol 60 no2-3 pp 165ndash170 1998

[78] K Belov K R Zenger L Hellman and DW Cooper ldquoEchidnaIgA supports mammalian unity and traditional Therian rela-tionshiprdquo Mammalian Genome vol 13 no 11 pp 656ndash6632002

[79] K Belov and L Hellman ldquoImmunoglobulin genetics of Orni-thorhynchus anatinus (platypus) and Tachyglossus aculeatus(short-beaked echidna)rdquo Comparative Biochemistry and Phys-iology vol 136 no 4 pp 811ndash819 2003

[80] M VernerssonM Aveskogh BMunday and L Hellman ldquoEvi-dence for an early appearance of modern post-switch immu-noglobulin isotypes in mammalian evolution (II) cloning ofIgE IgG1 and IgG2 fromamonotreme the duck-billed platypusOrnithorhynchus anatinusrdquo European Journal of Immunologyvol 32 no 8 pp 2145ndash2155 2002

[81] C Auffray R Nageotte and J L Sikorav ldquoMouse immunoglob-ulin A nucleotide sequence of the structural gene for the 120572heavy chain derived from cloned cDNAsrdquo Gene vol 13 no 4pp 365ndash374 1981

[82] T Ukaji D Sumiyama and O Kai ldquoSequence determinationof the heavy-chain constant region in four immunoglobulinclasses of Mongolian gerbils (Meriones unguiculatus)rdquo Experi-mental Animals vol 61 no 2 pp 99ndash107 2012

[83] R C Burnett W C Hanly S K Zhai and K L Knight ldquoTheIgA heavy chain gene family in rabbit cloning and sequence

analysis of 13 C120572 genesrdquo The EMBO Journal vol 8 no 13 pp4041ndash4047 1989

[84] D K Lanning S-K Zhai and K L Knight ldquoAnalysis of the 31015840C120583 region of the rabbit Ig heavy chain locusrdquoGene vol 309 no2 pp 135ndash144 2003

[85] F Ros J Puels N Reichenberger W van Schooten R Buelowand J Platzer ldquoSequence analysis of 05Mb of the rabbitgermline immunoglobulin heavy chain locusrdquo Gene vol 330no 1-2 pp 49ndash59 2004

[86] M Patel D Selinger G E Mark G J Hickey and G FHollis ldquoSequence of the dog immunoglobulin alpha and epsilonconstant region genesrdquo Immunogenetics vol 41 no 5 pp 282ndash286 1995

[87] Z Zhao Y Zhao Q Pan-Hammarstrom et al ldquoPhysical map-ping of the giant panda immunoglobulin heavy chain constantregion genesrdquo Developmental and Comparative Immunologyvol 31 no 10 pp 1034ndash1049 2007

[88] W R Brown and J E Butler ldquoCharacterization of a C120572 gene ofswinerdquoMolecular Immunology vol 31 no 8 pp 633ndash642 1994

[89] W R Brown H Rabbani J E Butler and L HammarstromldquoCharacterization of the bovine C120572 generdquo Immunology vol 91no 1 pp 1ndash6 1997

[90] G PWhite P Roche M R Brandon S E Newton and E N TMeeusen ldquoCloning and characterization of sheep (Ovis aries)immunoglobulin 120572 chainrdquo Immunogenetics vol 48 no 5 pp359ndash362 1998

[91] AMancia T A Romano H A Gefroh et al ldquoCharacterizationof the immunoglobulin A heavy chain gene of the Atlantic bot-tlenose dolphin (Tursiops truncatus)rdquo Veterinary Immunologyand Immunopathology vol 118 no 3-4 pp 304ndash309 2007

[92] B Wagner I Greiser-Wilke and D F Antczak ldquoCharacteriza-tion of the horse [Equus caballus] IGHA generdquo Immunogeneticsvol 55 no 8 pp 552ndash560 2003

[93] N Takahashi S Ueda and M Obata ldquoStructure of humanimmunoglobulin gamma genes implications for evolution of agene familyrdquo Cell vol 29 no 2 pp 671ndash679 1982

[94] J G Flanagan M-P Lefranc and T H Rabbitts ldquoMechanismsof divergence and convergence of the human immunoglobulin1205721 and 1205722 constant region gene sequencesrdquo Cell vol 36 no 3pp 681ndash688 1984

[95] S Kawamura K Omoto and S Ueda ldquoEvolutionary hypervari-ability in the hinge region of the immunoglobulin alpha generdquoJournal of Molecular Biology vol 215 no 2 pp 201ndash206 1990

[96] F Scinicariello F Masseoud L Jayashankar and R AttanasioldquoSooty mangabey (Cercocebus torquatus atys) IGHG and IGHAgenesrdquo Immunogenetics vol 58 no 12 pp 955ndash965 2006

[97] K A Rogers L Jayashankar F Scinicariello and R AttanasioldquoNonhuman primate IgA genetic heterogeneity and interac-tions with CD89rdquoThe Journal of Immunology vol 180 no 7 pp4816ndash4824 2008

[98] S Kawamura N Saitou and S Ueda ldquoConcerted evolution ofthe primate immunoglobulin 120572-gene through gene conversionrdquoThe Journal of Biological Chemistry vol 267 no 11 pp 7359ndash7367 1992

[99] S Kawamura and S Ueda ldquoImmunoglobulin C119867gene family in

hominoids and its evolutionary historyrdquo Genomics vol 13 no1 pp 194ndash200 1992

[100] A Brusco U Cariota A Bottaro et al ldquoStructural andimmunologic analysis of gene triplications in the Ig heavy chainconstant region locusrdquoThe Journal of Immunology vol 152 no1 pp 129ndash135 1994

18 ISRN Immunology

[101] H Rabbani Q Pan N Kondo C I E Smith and L Ham-marstrom ldquoDuplications and deletions of the human IGHClocus evolutionary implicationsrdquo Immunogenetics vol 45 no2 pp 136ndash141 1996

[102] P F Weinheimer J Mestecky and R T Acton ldquoSpecies distri-bution of J chainrdquoThe Journal of Immunology vol 107 no 4 pp1211ndash1212 1971

[103] F P Inman and J Mestecky ldquoThe J chain of polymeric immu-noglobulinsrdquo inContemporary Topics inMolecular Immunologyvol 3 pp 111ndash141 Springer New York NY USA 1974

[104] P Brandtzaeg ldquoPresence of J chain in human immunocytescontaining various immunoglobulin classesrdquo Nature vol 252no 5482 pp 418ndash420 1974

[105] L Tacchi E Larragoite and I Salinas ldquoDiscovery of J chain inAfrican lungfish (Protopterus dolloi Sarcopterygii) using highthroughput transcriptome sequencing implications in mucosalimmunityrdquo PLoS ONE vol 8 no 8 Article ID e70650 2013

[106] I K Zarkadis D Mastellos and J D Lambris ldquoPhylogeneticaspects of the complement systemrdquo Developmental and Com-parative Immunology vol 25 no 8-9 pp 745ndash762 2001

[107] A P West Jr A B Herr and P J Bjorkman ldquoThe chickenyolk sac IgY receptor a functional equivalent of themammalianMHC-related Fc receptor is a phospholipase A

2receptor

homologrdquo Immunity vol 20 no 5 pp 601ndash610 2004[108] D B Tesar E J Cheung and P J Bjorkman ldquoThe chicken

yolk sac IgY receptor a mammalian mannose receptor familymember transcytoses IgY across polarized epithelial cellsrdquoMolecular Biology of the Cell vol 19 no 4 pp 1587ndash1593 2008

[109] A I Taylor R L Beavil B J Sutton and R A Calvert ldquoAmonomeric chicken IgY receptor binds IgY with 21 stoichiom-etryrdquo The Journal of Biological Chemistry vol 284 no 36 pp24168ndash24175 2009

[110] K Baker S-W Qiao T Kuo et al ldquoImmune and non-immunefunctions of the (not so) neonatal Fc receptor FcRnrdquo Seminarsin Immunopathology vol 31 no 2 pp 223ndash236 2009

[111] K Baker R S Blumberg and C S Kaetzel ldquoImmunoglob-ulin transport and immunoglobulin receptorsrdquo in MucosalImmunology J Mestecky W Strober H Cheroutre B KelsallB N Lambrecht andMW Russell Eds chapter 20 AcademicPressElsevier Waltham Mass USA 2014

[112] C S Kaetzel ldquoThepolymeric immunoglobulin receptorrdquo in eLSJohn Wiley amp Sons Chichester UK 2013

[113] N J Mantis N Rol and B Corthesy ldquoSecretory IgArsquos complexroles in immunity andmucosal homeostasis in the gutrdquoMucosalImmunology vol 4 no 6 pp 603ndash611 2011

[114] J V Peppard M E Rose and P Hesketh ldquoA functional homo-logue of mammalian secretory component exists in chickensrdquoEuropean Journal of Immunology vol 13 no 7 pp 566ndash5701983

[115] K E Mostov M Friedlander and G Blobel ldquoThe receptorfor transepithelial transport of IgA and IgM contains multipleimmunoglobulin-like domainsrdquo Nature vol 308 no 5954 pp37ndash43 1984

[116] P Krajci R Solberg M Sandberg O Oyen T Jahnsen and PBrandtzaeg ldquoMolecular cloning of the human transmembranesecretory component (poly-Ig receptor) and its mRNA expres-sion in human tissuesrdquo Biochemical and Biophysical ResearchCommunications vol 158 no 3 pp 783ndash789 1989

[117] P Krajci D Kvale K Tasken and P Brandtzaeg ldquoMolecularcloning and exon-intron mapping of the gene encoding humantransmembrane secretory component (the poly-Ig receptor)rdquo

European Journal of Immunology vol 22 no 9 pp 2309ndash23151992

[118] J F Piskurich J A France C M Tamer C A Willmer CS Kaetzel and D M Kaetzel ldquoInterferon-120574 induces polymericimmunoglobulin receptormRNA in human intestinal epithelialcells by a protein synthesis dependent mechanismrdquo MolecularImmunology vol 30 no 4 pp 413ndash421 1993

[119] J F Piskurich M H Blanchard K R Youngman J A Franceand C S Kaetzel ldquoMolecular cloning of the mouse polymericIg receptor functional regions of the molecule are conservedamong five mammalian speciesrdquo The Journal of Immunologyvol 154 no 4 pp 1735ndash1747 1995

[120] M A Kulseth P Krajci O Myklebost and S RogneldquoCloning and characterization of two forms of bovine polymericimmunoglobulin receptor cDNArdquo DNA and Cell Biology vol14 no 3 pp 251ndash256 1995

[121] K S Koch A S Gleiberman T Aoki et al ldquoDiscordant expres-sion and variable numbers of neighboring GGA- and GAA-richtriplet repeats in the 31015840 untranslated regions of two groups ofmessenger RNAs encoded by the rat polymeric immunoglob-ulin receptor generdquo Nucleic Acids Research vol 23 no 7 pp1098ndash1112 1995

[122] F M Adamski and J Demmer ldquoTwo stages of increased IgAtransfer during lactation in themarsupialTrichosurus vulpecula(brushtail possum)rdquoThe Journal of Immunology vol 162 no 10pp 6009ndash6015 1999

[123] H Kumura T Sone K-I Shimazaki and E KobayashildquoSequence analysis of porcine polymeric immunoglobulinreceptor from mammary epithelial cells present in colostrumrdquoThe Journal of Dairy Research vol 67 no 4 pp 631ndash636 2000

[124] C L Taylor G A Harrison C M Watson and E M DeaneldquocDNA cloning of the polymeric immunoglobulin receptor ofthe marsupial Macropus eugenii (tammar wallaby)rdquo EuropeanJournal of Immunogenetics vol 29 no 2 pp 87ndash93 2002

[125] R Braathen V S Hohman P Brandtzaeg and F-E JohansenldquoSecretory antibody formation conserved binding interactionsbetween J chain and polymeric Ig receptor from humans andamphibiansrdquo The Journal of Immunology vol 178 no 3 pp1589ndash1597 2007

[126] M J Lewis BWagner R M Irvine and J MWoof ldquoIgA in thehorse cloning of equine polymeric Ig receptor and J chain andcharacterization of recombinant forms of equine IgArdquoMucosalImmunology vol 3 no 6 pp 610ndash621 2010

[127] A J Leon D Banner L Xu et al ldquoSequencing annotation andcharacterization of the influenza ferret infectomerdquo Journal ofVirology vol 87 no 4 pp 1957ndash1966 2013

[128] W H Wieland D Orzaez A Lammers H K ParmentierM W A Verstegen and A Schots ldquoA functional polymericimmunoglobulin receptor in chicken (Gallus gallus) indicatesancient role of secretory IgA inmucosal immunityrdquoBiochemicalJournal vol 380 no 3 pp 669ndash676 2004

[129] K Hamuro H Suetake N R Saha K Kikuchi and YSuzuki ldquoA teleost polymeric Ig receptor exhibiting two Ig-likedomains transports tetrameric IgM into the skinrdquo The Journalof Immunology vol 178 no 9 pp 5682ndash5689 2007

[130] J H W M Rombout S J L van der Tuin G Yang et alldquoExpression of the polymeric immunoglobulin receptor (pIgR)in mucosal tissues of common carp (Cyprinus carpio L)rdquo Fishand Shellfish Immunology vol 24 no 5 pp 620ndash628 2008

[131] L-N Feng D-Q Lu J-X Bei et al ldquoMolecular cloning andfunctional analysis of polymeric immunoglobulin receptor gene

ISRN Immunology 19

in orange-spotted grouper (Epinephelus coioides)rdquo ComparativeBiochemistry and Physiology B vol 154 no 3 pp 282ndash289 2009

[132] A E Oslashstergaard S A M Martin T Wang R J M Stet andC J Secombes ldquoRainbow trout (Oncorhynchus mykiss) pos-sessmultiple novel immunoglobulin-like transcripts containingeither an ITAM or ITIMsrdquo Developmental and ComparativeImmunology vol 33 no 4 pp 525ndash532 2009

[133] H Eiffert E Quentin and J Decker ldquoThe primary structureof the human free secretory component and the arrangementof disulfide bondsrdquo Hoppe-Seylerrsquos Zeitschrift fur PhysiologischeChemie vol 365 no 12 pp 1489ndash1495 1984

[134] E Fallgreen-Gebauer W Gebauer A Bastian et al ldquoThe cova-lent linkage of secretory component to IgA Structure of sIgArdquoBiological Chemistry Hoppe-Seyler vol 374 no 11 pp 1023ndash1028 1993

[135] J MWoof ldquoThe structure of IgArdquo inMucosal Immune DefenseImmunoglobulin A C S Kaetzel Ed chapter 1 pp 1ndash24Springer New York NY USA 2007

[136] A Bonner A Almogren P B Furtado M A Kerr and S JPerkins ldquoLocation of secretory component on the Fc edge ofdimeric IgA1 reveals insight into the role of secretory IgA1 inmucosal immunityrdquoMucosal Immunology vol 2 no 1 pp 74ndash84 2009

[137] A Bonner A Almogren P B Furtado M A Kerr and S JPerkins ldquoThe nonplanar secretory IgA2 and near planar secre-tory IgA1 solution structures rationalize their different mucosalimmune responsesrdquo The Journal of Biological Chemistry vol284 no 8 pp 5077ndash5087 2009

[138] J Johansen B Braathen and P Brandtzaeg ldquoRole of J chain insecretory immunoglobulin formationrdquo Scandinavian Journal ofImmunology vol 52 no 3 pp 240ndash248 2000

[139] B A Hendrickson D A Conner D J Ladd et al ldquoAlteredhepatic transport of immunoglobulin A in mice lacking the Jchainrdquo Journal of Experimental Medicine vol 182 no 6 pp1905ndash1911 1995

[140] B A Hendrickson L Rindisbacher B Corthesy et al ldquoLackof association of secretory component with IgA in J chain-deficient micerdquo The Journal of Immunology vol 157 no 2 pp750ndash754 1996

[141] N Lycke L Erlandsson L Ekman K Schon and T Lean-derson ldquoLack of J chain inhibits the transport of gut IgA andabrogates the development of intestinal antitoxic protectionrdquoThe Journal of Immunology vol 163 no 2 pp 913ndash919 1999

[142] F-E Johansen R Braathen and P Brandtzaeg ldquoThe J chainis essential for polymeric Ig receptor-mediated epithelial trans-port of IgArdquoThe Journal of Immunology vol 167 no 9 pp 5185ndash5192 2001

[143] R E Ley D A Peterson and J I Gordon ldquoEcological andevolutionary forces shaping microbial diversity in the humanintestinerdquo Cell vol 124 no 4 pp 837ndash848 2006

[144] M McFall-Ngai ldquoAdaptive immunity care for the communityrdquoNature vol 445 no 7124 p 153 2007

[145] A J Macpherson K D McCoy F-E Johansen and PBrandtzaeg ldquoThe immune geography of IgA induction andfunctionrdquoMucosal Immunology vol 1 no 1 pp 11ndash22 2008

[146] D Kvale and P Brandtzaeg ldquoConstitutive and cytokine inducedexpression of HLA molecules secretory component and inter-cellular adhesion molecule-1 is modulated by butyrate in thecolonic epithelial cell line HT-29rdquo Gut vol 36 no 5 pp 737ndash742 1995

[147] L VHooperMHWong AThelin L Hansson P G Falk andJ I Gordon ldquoMolecular analysis of commensal host-microbialrelationships in the intestinerdquo Science vol 291 no 5505 pp 881ndash884 2001

[148] S Hapfelmeier M A E Lawson E Slack et al ldquoReversiblemicrobial colonization of germ-free mice reveals the dynamicsof IgA immune responsesrdquo Science vol 328 no 5986 pp 1705ndash1709 2010

[149] DH ReikvamMDerrien R Islam et al ldquoEpithelial-microbialcross-talk in polymeric Ig receptor deficient micerdquo EuropeanJournal of Immunology vol 42 no 11 pp 2959ndash2970 2012

[150] EW Rogier A L Frantz M E C Bruno et al ldquoSecretory anti-bodies in breast milk promote long-term intestinal homeostasisby regulating the gut microbiota and host gene expressionrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 111 no 8 pp 3074ndash3079 2014

[151] G M Barton and R Medzhitov ldquoToll-like receptor signalingpathwaysrdquo Science vol 300 no 5625 pp 1524ndash1525 2003

[152] K Takeda and S Akira ldquoToll receptors and pathogen resis-tancerdquo Cellular Microbiology vol 5 no 3 pp 143ndash153 2003

[153] E Cario andD K Podolsky ldquoDifferential alteration in intestinalepithelial cell expression of Toll-like receptor 3 (TLR3) andTLR4 in inflammatory bowel diseaserdquo Infection and Immunityvol 68 no 12 pp 7010ndash7017 2000

[154] M Hausmann S Kiessling S Mestermann et al ldquoToll-likereceptors 2 and 4 are up-regulated during intestinal inflamma-tionrdquo Gastroenterology vol 122 no 7 pp 1987ndash2000 2002

[155] M T Abreu L S Thomas S Y Tesfay et al ldquoRegulation ofTLR4 and MD-2 in the intestinal epithelium evidence for dys-regulated LPS signaling in human inflammatory bowel diseaserdquoin Proceedings of the 90th Annual Meeting of the AmericanAssociation for Immunologists Abstract 3634 Denver ColoUSA 2003

[156] T A Schneeman M E C Bruno H Schjerven F-E JohansenL Chady and C S Kaetzel ldquoRegulation of the polymeric Igreceptor by signaling through TLRs 3 and 4 linking innate andadaptive immune responsesrdquo The Journal of Immunology vol175 no 1 pp 376ndash384 2005

[157] M E C Bruno A L Frantz E W Rogier F-E Johansen andC S Kaetzel ldquoRegulation of the polymeric immunoglobulinreceptor by the classical and alternative NF-120581B pathways inintestinal epithelial cellsrdquoMucosal Immunology vol 4 no 4 pp468ndash478 2011

[158] M E C Bruno E W Rogier A L Frantz A T Stefka SN Thompson and C S Kaetzel ldquoRegulation of the poly-meric immunoglobulin receptor in intestinal epithelial cellsby Enterobacteriaceae implications for mucosal homeostasisrdquoImmunological Investigations vol 39 no 4-5 pp 356ndash382 2010

[159] A L Frantz E W Rogier C R Weber et al ldquoTargeted deletionof MyD88 in intestinal epithelial cells results in compromisedantibacterial immunity associatedwith downregulation of poly-meric immunoglobulin receptor mucin-2 and antibacterialpeptidesrdquoMucosal Immunology vol 5 no 5 pp 501ndash512 2012

[160] E W Rogier A L Frantz M E C Bruno and C S KaetzelldquoSecretory IgA is concentrated in the outer layer of intestinalmucus along with gut bacteriardquo Pathogens In press

[161] M B Geuking K D McCoy and A J Macpherson ldquoThe func-tion of secretory IgA in the context of the intestinal continuumof adaptive immune responses in host-microbial mutualismrdquoSeminars in Immunology vol 24 no 1 pp 36ndash42 2012

20 ISRN Immunology

[162] L VHooper D R Littman andA JMacpherson ldquoInteractionsbetween the microbiota and the immune systemrdquo Science vol336 no 6086 pp 1268ndash1273 2012

[163] A J Macpherson M B Geuking E Slack S Hapfelmeierand K D McCoy ldquoThe habitat double life citizenship andforgetfulness of IgArdquo Immunological Reviews vol 245 no 1 pp132ndash146 2012

Submit your manuscripts athttpwwwhindawicom

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Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

ISRN Immunology 11

Linker

TMCytoplasmic

J chain

Hinge 1

2

34

5

CL

VLVH

C1205721C1205722 C1205723

(a)

Linker

TMCytoplasmic

J chain

1

3 4

5

CL

VL

VH

C1205941205721

C1205941205722C1205941205723 C1205941205724

(b)

11

5

LinkerTM

Cytoplasmic

5

CL

VL

VH

C1205911C1205912

C1205913 C1205914

pIgR Ig-like domain

H chain Ig-like domain

L chain Ig-like domain

J chain

Disulfide bond

(c)

Figure 7 Theoretical model for changes in the structure of secretory Igs during evolution (a) The structure for mammalian SIgA is adaptedfrom the model of Woof and Russell [16] for human SIgA1 with permission from Nature Publishing Group (b) and (c) Theoretical modelsfor the structure of IgXA from amphibians and birds and SIgT from teleost fish respectively are predicted from alignment of Ig heavy chainand pIgR sequences with mammalian homologs

well conserved in pIgR from birds and reptiles but not inpIgR from amphibians and fish suggesting that complexmechanisms of intracellular trafficking of pIgR coevolvedwith the increasing complexity of the mucosal immunesystem

7 Hypothetical Models for Changes inSecretory Ig Structure during Coevolutionof Mucosal Igs and pIgR

A large number of structural and functional analyses overthe past 30 years allowed the development of detailed modelsfor the structure of mammalian SIgA (reviewed in [111 135])(Figure 7(a)) Domains 1 and 5 of pIgR the most highlyconserved Ig-like domains associate with theC1205722 subunits oftwo adjacent IgA heavy chains in a near-planar structure [136137] During transcytosis a disulfide bond forms betweenhighly conserved cysteine residues in domain 5 of pIgRand the C1205722 domain of one of the IgA heavy chains [134]Domains 2 3 and 4 allow mammalian pIgR to assume aflexible extended structure which is thought to wrap aroundthe IgA heavy chains and protect against degradation fromhost and microbial proteases Binding of mammalian pIgRto polymeric IgA or IgM requires the presence of J chain

connecting the Ig subunits (reviewed in [138]) and J chain-deficient mice fail to transport IgA and IgM into externalsecretions [139ndash141] Structure-function studies usingmutantforms of human J chain suggested that J chain binds directlyto pIgR and also maintains polymeric Ig in an optimalconformation for pIgR binding and transcytosis [142] Theunstructured linker region connecting domain 5 of pIgRto the transmembrane (TM) region gives membrane-boundpIgR the flexibility to bind large polymeric Igs (with orwithout associated antigens) and provides an exposed site forproteolytic cleavage of pIgR to SC The C-terminal region ofpIgR extends past the cytoplasmic face of the plasma mem-brane allowing association with cytoplasmic factors thatregulate trafficking of pIgR with or without bound polymericIg

Although detailed structural studies have not yet beenperformed on secretory Igs from lower vertebrates hypo-thetical models can be constructed based on alignmentswith their mammalian homologs A model for secretoryIgXA in birds reptiles and amphibians is illustrated inFigure 7(b) showing the C

1205941205722 domain in place of the hinge

region ofmammalian IgAThenumbering of the extracellulardomains of pIgR corresponds to the homologous domainsin mammalian pIgR noting the absence of domain 2 In

12 ISRN Immunology

this model the C120594120572

3 domains of two adjacent IgXA heavychains (homologous to the C

1205722 domain of mammalian IgA)

bind to the highly conserved domains 1 and 5 of pIgRGiven the conservation of the analogous cysteine residuesin domain 5 of pIgR and the C

1205941205723 domain of IgXA it

is assumed that a disulfide bond forms between pIgR andpolymeric Ig during epithelial transcytosis in birds reptilesand amphibiansThe absence of domain 2 in pIgR from thesevertebrate orders necessitates a more rigid structure thanthat of mammalian pIgR with a corresponding decrease inits ability to wrap around the IgXA heavy chains and pro-vide protection against proteoltyic degradation Despite theshorter length of pIgR in birds reptiles and amphibians theassociation with the J chain subunit of polymeric IgXA stillappears to be required Recombinant pIgR from the Africanfrog (Xenopus laevis) was shown to bind with moderatelyhigh affinity to human polymeric IgA containing J chain butnot to monomeric IgA [125] The affinity of Xenopus pIgRfor human pIgA was improved when Xenopus J chain wassubstituted for human J chain in a chimeric polymeric IgAmolecule The lack of sequence conservation across speciesin the linker region connecting domain 5 of pIgR to the TMregion suggests that it acts as a nonspecific ldquospacerrdquo As statedabove the cytoplasmic region of pIgR appears to have evolvedover time to provide enhanced regulation of pIgR trafficking

The hypothetical structure of secretory IgT from teleostfish in Figure 7(c) illustrates how the most primitive form ofpIgR comprising only extracellular domains 1 and 5 couldassociate with polymeric Ig and mediate epithelial transcy-tosis Association of pIgR domain 1 with the C

1205913 domain of

IgT would preserve the functional homology with secretoryIgs in higher vertebrates The short length of teleost pIgRwould necessitate the association of domain 5 with a C

1205913

domain on one of the heavy chains of the same IgT ratherthan spanning across to the adjaent IgT subunit While thismodel preserves the highly conserved association of pIgRdomain 1 with the orthologous domain of the IgT heavychain it does not explain the selectivity of teleost pIgR forpolymeric rather than monomeric IgT Although there is noexperimental evidence to support this model it could behypothesized that dimerization of two pIgR molecules in theplasmamembrane is required for high affinity binding of IgTas illustrated in the model in Figure 7(c) This hypotheticalmodel would also explain the lack of a necessity for J chainin polymeric IgT since each subunit in the pIgR dimer wouldonly be in contact with one IgT subunit The unstructuredlinker region connecting domain 5 of pIgR to the TM regionwould provide flexibility for association of 2 membrane-bound pIgR molecules with a large polymeric IgT molecule

Taken together the structural models for secretory Igsshown in Figure 7 are consistent with the selection of a morefunctional pIgR molecule over evolutionary time Duplica-tion and diversification of the extracellular Ig-like domainsof pIgR would provide a longer more flexible surface forbinding to polymeric Igs with higher affinity and protectingthe Ig heavy chains against proteolytic attack Expansion ofthe cytoplasmic domain of pIgR and incorporation of motifsfor binding cytoplasmic proteins would allow regulated

trafficking of pIgR and polymeric Igs across mucosal andglandular epithelial cells Importantly these models illustratea potential path for coevolution of IGH and PIGR genesdriven by the common selective pressure to provide antigen-specific humoral immune responses at mucosal surfaces

8 Evidence that the CommensalMicrobiota Provided the Driving Force forCoevolution of Mucosal Igs and pIgR

From the earliest evolution of vertebrate animals mucosal Igshave been an integral part of the emerging adaptive immunesystem Clearly many environmental factors served as driv-ing forces for the evolution of the adaptive immune systemin vertebrates including a longer lifespan thanmany (but notall) invertebrates and amore diverse diet that could introducea broader range of potential gut pathogens However it hasbeen proposed that the most significant force may havebeen the dramatic increase in the numbers and complexityof the resident microbiota in the evolution of vertebratesfrom their invertebrate ancestors [1 143 144] Antibodiesin mucosal secretions contribute to immune homeostasis bylimiting access of microbes and their products to the bodyproper maintaining the integrity of the epithelial barrier andshaping the composition of the commensal microbiota infavor of metabolically beneficial microorganisms [145] Thepredominance of polymeric Igs in these secretions promotesthese functions by providing multiple antigen-binding sitesper Ig complex thus increasing the overall avidity of antigen-antibody interactions Structural and functional refinementsin mucosal Igs culminating with the multifunctional secre-tory IgA molecule in mammals have further enhanced theirability to enhance immune homeostasis

The early emergence of pIgR in vertebrate evolutionprovided a mechanism for efficient transport of mucosal Igsinto external secretions It is well documented that crosstalkbetween mucosal epithelial cells and the resident microbiotamodulates expression of pIgR (reviewed in [17 111 112]) andit is reasonable to assume that these host-microbe interac-tions provided a driving force for evolution of the PIGR genein vertebrates The first demonstration that gut bacteria maymodulate pIgR expression in epithelial cells was the findingthat butyrate a bacterial fermentation product and importantenergy source in the colon upregulated expression of pIgRin the human colonic epithelial cell line HT-29 [146] A rolefor commensal bacteria in pIgR regulation was subsequentlydemonstrated by the observation that pIgR expression wasincreased when germ-free mice were colonized with Bacteri-oides thetaiotaomicron a prominent organism of the normalmouse and human intestinal microbiota [147] Amore recentstudy using a model of reversible colonization of germ-free mice with a nondividing mutant of Escherichia colidemonstrated that a long-lived SIgA response could besustained that specifically recognized the inducing bacteria[148] However exposure of E coli-colonized mice to otherbacteria limited the duration of the SIgA response against theoriginal colonizer suggesting a dynamic equilibriumbetweenmembers of the gut microbial community and host SIgA A

ISRN Immunology 13

study from the laboratory of Finn-Eirik Johansen demon-strated that diversity of the bacterial community in the cecallumen was reduced in pIgR-knockoutmice supporting a rolefor SIgA in limiting overgrowth of selected species [149] Incontrast the community of bacteria adherent to the epithelialsurface was more diverse in pIgR-knockout mice than inwild-typemice and these adherent bacteria caused enhancedexpression of several epithelial antimicrobial peptides Thesefindings suggest that bacteria-specific SIgA anchored in themucus layer restricts adhesion of bacteria to the epithelialsurface and limits bacterial stimulation of host epithelial cellsA recent study from the authorrsquos laboratory employing abreeding scheme in which119875119894119892119903minusminus damswere bred to119875119894119892119903+minusmales and vice versa demonstrated that SIgA antibodiesin breast milk promote long-term intestinal homeostasis byregulating the gut microbiota and gene expression in colonicepithelial cells [150]

A direct role for commensal andor pathogenic bacteriain the regulation of pIgR expression suggests that the innateimmune system may ldquoprimerdquo epithelial cells for transportof polymeric Ig produced during the adaptive immuneresponse Host cells mediate innate immune responses tomicrobial components through toll-like receptor (TLR) sig-naling (reviewed in [151 152]) Intestinal epithelial cells havebeen shown to express a wide variety of TLRs the expressionof which is upregulated during intestinal inflammation [153ndash155] Significantly expression of pIgR was shown to beupregulated in the HT-29 human intestinal epithelial cellline by bacterial LPS a ligand for TLR4 [156 157] Similarinduction of PIGR gene transcription was seen followingdirect binding of bacteria of the family Enterobacteriaceaewhich express a form of LPS that stimulates TLR4 [158]A recent study from the authorrsquos laboratory demonstratedthat shRNA-mediated knockdown of myeloid differentiationprimary response protein 88 (MyD88) a cytoplasmic adapterprotein that transduces signals from cell surface TLR4blocked the induction of PIGR gene transcription by LPS inHT-29 cells [159] The in vivo significance was confirmed bythe finding that mice with a targeted deletion of the Myd88gene only in intestinal epithelial cells had reduced expressionof pIgR compared to wild-type littermates [159] Mice withtargeted depletion of MyD88 in intestinal epithelial cells alsoexhibited reduced expression of mucin-2 the major compo-nent of the intestinal mucus layer and several antimicrobialpeptides and decreased transmucosal electrical resistanceThese alterations in epithelial barrier function were accom-panied by significant changes in the composition of the fecalmicrobiota increased numbers of bacteria adherent to theintestinal mucus layer and a dramatic increase in transloca-tion of gut bacteria into the drainingmesenteric lymphnodesincluding the opportunistic pathogen Klebsiella pneumoniaeThese findings demonstrate that MyD88-mediated crosstalkbetween the gut microbiota and intestinal epithelial cells iscrucial for optimal expression of pIgR production of SIgAdevelopment of a healthy gut microbiota and maintenanceof intestinal homeostasis

A model can be proposed in which continuous stimu-lation of intestinal epithelial cells by gut bacteria regulates

Lumen

Mucus

Epithelium

Lamina

PIGR

TLRs

MyD88

Bacteria

Plasma cells

propria

Polymeric Ig

Polymeric Ig receptor

Secretory component

Figure 8 Crosstalk between the polymeric immunoglobulin recep-tor secretory immunoglobulins and the gut microbiotaThe single-layered epithelium that lines the gastrointestinal tract is coveredwith a thick mucus layer which physically excludes members ofthe resident microbiota but allows diffusion of shed components ofmicrobial cells Stimulation of epithelial toll-like receptors (TLRs)with microbial products engages the cytoplasmic adaptor proteinMyD88 and initiates NF120581B-dependent signaling pathways Translo-cation of activated NF120581B and other transcription factors to thenucleus enhances transcription of thePIGR gene Activation of TLRsmay also stimulate pIgR transcytosis Polymeric Igs secreted bylamina propria plasma cells bind to pIgRon the basolateral surface ofepithelial cells and are transcytosed to the apical surface along withunoccupied pIgR Proteolytic cleavage of pIgR at the apical surfacereleases secretory SIg and free secretory component (SC) Binding ofSIg and SC to luminal bacteria promotes association with themucuslayer and prevents direct access of bacteria to the epithelial surfaceOver time the continuous crosstalk with SIg shapes the compositionof the gut microbiota Modified from [17] under terms of authorrsquoscopyright with Nature Publishing Group

pIgR expression and transport of SIgA and promotes immuneexclusion of resident and pathogenic bacteria (Figure 8) Adense layer of mucus which increases in thickness fromthe proximal to the distal colon serves to separate bacteriafrom direct contact with the epithelial surface Secretionof microbial-associated molecular patterns (MAMPs) bycommensal bacteria stimulates MyD88-dependent TLR sig-naling leading to enhanced expression of pIgR and antimi-crobial peptides and increased mucus production Bindingof pIgA to pIgR and possibly also signaling via MAMPs

14 ISRN Immunology

enhances transcytosis of pIgA pIgA-containing immunecomplexes and unoccupied pIgR which promotes clearanceof antigens and pathogens from the lamina propria intra-cellular neutralization and release of SIgA and SC at theluminal surface SIgA and SC serve to trap bacteria in themucus layer limiting their access to the epithelial surface Inmice with a targeted deletion of the Muc2 gene which havea severely depleted mucus layer in the colon SIgA and SCfail to associate with the surface of colonic epithelial cells[160] The presence of SIgA in the intestinal lumen whetherderived passively frommaternalmilk or actively via epithelialtranscytosis shapes the composition of the gut microbiotaand modulates intestinal epithelial gene expression

9 Concluding Remarks

The first microbes that emerged on Earth almost 4 billionyears ago encountered a hostile world where nutrients werescarce hazards were everywhere and life was short Withthe evolution of multicellular organisms about 3 billion yearslater a select group ofmicrobes chose to sacrifice an indepen-dent existence for the benefits of a mutualistic relationshipwith eukaryotic hosts Prokaryotic-eukaryotic mutualismreached its apex some 500 million years ago with theemergence of primitive vertebrates whose gastrointestinaltracts were populated by an abundant and diverse commensalmicrobiota In humans the large intestine is home to some100 trillion microorganisms 10 times more than the totalnumber of eukaryotic cells in the entire body The microbesthat inhabit the vertebrate GI tract provide many benefitsto the eukaryotic host including digestion of complex foodmolecules synthesis of vitamins and production of solublefactors that enhance the development of the host immunesystem In return the eukaryotic host provides the microbeswith a warm moist place to live abundant food low oxygentension and a soft bed of mucus on which to form biofilmsWhen this mutually beneficial arrangement is challenged bypathogenicmicrobes the eukaryotic host and the commensalmicrobiota join forces to battle the pathogens and protectthe body from invasion The vertebrate immune system isequipped with a well-trained army of immune cells and asophisticated arsenal of weapons (cell surface molecules andsecreted factors) that protect the host from all but the mostvirulent pathogens This immune ldquoarmyrdquo also serves as aconstant reminder to the commensal microbes that whilethey are free to enjoy the amenities of the mucosal surfacesthey are not welcome in the body proper The emergence ofantigen-specific Igs and T-cell receptors in jawed vertebratesbegan a process of immunological diversification that led tothe development of a specialized mucosal immune systemin higher vertebrates in which secretory Igs play a centralrole The relationship between host and microbiota is clearlyreciprocal the mucosal Igs that evolved in response toselective pressure from the commensal microbiota play acentral role throughout life in shaping the compositiongenetics andmetabolic activity of themicrobiota [1 161 162]

The epithelial layer lining mucosal surfaces provides aphysical and innate immune barrier against penetration of

the body proper by microbes undigested food antigens andpotentially noxious environmental substances The evolu-tionary challenge of transporting mucosal Igs into externalsecretions without compromising the epithelial barrier wasmet by the emergence of the PIGR gene in an ancestor ofbony fishes encoding an epithelial-specific transmembraneprotein that actively transports polymeric Igs across mucosaland glandular epithelia (Figure 4) Structural similaritiesbetween Igs and the extracellular Ig-binding domains of pIgR(Figure 6) suggest that duplication and diversification of agene encoding primordial Ig-like domain may have givenrise to the PIGR gene in a primitive vertebrate ancestorParallel refinement of the structures of mucosal Igs andpIgR during tetrapod evolution (Figures 6 and 7) culminatedin the evolution of the multifunctional SIgA molecule inmammals in which the pIgR-derived SC subunit providesinnate immune functions and protects the antigen-bindingIgA polymer from proteolytic degradation In addition toacting as a powerful force during vertebrate evolution thereciprocal relationship between pIgR mucosal Igs and thecommensal microbiota provides benefits throughout thelife of the individual Microbial colonization of newbornvertebrates stimulates development of mucosal B cells andclass switching to mucosal Ig isotypes [1 163] Microbialfactors upregulate expression of pIgR enhancing transportof mucosal Igs into external secretions where they in turnregulate the microbiotaThis beautifully orchestrated processallows us to maintain a healthy relationship with our resi-dent microbiota while providing mutual protection againstpathogens

Conflict of Interests

The author declares that there is no conflict of interestsregarding the publication of this paper

Acknowledgments

This work was supported by Grant no AI069027 from theNational Institutes of Health of the United States of America(and an associatedAmerican Recovery andReinvestmentActsupplement) and a Senior Research Award from the Crohnrsquosand Colitis Foundation of America

References

[1] C L Maynard C O Elson R D Hatton and C T WeaverldquoReciprocal interactions of the intestinal microbiota andimmune systemrdquo Nature vol 489 no 7415 pp 231ndash241 2012

[2] M F Flajnik and M Kasahara ldquoOrigin and evolution of theadaptive immune system genetic events and selective pres-suresrdquo Nature Reviews Genetics vol 11 no 1 pp 47ndash59 2010

[3] M F Flajnik and L du Pasquier ldquoEvolution of the immunesystemrdquo in Fundamental Immunology W E Paul Ed chapter4 pp 67ndash128 Lippincott Williams ampWilkins Philadelphia PaUSA 2012

[4] M Hirano S Das P Guo and M D Cooper ldquoThe evolutionof adaptive immunity in vertebratesrdquo Advances in Immunologyvol 109 pp 125ndash157 2011

ISRN Immunology 15

[5] T BoehmNMcCurley Y SutohM SchorppMKasahara andM D Cooper ldquoVLR-based adaptive immunityrdquo Annual Reviewof Immunology vol 30 pp 203ndash220 2012

[6] T Hunkapiller and L Hood ldquoImmunology the growing immu-noglobulin gene superfamilyrdquoNature vol 323 no 6083 pp 15ndash16 1986

[7] P Bork L Holm and C Sander ldquoThe immunoglobulin foldstructural classification sequence patterns and common corerdquoJournal of Molecular Biology vol 242 no 4 pp 309ndash320 1994

[8] C S Kaetzel and M W Russell ldquoPhylogeny and comparativephysiology of IgArdquo in Mucosal Immunology J Mestecky WStrober H Cheroutre B Kelsall B N Lambrecht and M WRussell Eds chapter 19 Academic PressElsevier WalthamMass USA 2014

[9] Y He and P J Bjorkman ldquoStructure of FcRY an avian immu-noglobulin receptor related to mammalian mannose receptorsand its complex with IgYrdquo Proceedings of the National Academyof Sciences of the United States of America vol 108 no 30 pp12431ndash12436 2011

[10] J M Woof and D R Burton ldquoHuman antibody-Fc receptorinteractions illuminated by crystal structuresrdquo Nature ReviewsImmunology vol 4 no 2 pp 89ndash99 2004

[11] W L Martin A P West Jr L Gan and P J Bjorkman ldquoCrystalstructure at 28 A of an FcRnheterodimeric Fc complexmechanism of pH-dependent bindingrdquo Molecular Cell vol 7no 4 pp 867ndash877 2001

[12] E S Ward ldquoAcquiring maternal immunoglobulin differentreceptors similar functionsrdquo Immunity vol 20 no 5 pp 507ndash508 2004

[13] C S Kaetzel ldquoThe polymeric immunoglobulin receptor bridg-ing innate and adaptive immune responses atmucosal surfacesrdquoImmunological Reviews vol 206 no 1 pp 83ndash99 2005

[14] M Acharya G Borland A L Edkins et al ldquoCD23Fc120576RIImolecular multi-taskingrdquo Clinical and Experimental Immunol-ogy vol 162 no 1 pp 12ndash23 2010

[15] V B Klimovich ldquoIgM and its receptors structural and func-tional aspectsrdquo Biochemistry vol 76 no 5 pp 534ndash549 2011

[16] J MWoof andMW Russell ldquoStructure and function relation-ships in IgArdquo Mucosal Immunology vol 4 no 6 pp 590ndash5972011

[17] F-E Johansen and C S Kaetzel ldquoRegulation of the polymericimmunoglobulin receptor and IgA transport new advances inenvironmental factors that stimulate pIgR expression and itsrole in mucosal immunityrdquo Mucosal Immunology vol 4 no 6pp 598ndash602 2011

[18] F Kokubu K Hinds R Litman M J Shamblott and G WLitman ldquoExtensive families of constant region genes in a phy-logenetically primitive vertebrate indicate an additional levelof immunoglobulin complexityrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 84 no16 pp 5868ndash5872 1987

[19] A S Greenberg A L Hughes J Guo D Avila E CMcKinneyand M F Flajnik ldquoA novel ldquochimericrdquo antibody class in carti-laginous fish IgMmay not be the primordial immunoglobulinrdquoEuropean Journal of Immunology vol 26 no 5 pp 1123ndash11291996

[20] H Dooley and M F Flajnik ldquoShark immunity bites back affin-ity maturation and memory response in the nurse shark Ging-lymostoma cirratumrdquo European Journal of Immunology vol 35no 3 pp 936ndash945 2005

[21] S F Schluter R M Bernstein and J J Marchalonis ldquoMolecularorigins and evolution of immunoglobulin heavy-chain genes ofjawed vertebratesrdquo Immunology Today vol 18 no 11 pp 543ndash549 1997

[22] Y Ohta and M Flajnik ldquoIgD like IgM is a primordial immu-noglobulin class perpetuated in most jawed vertebratesrdquo Pro-ceedings of the National Academy of Sciences of the United Statesof America vol 103 no 28 pp 10723ndash10728 2006

[23] S Fillatreau A Six S Magadan R Castro J O Sunyer andP Boudinot ldquoThe astonishing diversity of Ig classes and B cellrepertoires in teleost fishrdquo Frontiers in Immunology vol 4 no28 2013

[24] W Harriman H Volk N Defranoux and M Wabl ldquoImmu-noglobulin class switch recombinationrdquo Annual Review ofImmunology vol 11 pp 361ndash384 1993

[25] J Stavnezer and C T Amemiya ldquoEvolution of isotype switch-ingrdquo Seminars in Immunology vol 16 no 4 pp 257ndash275 2004

[26] V M Barreto Q Pan-Hammarstrom Y Zhao L Ham-marstrom Z Misulovin and M C Nussenzweig ldquoAID frombony fish catalyzes class switch recombinationrdquo Journal ofExperimental Medicine vol 202 no 6 pp 733ndash738 2005

[27] T C Fletcher and AWhite ldquoAntibody production in the plaice(Pleuronectes platessa L) after oral and parenteral immuniza-tion with Vibrio anguillarum antigensrdquo Aquaculture vol 1 pp417ndash428 1972

[28] J W H M Rombout L J Blok C H J Lamers and E EgbertsldquoImmunization of carp (Cyprinus carpio) with a Vibrio anguil-larum bacterin indications for a common mucosal immunesystemrdquo Developmental and Comparative Immunology vol 10no 3 pp 341ndash351 1986

[29] U Georgopoulou and J-M Vernier ldquoLocal immunologicalresponse in the posterior intestinal segment of the rainbowtrout after oral administration of macromoleculesrdquo Develop-mental andComparative Immunology vol 10 no 4 pp 529ndash5371986

[30] C J Lobb ldquoSecretory immunity induced in catfish Ictaluruspunctatus following bath immunizationrdquo Developmental andComparative Immunology vol 11 no 4 pp 727ndash738 1987

[31] J D Hansen E D Landis and R B Phillips ldquoDiscovery ofa unique Ig heavy-chain (IgT) in rainbow trout implicationsfor a distinctive B cell developmental pathway in teleost fishrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 102 no 19 pp 6919ndash6924 2005

[32] N Danilova J Bussmann K Jekosch and L A Steiner ldquoTheimmunoglobulin heavy-chain locus in zebrafish identificationand expression of a previously unknown isotype immunoglob-ulin Zrdquo Nature Immunology vol 6 no 3 pp 295ndash302 2005

[33] R Savan A Aman K Sato R Yamaguchi and M Sakai ldquoDis-covery of a new class of immunoglobulin heavy chain fromfugurdquo European Journal of Immunology vol 35 no 11 pp 3320ndash3331 2005

[34] R Savan A AmanMNakao HWatanuki andM Sakai ldquoDis-covery of a novel immunoglobulin heavy chain gene chimerafrom common carp (Cyprinus carpio L)rdquo Immunogenetics vol57 no 6 pp 458ndash463 2005

[35] F Gambon-Deza C Sanchez-Espinel and S Magadan-Mompo ldquoPresence of an unique IgT on the IGH locus in three-spined stickleback fish (Gasterosteus aculeatus) and the veryrecent generation of a repertoire of VH genesrdquo Developmentaland Comparative Immunology vol 34 no 2 pp 114ndash122 2010

[36] T M Tadiso K K Lie and I Hordvik ldquoMolecular cloning ofIgT fromAtlantic salmon and analysis of the relative expression

16 ISRN Immunology

of 120591 120583 and 120575 in different tissuesrdquo Veterinary Immunology andImmunopathology vol 139 no 1 pp 17ndash26 2011

[37] S Mashoof C Pohlenz P L Chen et al ldquoExpressed IgH 120583and 120591 transcripts share diversity segment in ranched Thunnusorientalisrdquo Developmental and Comparative Immunology vol43 no 1 pp 76ndash86 2014

[38] Y-A Zhang I Salinas J Li et al ldquoIgT a primitive immunoglob-ulin class specialized in mucosal immunityrdquo Nature Immunol-ogy vol 11 no 9 pp 827ndash835 2010

[39] S Magadan-Mompo C Sanchez-Espinel and F Gambon-Deza ldquoImmunoglobulin heavy chains in medaka (Oryziaslatipes)rdquo BMC Evolutionary Biology vol 11 no 1 article 1652011

[40] C T Amemiya J Alfoldi A P Lee et al ldquoThe African coela-canth genome provides insights into tetrapod evolutionrdquoNature vol 496 no 7445 pp 311ndash316 2013

[41] T Ota J P Rast G W Litman and C T Amemiya ldquoLineage-restricted retention of a primitive immunoglobulin heavy chainisotype within the Dipnoi reveals an evolutionary paradoxrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 100 no 5 pp 2501ndash2506 2003

[42] Y Sun Z Wei N Li and Y Zhao ldquoA comparative overview ofimmunoglobulin genes and the generation of their diversity intetrapodsrdquo Developmental and Comparative Immunology vol39 no 1-2 pp 103ndash109 2013

[43] I Hadji-Azimi ldquoAnuran immunoglobulins a reviewrdquo Develop-mental and Comparative Immunology vol 3 no 2 pp 223ndash2431979

[44] E Hsu M F Flajnik and L du Pasquier ldquoA third immunoglob-ulin class in amphibiansrdquo The Journal of Immunology vol 135no 3 pp 1998ndash2004 1985

[45] C T Amemiya R N Haire and G W Litman ldquoNucleotidesequence of a cDNA encoding a third distinct Xenopusimmunoglobulin heavy chain isotyperdquo Nucleic Acids Researchvol 17 no 13 p 5388 1989

[46] R Muszligmann M Wilson A Marcuz M Courtet and L duPasquier ldquoMembrane exon sequences of the three Xenopus Igclasses explain the evolutionary origin of mammalian isotypesrdquoEuropean Journal of Immunology vol 26 no 2 pp 409ndash4141996

[47] R Muszligmann L du Pasquier and E Hsu ldquoIs Xenopus IgX ananalog of IgArdquo European Journal of Immunology vol 26 no12 pp 2823ndash2830 1996

[48] B Schaerlinger and J-P Frippiat ldquoIgX antibodies in the urodeleamphibian Ambystoma mexicanumrdquo Developmental and Com-parative Immunology vol 32 no 8 pp 908ndash915 2008

[49] B Schaerlinger M Bascove and J-P Frippiat ldquoA new isotypeof immunoglobulin heavy chain in the urodele amphibianPleurodeles waltl predominantly expressed in larvaerdquoMolecularImmunology vol 45 no 3 pp 776ndash786 2008

[50] S Mashoof A Goodroe C C Du et al ldquoAncient T-independence of mucosal IgXA gut microbiota unaffected bylarval thymectomy in Xenopus laevisrdquo Mucosal Immunologyvol 6 no 2 pp 358ndash368 2013

[51] J P Vaerman J Picard and J F Heremans ldquoStructural dataon chicken IgA and failure to identify the IgA of the tortoiserdquoin Immunologic Phylogeny vol 64 of Advances in ExperimentalMedicine and Biology pp 185ndash195 Springer New York NYUSA 1975

[52] J L Portis and J E Coe ldquoIgM the secretory immunoglobulinof reptiles and amphibiansrdquo Nature vol 258 no 5535 pp 547ndash548 1975

[53] J E Coe D Leong J L Portis and L A Thomas ldquoImmuneresponse in the garter snake (Thamnophis ordinoides)rdquo Immu-nology vol 31 no 3 pp 417ndash424 1976

[54] D Hadge and H Ambrosius ldquoEvolution of low molecularweight immunoglobulinsmdashIV IgY-like immunoglobulins ofbirds reptiles and amphibians precursors of mammalian IgArdquoMolecular Immunology vol 21 no 8 pp 699ndash707 1984

[55] D Hadge and H Ambrosius ldquoEvolution of low molecularweight immunoglobulins V Degree of antigenic relationshipbetween the 7S immunoglobulins ofmammals birds and lowervertebrates to the turkey IgYrdquo Developmental and ComparativeImmunology vol 10 no 3 pp 377ndash385 1986

[56] S Magadan-Mompo C Sanchez-Espinel and F Gambon-Deza ldquoImmunoglobulin genes of the turtlesrdquo Immunogeneticsvol 65 no 3 pp 227ndash237 2013

[57] Z Wei Q Wu L Ren et al ldquoExpression of IgM IgD and IgYin a reptile Anolis carolinensisrdquoThe Journal of Immunology vol183 no 6 pp 3858ndash3864 2009

[58] F Gambon-Deza C Sanchez-Espinel and J V Beneitez ldquoAnovel IgA-like immunoglobulin in the reptile Eublepharis mac-ulariusrdquo Developmental and Comparative Immunology vol 31no 6 pp 596ndash605 2007

[59] G Cheng Y Gao T Wang et al ldquoExtensive diversification ofIgH subclass-encoding genes and IgM subclass switching incrocodiliansrdquo Nature Communications vol 4 article 1337 2013

[60] S Magadan-Mompo C Sanchez-Espinel and F Gambon-Deza ldquoIgH loci of American alligator and saltwater crocodileshed light on IgA evolutionrdquo Immunogenetics vol 65 no 7 pp531ndash541 2013

[61] E Orlans and M E Rose ldquoAn IgA-like immunoglobulin in thefowlrdquo Immunochemistry vol 9 no 8 pp 833ndash838 1972

[62] G A Leslie and L N Martin ldquoStudies on the secretory immu-nologic system of fowl 3 Serum and secretory IgA of thechickenrdquoThe Journal of Immunology vol 110 no 1 pp 1ndash9 1973

[63] J Bienenstock D Y Perey J Gauldie and B J UnderdownldquoChicken 120574A physicochemical and immunochemical charac-teristicsrdquoThe Journal of Immunology vol 110 no 2 pp 524ndash5331973

[64] A M Lebacq-Verheyden J P Vaerman and J F HeremansldquoQuantification and distribution of chicken immunoglobulinsIgA IgM and IgG in serum and secretionsrdquo Immunology vol27 no 4 pp 683ndash692 1974

[65] J Goudswaard A Noordzij R H van Dam J A vanderDonk and J P Vaerman ldquoThe immunoglobulins of the turkey(Meleagris gallopavo) Isolation and characterization of IgGIgM and IgA in body fluids eggs and intraocular tissuesrdquoPoultry science vol 56 no 6 pp 1847ndash1851 1977

[66] D Hadge and H Ambrosius ldquoComparative studies on thestructure of biliary immunoglobulins of some avian speciesII Antigenic properties of the biliary immunoglobulins ofchicken turkey duck and gooserdquo Developmental and Compar-ative Immunology vol 12 no 2 pp 319ndash329 1988

[67] J Goudswaard J P Vaerman and J F Heremans ldquoThreeimmunoglobulin classes in the pigeon (Columbia livia)rdquo Inter-national Archives of Allergy andApplied Immunology vol 53 no5 pp 409ndash419 1977

[68] P L K Ng and D A Higgins ldquoBile immunoglobulin of theduck (Anas platyrhynchos) I Preliminary characterization andontogenyrdquo Immunology vol 58 no 2 pp 323ndash327 1986

[69] K E Magor G W Warr Y Bando D L Middleton and DA Higgins ldquoSecretory immune system of the duck (Anas

ISRN Immunology 17

platyrhynchos) Identification and expression of the genesencoding IgA and IgM heavy chainsrdquo European Journal ofImmunology vol 28 no 3 pp 1063ndash1068 1998

[70] Y Zhao H Rabbani A Shimizu and L Hammarstrom ldquoMap-ping of the chicken immunoglobulin heavy-chain constantregion gene locus reveals an inverted 120572 gene upstream of acondensed 120592 generdquo Immunology vol 101 no 3 pp 348ndash3532000

[71] M L Lundqvist D L Middleton S Hazard and G W WarrldquoThe immunoglobulin heavy chain locus of the duck genomicorganization and expression of D J and C region genesrdquo TheJournal of Biological Chemistry vol 276 no 50 pp 46729ndash46736 2001

[72] T HuangM Zhang ZWei et al ldquoAnalysis of immunoglobulintranscripts in the ostrich Struthio camelus a primitive avianspeciesrdquo PLoS ONE vol 7 no 3 Article ID e34346 2012

[73] K H Roux ldquoImmunoglobulin structure and function asrevealed by electron microscopyrdquo International Archives ofAllergy and Immunology vol 120 no 2 pp 85ndash99 1999

[74] F Gambon-Deza C Sanchez-Espinel and S Magadan-Mompo ldquoThe immunoglobulin heavy chain locus in the platy-pus (Ornithorhynchus anatinus)rdquo Molecular Immunology vol46 no 13 pp 2515ndash2523 2009

[75] Y Zhao H Cui C M Whittington et al ldquoOrnithorhynchusanatinus (platypus) links the evolution of immunoglobulingenes in eutherian mammals and nonmammalian tetrapodsrdquoThe Journal of Immunology vol 183 no 5 pp 3285ndash3293 2009

[76] M Aveskogh and L Hellman ldquoEvidence for an early appear-ance of modern post-switch isotypes in mammalian evolutioncloning of IgE IgG and IgA from the marsupial Monodelphisdomesticardquo European Journal of Immunology vol 28 no 9 pp2738ndash2750 1998

[77] K Belov G A Harrison and DW Cooper ldquoMolecular cloningof the cDNA encoding the constant region of the immunoglob-ulin a heavy chain (C120572) from amarsupialTrichosurus vulpecula(common brushtail possum)rdquo Immunology Letters vol 60 no2-3 pp 165ndash170 1998

[78] K Belov K R Zenger L Hellman and DW Cooper ldquoEchidnaIgA supports mammalian unity and traditional Therian rela-tionshiprdquo Mammalian Genome vol 13 no 11 pp 656ndash6632002

[79] K Belov and L Hellman ldquoImmunoglobulin genetics of Orni-thorhynchus anatinus (platypus) and Tachyglossus aculeatus(short-beaked echidna)rdquo Comparative Biochemistry and Phys-iology vol 136 no 4 pp 811ndash819 2003

[80] M VernerssonM Aveskogh BMunday and L Hellman ldquoEvi-dence for an early appearance of modern post-switch immu-noglobulin isotypes in mammalian evolution (II) cloning ofIgE IgG1 and IgG2 fromamonotreme the duck-billed platypusOrnithorhynchus anatinusrdquo European Journal of Immunologyvol 32 no 8 pp 2145ndash2155 2002

[81] C Auffray R Nageotte and J L Sikorav ldquoMouse immunoglob-ulin A nucleotide sequence of the structural gene for the 120572heavy chain derived from cloned cDNAsrdquo Gene vol 13 no 4pp 365ndash374 1981

[82] T Ukaji D Sumiyama and O Kai ldquoSequence determinationof the heavy-chain constant region in four immunoglobulinclasses of Mongolian gerbils (Meriones unguiculatus)rdquo Experi-mental Animals vol 61 no 2 pp 99ndash107 2012

[83] R C Burnett W C Hanly S K Zhai and K L Knight ldquoTheIgA heavy chain gene family in rabbit cloning and sequence

analysis of 13 C120572 genesrdquo The EMBO Journal vol 8 no 13 pp4041ndash4047 1989

[84] D K Lanning S-K Zhai and K L Knight ldquoAnalysis of the 31015840C120583 region of the rabbit Ig heavy chain locusrdquoGene vol 309 no2 pp 135ndash144 2003

[85] F Ros J Puels N Reichenberger W van Schooten R Buelowand J Platzer ldquoSequence analysis of 05Mb of the rabbitgermline immunoglobulin heavy chain locusrdquo Gene vol 330no 1-2 pp 49ndash59 2004

[86] M Patel D Selinger G E Mark G J Hickey and G FHollis ldquoSequence of the dog immunoglobulin alpha and epsilonconstant region genesrdquo Immunogenetics vol 41 no 5 pp 282ndash286 1995

[87] Z Zhao Y Zhao Q Pan-Hammarstrom et al ldquoPhysical map-ping of the giant panda immunoglobulin heavy chain constantregion genesrdquo Developmental and Comparative Immunologyvol 31 no 10 pp 1034ndash1049 2007

[88] W R Brown and J E Butler ldquoCharacterization of a C120572 gene ofswinerdquoMolecular Immunology vol 31 no 8 pp 633ndash642 1994

[89] W R Brown H Rabbani J E Butler and L HammarstromldquoCharacterization of the bovine C120572 generdquo Immunology vol 91no 1 pp 1ndash6 1997

[90] G PWhite P Roche M R Brandon S E Newton and E N TMeeusen ldquoCloning and characterization of sheep (Ovis aries)immunoglobulin 120572 chainrdquo Immunogenetics vol 48 no 5 pp359ndash362 1998

[91] AMancia T A Romano H A Gefroh et al ldquoCharacterizationof the immunoglobulin A heavy chain gene of the Atlantic bot-tlenose dolphin (Tursiops truncatus)rdquo Veterinary Immunologyand Immunopathology vol 118 no 3-4 pp 304ndash309 2007

[92] B Wagner I Greiser-Wilke and D F Antczak ldquoCharacteriza-tion of the horse [Equus caballus] IGHA generdquo Immunogeneticsvol 55 no 8 pp 552ndash560 2003

[93] N Takahashi S Ueda and M Obata ldquoStructure of humanimmunoglobulin gamma genes implications for evolution of agene familyrdquo Cell vol 29 no 2 pp 671ndash679 1982

[94] J G Flanagan M-P Lefranc and T H Rabbitts ldquoMechanismsof divergence and convergence of the human immunoglobulin1205721 and 1205722 constant region gene sequencesrdquo Cell vol 36 no 3pp 681ndash688 1984

[95] S Kawamura K Omoto and S Ueda ldquoEvolutionary hypervari-ability in the hinge region of the immunoglobulin alpha generdquoJournal of Molecular Biology vol 215 no 2 pp 201ndash206 1990

[96] F Scinicariello F Masseoud L Jayashankar and R AttanasioldquoSooty mangabey (Cercocebus torquatus atys) IGHG and IGHAgenesrdquo Immunogenetics vol 58 no 12 pp 955ndash965 2006

[97] K A Rogers L Jayashankar F Scinicariello and R AttanasioldquoNonhuman primate IgA genetic heterogeneity and interac-tions with CD89rdquoThe Journal of Immunology vol 180 no 7 pp4816ndash4824 2008

[98] S Kawamura N Saitou and S Ueda ldquoConcerted evolution ofthe primate immunoglobulin 120572-gene through gene conversionrdquoThe Journal of Biological Chemistry vol 267 no 11 pp 7359ndash7367 1992

[99] S Kawamura and S Ueda ldquoImmunoglobulin C119867gene family in

hominoids and its evolutionary historyrdquo Genomics vol 13 no1 pp 194ndash200 1992

[100] A Brusco U Cariota A Bottaro et al ldquoStructural andimmunologic analysis of gene triplications in the Ig heavy chainconstant region locusrdquoThe Journal of Immunology vol 152 no1 pp 129ndash135 1994

18 ISRN Immunology

[101] H Rabbani Q Pan N Kondo C I E Smith and L Ham-marstrom ldquoDuplications and deletions of the human IGHClocus evolutionary implicationsrdquo Immunogenetics vol 45 no2 pp 136ndash141 1996

[102] P F Weinheimer J Mestecky and R T Acton ldquoSpecies distri-bution of J chainrdquoThe Journal of Immunology vol 107 no 4 pp1211ndash1212 1971

[103] F P Inman and J Mestecky ldquoThe J chain of polymeric immu-noglobulinsrdquo inContemporary Topics inMolecular Immunologyvol 3 pp 111ndash141 Springer New York NY USA 1974

[104] P Brandtzaeg ldquoPresence of J chain in human immunocytescontaining various immunoglobulin classesrdquo Nature vol 252no 5482 pp 418ndash420 1974

[105] L Tacchi E Larragoite and I Salinas ldquoDiscovery of J chain inAfrican lungfish (Protopterus dolloi Sarcopterygii) using highthroughput transcriptome sequencing implications in mucosalimmunityrdquo PLoS ONE vol 8 no 8 Article ID e70650 2013

[106] I K Zarkadis D Mastellos and J D Lambris ldquoPhylogeneticaspects of the complement systemrdquo Developmental and Com-parative Immunology vol 25 no 8-9 pp 745ndash762 2001

[107] A P West Jr A B Herr and P J Bjorkman ldquoThe chickenyolk sac IgY receptor a functional equivalent of themammalianMHC-related Fc receptor is a phospholipase A

2receptor

homologrdquo Immunity vol 20 no 5 pp 601ndash610 2004[108] D B Tesar E J Cheung and P J Bjorkman ldquoThe chicken

yolk sac IgY receptor a mammalian mannose receptor familymember transcytoses IgY across polarized epithelial cellsrdquoMolecular Biology of the Cell vol 19 no 4 pp 1587ndash1593 2008

[109] A I Taylor R L Beavil B J Sutton and R A Calvert ldquoAmonomeric chicken IgY receptor binds IgY with 21 stoichiom-etryrdquo The Journal of Biological Chemistry vol 284 no 36 pp24168ndash24175 2009

[110] K Baker S-W Qiao T Kuo et al ldquoImmune and non-immunefunctions of the (not so) neonatal Fc receptor FcRnrdquo Seminarsin Immunopathology vol 31 no 2 pp 223ndash236 2009

[111] K Baker R S Blumberg and C S Kaetzel ldquoImmunoglob-ulin transport and immunoglobulin receptorsrdquo in MucosalImmunology J Mestecky W Strober H Cheroutre B KelsallB N Lambrecht andMW Russell Eds chapter 20 AcademicPressElsevier Waltham Mass USA 2014

[112] C S Kaetzel ldquoThepolymeric immunoglobulin receptorrdquo in eLSJohn Wiley amp Sons Chichester UK 2013

[113] N J Mantis N Rol and B Corthesy ldquoSecretory IgArsquos complexroles in immunity andmucosal homeostasis in the gutrdquoMucosalImmunology vol 4 no 6 pp 603ndash611 2011

[114] J V Peppard M E Rose and P Hesketh ldquoA functional homo-logue of mammalian secretory component exists in chickensrdquoEuropean Journal of Immunology vol 13 no 7 pp 566ndash5701983

[115] K E Mostov M Friedlander and G Blobel ldquoThe receptorfor transepithelial transport of IgA and IgM contains multipleimmunoglobulin-like domainsrdquo Nature vol 308 no 5954 pp37ndash43 1984

[116] P Krajci R Solberg M Sandberg O Oyen T Jahnsen and PBrandtzaeg ldquoMolecular cloning of the human transmembranesecretory component (poly-Ig receptor) and its mRNA expres-sion in human tissuesrdquo Biochemical and Biophysical ResearchCommunications vol 158 no 3 pp 783ndash789 1989

[117] P Krajci D Kvale K Tasken and P Brandtzaeg ldquoMolecularcloning and exon-intron mapping of the gene encoding humantransmembrane secretory component (the poly-Ig receptor)rdquo

European Journal of Immunology vol 22 no 9 pp 2309ndash23151992

[118] J F Piskurich J A France C M Tamer C A Willmer CS Kaetzel and D M Kaetzel ldquoInterferon-120574 induces polymericimmunoglobulin receptormRNA in human intestinal epithelialcells by a protein synthesis dependent mechanismrdquo MolecularImmunology vol 30 no 4 pp 413ndash421 1993

[119] J F Piskurich M H Blanchard K R Youngman J A Franceand C S Kaetzel ldquoMolecular cloning of the mouse polymericIg receptor functional regions of the molecule are conservedamong five mammalian speciesrdquo The Journal of Immunologyvol 154 no 4 pp 1735ndash1747 1995

[120] M A Kulseth P Krajci O Myklebost and S RogneldquoCloning and characterization of two forms of bovine polymericimmunoglobulin receptor cDNArdquo DNA and Cell Biology vol14 no 3 pp 251ndash256 1995

[121] K S Koch A S Gleiberman T Aoki et al ldquoDiscordant expres-sion and variable numbers of neighboring GGA- and GAA-richtriplet repeats in the 31015840 untranslated regions of two groups ofmessenger RNAs encoded by the rat polymeric immunoglob-ulin receptor generdquo Nucleic Acids Research vol 23 no 7 pp1098ndash1112 1995

[122] F M Adamski and J Demmer ldquoTwo stages of increased IgAtransfer during lactation in themarsupialTrichosurus vulpecula(brushtail possum)rdquoThe Journal of Immunology vol 162 no 10pp 6009ndash6015 1999

[123] H Kumura T Sone K-I Shimazaki and E KobayashildquoSequence analysis of porcine polymeric immunoglobulinreceptor from mammary epithelial cells present in colostrumrdquoThe Journal of Dairy Research vol 67 no 4 pp 631ndash636 2000

[124] C L Taylor G A Harrison C M Watson and E M DeaneldquocDNA cloning of the polymeric immunoglobulin receptor ofthe marsupial Macropus eugenii (tammar wallaby)rdquo EuropeanJournal of Immunogenetics vol 29 no 2 pp 87ndash93 2002

[125] R Braathen V S Hohman P Brandtzaeg and F-E JohansenldquoSecretory antibody formation conserved binding interactionsbetween J chain and polymeric Ig receptor from humans andamphibiansrdquo The Journal of Immunology vol 178 no 3 pp1589ndash1597 2007

[126] M J Lewis BWagner R M Irvine and J MWoof ldquoIgA in thehorse cloning of equine polymeric Ig receptor and J chain andcharacterization of recombinant forms of equine IgArdquoMucosalImmunology vol 3 no 6 pp 610ndash621 2010

[127] A J Leon D Banner L Xu et al ldquoSequencing annotation andcharacterization of the influenza ferret infectomerdquo Journal ofVirology vol 87 no 4 pp 1957ndash1966 2013

[128] W H Wieland D Orzaez A Lammers H K ParmentierM W A Verstegen and A Schots ldquoA functional polymericimmunoglobulin receptor in chicken (Gallus gallus) indicatesancient role of secretory IgA inmucosal immunityrdquoBiochemicalJournal vol 380 no 3 pp 669ndash676 2004

[129] K Hamuro H Suetake N R Saha K Kikuchi and YSuzuki ldquoA teleost polymeric Ig receptor exhibiting two Ig-likedomains transports tetrameric IgM into the skinrdquo The Journalof Immunology vol 178 no 9 pp 5682ndash5689 2007

[130] J H W M Rombout S J L van der Tuin G Yang et alldquoExpression of the polymeric immunoglobulin receptor (pIgR)in mucosal tissues of common carp (Cyprinus carpio L)rdquo Fishand Shellfish Immunology vol 24 no 5 pp 620ndash628 2008

[131] L-N Feng D-Q Lu J-X Bei et al ldquoMolecular cloning andfunctional analysis of polymeric immunoglobulin receptor gene

ISRN Immunology 19

in orange-spotted grouper (Epinephelus coioides)rdquo ComparativeBiochemistry and Physiology B vol 154 no 3 pp 282ndash289 2009

[132] A E Oslashstergaard S A M Martin T Wang R J M Stet andC J Secombes ldquoRainbow trout (Oncorhynchus mykiss) pos-sessmultiple novel immunoglobulin-like transcripts containingeither an ITAM or ITIMsrdquo Developmental and ComparativeImmunology vol 33 no 4 pp 525ndash532 2009

[133] H Eiffert E Quentin and J Decker ldquoThe primary structureof the human free secretory component and the arrangementof disulfide bondsrdquo Hoppe-Seylerrsquos Zeitschrift fur PhysiologischeChemie vol 365 no 12 pp 1489ndash1495 1984

[134] E Fallgreen-Gebauer W Gebauer A Bastian et al ldquoThe cova-lent linkage of secretory component to IgA Structure of sIgArdquoBiological Chemistry Hoppe-Seyler vol 374 no 11 pp 1023ndash1028 1993

[135] J MWoof ldquoThe structure of IgArdquo inMucosal Immune DefenseImmunoglobulin A C S Kaetzel Ed chapter 1 pp 1ndash24Springer New York NY USA 2007

[136] A Bonner A Almogren P B Furtado M A Kerr and S JPerkins ldquoLocation of secretory component on the Fc edge ofdimeric IgA1 reveals insight into the role of secretory IgA1 inmucosal immunityrdquoMucosal Immunology vol 2 no 1 pp 74ndash84 2009

[137] A Bonner A Almogren P B Furtado M A Kerr and S JPerkins ldquoThe nonplanar secretory IgA2 and near planar secre-tory IgA1 solution structures rationalize their different mucosalimmune responsesrdquo The Journal of Biological Chemistry vol284 no 8 pp 5077ndash5087 2009

[138] J Johansen B Braathen and P Brandtzaeg ldquoRole of J chain insecretory immunoglobulin formationrdquo Scandinavian Journal ofImmunology vol 52 no 3 pp 240ndash248 2000

[139] B A Hendrickson D A Conner D J Ladd et al ldquoAlteredhepatic transport of immunoglobulin A in mice lacking the Jchainrdquo Journal of Experimental Medicine vol 182 no 6 pp1905ndash1911 1995

[140] B A Hendrickson L Rindisbacher B Corthesy et al ldquoLackof association of secretory component with IgA in J chain-deficient micerdquo The Journal of Immunology vol 157 no 2 pp750ndash754 1996

[141] N Lycke L Erlandsson L Ekman K Schon and T Lean-derson ldquoLack of J chain inhibits the transport of gut IgA andabrogates the development of intestinal antitoxic protectionrdquoThe Journal of Immunology vol 163 no 2 pp 913ndash919 1999

[142] F-E Johansen R Braathen and P Brandtzaeg ldquoThe J chainis essential for polymeric Ig receptor-mediated epithelial trans-port of IgArdquoThe Journal of Immunology vol 167 no 9 pp 5185ndash5192 2001

[143] R E Ley D A Peterson and J I Gordon ldquoEcological andevolutionary forces shaping microbial diversity in the humanintestinerdquo Cell vol 124 no 4 pp 837ndash848 2006

[144] M McFall-Ngai ldquoAdaptive immunity care for the communityrdquoNature vol 445 no 7124 p 153 2007

[145] A J Macpherson K D McCoy F-E Johansen and PBrandtzaeg ldquoThe immune geography of IgA induction andfunctionrdquoMucosal Immunology vol 1 no 1 pp 11ndash22 2008

[146] D Kvale and P Brandtzaeg ldquoConstitutive and cytokine inducedexpression of HLA molecules secretory component and inter-cellular adhesion molecule-1 is modulated by butyrate in thecolonic epithelial cell line HT-29rdquo Gut vol 36 no 5 pp 737ndash742 1995

[147] L VHooperMHWong AThelin L Hansson P G Falk andJ I Gordon ldquoMolecular analysis of commensal host-microbialrelationships in the intestinerdquo Science vol 291 no 5505 pp 881ndash884 2001

[148] S Hapfelmeier M A E Lawson E Slack et al ldquoReversiblemicrobial colonization of germ-free mice reveals the dynamicsof IgA immune responsesrdquo Science vol 328 no 5986 pp 1705ndash1709 2010

[149] DH ReikvamMDerrien R Islam et al ldquoEpithelial-microbialcross-talk in polymeric Ig receptor deficient micerdquo EuropeanJournal of Immunology vol 42 no 11 pp 2959ndash2970 2012

[150] EW Rogier A L Frantz M E C Bruno et al ldquoSecretory anti-bodies in breast milk promote long-term intestinal homeostasisby regulating the gut microbiota and host gene expressionrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 111 no 8 pp 3074ndash3079 2014

[151] G M Barton and R Medzhitov ldquoToll-like receptor signalingpathwaysrdquo Science vol 300 no 5625 pp 1524ndash1525 2003

[152] K Takeda and S Akira ldquoToll receptors and pathogen resis-tancerdquo Cellular Microbiology vol 5 no 3 pp 143ndash153 2003

[153] E Cario andD K Podolsky ldquoDifferential alteration in intestinalepithelial cell expression of Toll-like receptor 3 (TLR3) andTLR4 in inflammatory bowel diseaserdquo Infection and Immunityvol 68 no 12 pp 7010ndash7017 2000

[154] M Hausmann S Kiessling S Mestermann et al ldquoToll-likereceptors 2 and 4 are up-regulated during intestinal inflamma-tionrdquo Gastroenterology vol 122 no 7 pp 1987ndash2000 2002

[155] M T Abreu L S Thomas S Y Tesfay et al ldquoRegulation ofTLR4 and MD-2 in the intestinal epithelium evidence for dys-regulated LPS signaling in human inflammatory bowel diseaserdquoin Proceedings of the 90th Annual Meeting of the AmericanAssociation for Immunologists Abstract 3634 Denver ColoUSA 2003

[156] T A Schneeman M E C Bruno H Schjerven F-E JohansenL Chady and C S Kaetzel ldquoRegulation of the polymeric Igreceptor by signaling through TLRs 3 and 4 linking innate andadaptive immune responsesrdquo The Journal of Immunology vol175 no 1 pp 376ndash384 2005

[157] M E C Bruno A L Frantz E W Rogier F-E Johansen andC S Kaetzel ldquoRegulation of the polymeric immunoglobulinreceptor by the classical and alternative NF-120581B pathways inintestinal epithelial cellsrdquoMucosal Immunology vol 4 no 4 pp468ndash478 2011

[158] M E C Bruno E W Rogier A L Frantz A T Stefka SN Thompson and C S Kaetzel ldquoRegulation of the poly-meric immunoglobulin receptor in intestinal epithelial cellsby Enterobacteriaceae implications for mucosal homeostasisrdquoImmunological Investigations vol 39 no 4-5 pp 356ndash382 2010

[159] A L Frantz E W Rogier C R Weber et al ldquoTargeted deletionof MyD88 in intestinal epithelial cells results in compromisedantibacterial immunity associatedwith downregulation of poly-meric immunoglobulin receptor mucin-2 and antibacterialpeptidesrdquoMucosal Immunology vol 5 no 5 pp 501ndash512 2012

[160] E W Rogier A L Frantz M E C Bruno and C S KaetzelldquoSecretory IgA is concentrated in the outer layer of intestinalmucus along with gut bacteriardquo Pathogens In press

[161] M B Geuking K D McCoy and A J Macpherson ldquoThe func-tion of secretory IgA in the context of the intestinal continuumof adaptive immune responses in host-microbial mutualismrdquoSeminars in Immunology vol 24 no 1 pp 36ndash42 2012

20 ISRN Immunology

[162] L VHooper D R Littman andA JMacpherson ldquoInteractionsbetween the microbiota and the immune systemrdquo Science vol336 no 6086 pp 1268ndash1273 2012

[163] A J Macpherson M B Geuking E Slack S Hapfelmeierand K D McCoy ldquoThe habitat double life citizenship andforgetfulness of IgArdquo Immunological Reviews vol 245 no 1 pp132ndash146 2012

Submit your manuscripts athttpwwwhindawicom

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Behavioural Neurology

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Disease Markers

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OncologyJournal of

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The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

12 ISRN Immunology

this model the C120594120572

3 domains of two adjacent IgXA heavychains (homologous to the C

1205722 domain of mammalian IgA)

bind to the highly conserved domains 1 and 5 of pIgRGiven the conservation of the analogous cysteine residuesin domain 5 of pIgR and the C

1205941205723 domain of IgXA it

is assumed that a disulfide bond forms between pIgR andpolymeric Ig during epithelial transcytosis in birds reptilesand amphibiansThe absence of domain 2 in pIgR from thesevertebrate orders necessitates a more rigid structure thanthat of mammalian pIgR with a corresponding decrease inits ability to wrap around the IgXA heavy chains and pro-vide protection against proteoltyic degradation Despite theshorter length of pIgR in birds reptiles and amphibians theassociation with the J chain subunit of polymeric IgXA stillappears to be required Recombinant pIgR from the Africanfrog (Xenopus laevis) was shown to bind with moderatelyhigh affinity to human polymeric IgA containing J chain butnot to monomeric IgA [125] The affinity of Xenopus pIgRfor human pIgA was improved when Xenopus J chain wassubstituted for human J chain in a chimeric polymeric IgAmolecule The lack of sequence conservation across speciesin the linker region connecting domain 5 of pIgR to the TMregion suggests that it acts as a nonspecific ldquospacerrdquo As statedabove the cytoplasmic region of pIgR appears to have evolvedover time to provide enhanced regulation of pIgR trafficking

The hypothetical structure of secretory IgT from teleostfish in Figure 7(c) illustrates how the most primitive form ofpIgR comprising only extracellular domains 1 and 5 couldassociate with polymeric Ig and mediate epithelial transcy-tosis Association of pIgR domain 1 with the C

1205913 domain of

IgT would preserve the functional homology with secretoryIgs in higher vertebrates The short length of teleost pIgRwould necessitate the association of domain 5 with a C

1205913

domain on one of the heavy chains of the same IgT ratherthan spanning across to the adjaent IgT subunit While thismodel preserves the highly conserved association of pIgRdomain 1 with the orthologous domain of the IgT heavychain it does not explain the selectivity of teleost pIgR forpolymeric rather than monomeric IgT Although there is noexperimental evidence to support this model it could behypothesized that dimerization of two pIgR molecules in theplasmamembrane is required for high affinity binding of IgTas illustrated in the model in Figure 7(c) This hypotheticalmodel would also explain the lack of a necessity for J chainin polymeric IgT since each subunit in the pIgR dimer wouldonly be in contact with one IgT subunit The unstructuredlinker region connecting domain 5 of pIgR to the TM regionwould provide flexibility for association of 2 membrane-bound pIgR molecules with a large polymeric IgT molecule

Taken together the structural models for secretory Igsshown in Figure 7 are consistent with the selection of a morefunctional pIgR molecule over evolutionary time Duplica-tion and diversification of the extracellular Ig-like domainsof pIgR would provide a longer more flexible surface forbinding to polymeric Igs with higher affinity and protectingthe Ig heavy chains against proteolytic attack Expansion ofthe cytoplasmic domain of pIgR and incorporation of motifsfor binding cytoplasmic proteins would allow regulated

trafficking of pIgR and polymeric Igs across mucosal andglandular epithelial cells Importantly these models illustratea potential path for coevolution of IGH and PIGR genesdriven by the common selective pressure to provide antigen-specific humoral immune responses at mucosal surfaces

8 Evidence that the CommensalMicrobiota Provided the Driving Force forCoevolution of Mucosal Igs and pIgR

From the earliest evolution of vertebrate animals mucosal Igshave been an integral part of the emerging adaptive immunesystem Clearly many environmental factors served as driv-ing forces for the evolution of the adaptive immune systemin vertebrates including a longer lifespan thanmany (but notall) invertebrates and amore diverse diet that could introducea broader range of potential gut pathogens However it hasbeen proposed that the most significant force may havebeen the dramatic increase in the numbers and complexityof the resident microbiota in the evolution of vertebratesfrom their invertebrate ancestors [1 143 144] Antibodiesin mucosal secretions contribute to immune homeostasis bylimiting access of microbes and their products to the bodyproper maintaining the integrity of the epithelial barrier andshaping the composition of the commensal microbiota infavor of metabolically beneficial microorganisms [145] Thepredominance of polymeric Igs in these secretions promotesthese functions by providing multiple antigen-binding sitesper Ig complex thus increasing the overall avidity of antigen-antibody interactions Structural and functional refinementsin mucosal Igs culminating with the multifunctional secre-tory IgA molecule in mammals have further enhanced theirability to enhance immune homeostasis

The early emergence of pIgR in vertebrate evolutionprovided a mechanism for efficient transport of mucosal Igsinto external secretions It is well documented that crosstalkbetween mucosal epithelial cells and the resident microbiotamodulates expression of pIgR (reviewed in [17 111 112]) andit is reasonable to assume that these host-microbe interac-tions provided a driving force for evolution of the PIGR genein vertebrates The first demonstration that gut bacteria maymodulate pIgR expression in epithelial cells was the findingthat butyrate a bacterial fermentation product and importantenergy source in the colon upregulated expression of pIgRin the human colonic epithelial cell line HT-29 [146] A rolefor commensal bacteria in pIgR regulation was subsequentlydemonstrated by the observation that pIgR expression wasincreased when germ-free mice were colonized with Bacteri-oides thetaiotaomicron a prominent organism of the normalmouse and human intestinal microbiota [147] Amore recentstudy using a model of reversible colonization of germ-free mice with a nondividing mutant of Escherichia colidemonstrated that a long-lived SIgA response could besustained that specifically recognized the inducing bacteria[148] However exposure of E coli-colonized mice to otherbacteria limited the duration of the SIgA response against theoriginal colonizer suggesting a dynamic equilibriumbetweenmembers of the gut microbial community and host SIgA A

ISRN Immunology 13

study from the laboratory of Finn-Eirik Johansen demon-strated that diversity of the bacterial community in the cecallumen was reduced in pIgR-knockoutmice supporting a rolefor SIgA in limiting overgrowth of selected species [149] Incontrast the community of bacteria adherent to the epithelialsurface was more diverse in pIgR-knockout mice than inwild-typemice and these adherent bacteria caused enhancedexpression of several epithelial antimicrobial peptides Thesefindings suggest that bacteria-specific SIgA anchored in themucus layer restricts adhesion of bacteria to the epithelialsurface and limits bacterial stimulation of host epithelial cellsA recent study from the authorrsquos laboratory employing abreeding scheme in which119875119894119892119903minusminus damswere bred to119875119894119892119903+minusmales and vice versa demonstrated that SIgA antibodiesin breast milk promote long-term intestinal homeostasis byregulating the gut microbiota and gene expression in colonicepithelial cells [150]

A direct role for commensal andor pathogenic bacteriain the regulation of pIgR expression suggests that the innateimmune system may ldquoprimerdquo epithelial cells for transportof polymeric Ig produced during the adaptive immuneresponse Host cells mediate innate immune responses tomicrobial components through toll-like receptor (TLR) sig-naling (reviewed in [151 152]) Intestinal epithelial cells havebeen shown to express a wide variety of TLRs the expressionof which is upregulated during intestinal inflammation [153ndash155] Significantly expression of pIgR was shown to beupregulated in the HT-29 human intestinal epithelial cellline by bacterial LPS a ligand for TLR4 [156 157] Similarinduction of PIGR gene transcription was seen followingdirect binding of bacteria of the family Enterobacteriaceaewhich express a form of LPS that stimulates TLR4 [158]A recent study from the authorrsquos laboratory demonstratedthat shRNA-mediated knockdown of myeloid differentiationprimary response protein 88 (MyD88) a cytoplasmic adapterprotein that transduces signals from cell surface TLR4blocked the induction of PIGR gene transcription by LPS inHT-29 cells [159] The in vivo significance was confirmed bythe finding that mice with a targeted deletion of the Myd88gene only in intestinal epithelial cells had reduced expressionof pIgR compared to wild-type littermates [159] Mice withtargeted depletion of MyD88 in intestinal epithelial cells alsoexhibited reduced expression of mucin-2 the major compo-nent of the intestinal mucus layer and several antimicrobialpeptides and decreased transmucosal electrical resistanceThese alterations in epithelial barrier function were accom-panied by significant changes in the composition of the fecalmicrobiota increased numbers of bacteria adherent to theintestinal mucus layer and a dramatic increase in transloca-tion of gut bacteria into the drainingmesenteric lymphnodesincluding the opportunistic pathogen Klebsiella pneumoniaeThese findings demonstrate that MyD88-mediated crosstalkbetween the gut microbiota and intestinal epithelial cells iscrucial for optimal expression of pIgR production of SIgAdevelopment of a healthy gut microbiota and maintenanceof intestinal homeostasis

A model can be proposed in which continuous stimu-lation of intestinal epithelial cells by gut bacteria regulates

Lumen

Mucus

Epithelium

Lamina

PIGR

TLRs

MyD88

Bacteria

Plasma cells

propria

Polymeric Ig

Polymeric Ig receptor

Secretory component

Figure 8 Crosstalk between the polymeric immunoglobulin recep-tor secretory immunoglobulins and the gut microbiotaThe single-layered epithelium that lines the gastrointestinal tract is coveredwith a thick mucus layer which physically excludes members ofthe resident microbiota but allows diffusion of shed components ofmicrobial cells Stimulation of epithelial toll-like receptors (TLRs)with microbial products engages the cytoplasmic adaptor proteinMyD88 and initiates NF120581B-dependent signaling pathways Translo-cation of activated NF120581B and other transcription factors to thenucleus enhances transcription of thePIGR gene Activation of TLRsmay also stimulate pIgR transcytosis Polymeric Igs secreted bylamina propria plasma cells bind to pIgRon the basolateral surface ofepithelial cells and are transcytosed to the apical surface along withunoccupied pIgR Proteolytic cleavage of pIgR at the apical surfacereleases secretory SIg and free secretory component (SC) Binding ofSIg and SC to luminal bacteria promotes association with themucuslayer and prevents direct access of bacteria to the epithelial surfaceOver time the continuous crosstalk with SIg shapes the compositionof the gut microbiota Modified from [17] under terms of authorrsquoscopyright with Nature Publishing Group

pIgR expression and transport of SIgA and promotes immuneexclusion of resident and pathogenic bacteria (Figure 8) Adense layer of mucus which increases in thickness fromthe proximal to the distal colon serves to separate bacteriafrom direct contact with the epithelial surface Secretionof microbial-associated molecular patterns (MAMPs) bycommensal bacteria stimulates MyD88-dependent TLR sig-naling leading to enhanced expression of pIgR and antimi-crobial peptides and increased mucus production Bindingof pIgA to pIgR and possibly also signaling via MAMPs

14 ISRN Immunology

enhances transcytosis of pIgA pIgA-containing immunecomplexes and unoccupied pIgR which promotes clearanceof antigens and pathogens from the lamina propria intra-cellular neutralization and release of SIgA and SC at theluminal surface SIgA and SC serve to trap bacteria in themucus layer limiting their access to the epithelial surface Inmice with a targeted deletion of the Muc2 gene which havea severely depleted mucus layer in the colon SIgA and SCfail to associate with the surface of colonic epithelial cells[160] The presence of SIgA in the intestinal lumen whetherderived passively frommaternalmilk or actively via epithelialtranscytosis shapes the composition of the gut microbiotaand modulates intestinal epithelial gene expression

9 Concluding Remarks

The first microbes that emerged on Earth almost 4 billionyears ago encountered a hostile world where nutrients werescarce hazards were everywhere and life was short Withthe evolution of multicellular organisms about 3 billion yearslater a select group ofmicrobes chose to sacrifice an indepen-dent existence for the benefits of a mutualistic relationshipwith eukaryotic hosts Prokaryotic-eukaryotic mutualismreached its apex some 500 million years ago with theemergence of primitive vertebrates whose gastrointestinaltracts were populated by an abundant and diverse commensalmicrobiota In humans the large intestine is home to some100 trillion microorganisms 10 times more than the totalnumber of eukaryotic cells in the entire body The microbesthat inhabit the vertebrate GI tract provide many benefitsto the eukaryotic host including digestion of complex foodmolecules synthesis of vitamins and production of solublefactors that enhance the development of the host immunesystem In return the eukaryotic host provides the microbeswith a warm moist place to live abundant food low oxygentension and a soft bed of mucus on which to form biofilmsWhen this mutually beneficial arrangement is challenged bypathogenicmicrobes the eukaryotic host and the commensalmicrobiota join forces to battle the pathogens and protectthe body from invasion The vertebrate immune system isequipped with a well-trained army of immune cells and asophisticated arsenal of weapons (cell surface molecules andsecreted factors) that protect the host from all but the mostvirulent pathogens This immune ldquoarmyrdquo also serves as aconstant reminder to the commensal microbes that whilethey are free to enjoy the amenities of the mucosal surfacesthey are not welcome in the body proper The emergence ofantigen-specific Igs and T-cell receptors in jawed vertebratesbegan a process of immunological diversification that led tothe development of a specialized mucosal immune systemin higher vertebrates in which secretory Igs play a centralrole The relationship between host and microbiota is clearlyreciprocal the mucosal Igs that evolved in response toselective pressure from the commensal microbiota play acentral role throughout life in shaping the compositiongenetics andmetabolic activity of themicrobiota [1 161 162]

The epithelial layer lining mucosal surfaces provides aphysical and innate immune barrier against penetration of

the body proper by microbes undigested food antigens andpotentially noxious environmental substances The evolu-tionary challenge of transporting mucosal Igs into externalsecretions without compromising the epithelial barrier wasmet by the emergence of the PIGR gene in an ancestor ofbony fishes encoding an epithelial-specific transmembraneprotein that actively transports polymeric Igs across mucosaland glandular epithelia (Figure 4) Structural similaritiesbetween Igs and the extracellular Ig-binding domains of pIgR(Figure 6) suggest that duplication and diversification of agene encoding primordial Ig-like domain may have givenrise to the PIGR gene in a primitive vertebrate ancestorParallel refinement of the structures of mucosal Igs andpIgR during tetrapod evolution (Figures 6 and 7) culminatedin the evolution of the multifunctional SIgA molecule inmammals in which the pIgR-derived SC subunit providesinnate immune functions and protects the antigen-bindingIgA polymer from proteolytic degradation In addition toacting as a powerful force during vertebrate evolution thereciprocal relationship between pIgR mucosal Igs and thecommensal microbiota provides benefits throughout thelife of the individual Microbial colonization of newbornvertebrates stimulates development of mucosal B cells andclass switching to mucosal Ig isotypes [1 163] Microbialfactors upregulate expression of pIgR enhancing transportof mucosal Igs into external secretions where they in turnregulate the microbiotaThis beautifully orchestrated processallows us to maintain a healthy relationship with our resi-dent microbiota while providing mutual protection againstpathogens

Conflict of Interests

The author declares that there is no conflict of interestsregarding the publication of this paper

Acknowledgments

This work was supported by Grant no AI069027 from theNational Institutes of Health of the United States of America(and an associatedAmerican Recovery andReinvestmentActsupplement) and a Senior Research Award from the Crohnrsquosand Colitis Foundation of America

References

[1] C L Maynard C O Elson R D Hatton and C T WeaverldquoReciprocal interactions of the intestinal microbiota andimmune systemrdquo Nature vol 489 no 7415 pp 231ndash241 2012

[2] M F Flajnik and M Kasahara ldquoOrigin and evolution of theadaptive immune system genetic events and selective pres-suresrdquo Nature Reviews Genetics vol 11 no 1 pp 47ndash59 2010

[3] M F Flajnik and L du Pasquier ldquoEvolution of the immunesystemrdquo in Fundamental Immunology W E Paul Ed chapter4 pp 67ndash128 Lippincott Williams ampWilkins Philadelphia PaUSA 2012

[4] M Hirano S Das P Guo and M D Cooper ldquoThe evolutionof adaptive immunity in vertebratesrdquo Advances in Immunologyvol 109 pp 125ndash157 2011

ISRN Immunology 15

[5] T BoehmNMcCurley Y SutohM SchorppMKasahara andM D Cooper ldquoVLR-based adaptive immunityrdquo Annual Reviewof Immunology vol 30 pp 203ndash220 2012

[6] T Hunkapiller and L Hood ldquoImmunology the growing immu-noglobulin gene superfamilyrdquoNature vol 323 no 6083 pp 15ndash16 1986

[7] P Bork L Holm and C Sander ldquoThe immunoglobulin foldstructural classification sequence patterns and common corerdquoJournal of Molecular Biology vol 242 no 4 pp 309ndash320 1994

[8] C S Kaetzel and M W Russell ldquoPhylogeny and comparativephysiology of IgArdquo in Mucosal Immunology J Mestecky WStrober H Cheroutre B Kelsall B N Lambrecht and M WRussell Eds chapter 19 Academic PressElsevier WalthamMass USA 2014

[9] Y He and P J Bjorkman ldquoStructure of FcRY an avian immu-noglobulin receptor related to mammalian mannose receptorsand its complex with IgYrdquo Proceedings of the National Academyof Sciences of the United States of America vol 108 no 30 pp12431ndash12436 2011

[10] J M Woof and D R Burton ldquoHuman antibody-Fc receptorinteractions illuminated by crystal structuresrdquo Nature ReviewsImmunology vol 4 no 2 pp 89ndash99 2004

[11] W L Martin A P West Jr L Gan and P J Bjorkman ldquoCrystalstructure at 28 A of an FcRnheterodimeric Fc complexmechanism of pH-dependent bindingrdquo Molecular Cell vol 7no 4 pp 867ndash877 2001

[12] E S Ward ldquoAcquiring maternal immunoglobulin differentreceptors similar functionsrdquo Immunity vol 20 no 5 pp 507ndash508 2004

[13] C S Kaetzel ldquoThe polymeric immunoglobulin receptor bridg-ing innate and adaptive immune responses atmucosal surfacesrdquoImmunological Reviews vol 206 no 1 pp 83ndash99 2005

[14] M Acharya G Borland A L Edkins et al ldquoCD23Fc120576RIImolecular multi-taskingrdquo Clinical and Experimental Immunol-ogy vol 162 no 1 pp 12ndash23 2010

[15] V B Klimovich ldquoIgM and its receptors structural and func-tional aspectsrdquo Biochemistry vol 76 no 5 pp 534ndash549 2011

[16] J MWoof andMW Russell ldquoStructure and function relation-ships in IgArdquo Mucosal Immunology vol 4 no 6 pp 590ndash5972011

[17] F-E Johansen and C S Kaetzel ldquoRegulation of the polymericimmunoglobulin receptor and IgA transport new advances inenvironmental factors that stimulate pIgR expression and itsrole in mucosal immunityrdquo Mucosal Immunology vol 4 no 6pp 598ndash602 2011

[18] F Kokubu K Hinds R Litman M J Shamblott and G WLitman ldquoExtensive families of constant region genes in a phy-logenetically primitive vertebrate indicate an additional levelof immunoglobulin complexityrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 84 no16 pp 5868ndash5872 1987

[19] A S Greenberg A L Hughes J Guo D Avila E CMcKinneyand M F Flajnik ldquoA novel ldquochimericrdquo antibody class in carti-laginous fish IgMmay not be the primordial immunoglobulinrdquoEuropean Journal of Immunology vol 26 no 5 pp 1123ndash11291996

[20] H Dooley and M F Flajnik ldquoShark immunity bites back affin-ity maturation and memory response in the nurse shark Ging-lymostoma cirratumrdquo European Journal of Immunology vol 35no 3 pp 936ndash945 2005

[21] S F Schluter R M Bernstein and J J Marchalonis ldquoMolecularorigins and evolution of immunoglobulin heavy-chain genes ofjawed vertebratesrdquo Immunology Today vol 18 no 11 pp 543ndash549 1997

[22] Y Ohta and M Flajnik ldquoIgD like IgM is a primordial immu-noglobulin class perpetuated in most jawed vertebratesrdquo Pro-ceedings of the National Academy of Sciences of the United Statesof America vol 103 no 28 pp 10723ndash10728 2006

[23] S Fillatreau A Six S Magadan R Castro J O Sunyer andP Boudinot ldquoThe astonishing diversity of Ig classes and B cellrepertoires in teleost fishrdquo Frontiers in Immunology vol 4 no28 2013

[24] W Harriman H Volk N Defranoux and M Wabl ldquoImmu-noglobulin class switch recombinationrdquo Annual Review ofImmunology vol 11 pp 361ndash384 1993

[25] J Stavnezer and C T Amemiya ldquoEvolution of isotype switch-ingrdquo Seminars in Immunology vol 16 no 4 pp 257ndash275 2004

[26] V M Barreto Q Pan-Hammarstrom Y Zhao L Ham-marstrom Z Misulovin and M C Nussenzweig ldquoAID frombony fish catalyzes class switch recombinationrdquo Journal ofExperimental Medicine vol 202 no 6 pp 733ndash738 2005

[27] T C Fletcher and AWhite ldquoAntibody production in the plaice(Pleuronectes platessa L) after oral and parenteral immuniza-tion with Vibrio anguillarum antigensrdquo Aquaculture vol 1 pp417ndash428 1972

[28] J W H M Rombout L J Blok C H J Lamers and E EgbertsldquoImmunization of carp (Cyprinus carpio) with a Vibrio anguil-larum bacterin indications for a common mucosal immunesystemrdquo Developmental and Comparative Immunology vol 10no 3 pp 341ndash351 1986

[29] U Georgopoulou and J-M Vernier ldquoLocal immunologicalresponse in the posterior intestinal segment of the rainbowtrout after oral administration of macromoleculesrdquo Develop-mental andComparative Immunology vol 10 no 4 pp 529ndash5371986

[30] C J Lobb ldquoSecretory immunity induced in catfish Ictaluruspunctatus following bath immunizationrdquo Developmental andComparative Immunology vol 11 no 4 pp 727ndash738 1987

[31] J D Hansen E D Landis and R B Phillips ldquoDiscovery ofa unique Ig heavy-chain (IgT) in rainbow trout implicationsfor a distinctive B cell developmental pathway in teleost fishrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 102 no 19 pp 6919ndash6924 2005

[32] N Danilova J Bussmann K Jekosch and L A Steiner ldquoTheimmunoglobulin heavy-chain locus in zebrafish identificationand expression of a previously unknown isotype immunoglob-ulin Zrdquo Nature Immunology vol 6 no 3 pp 295ndash302 2005

[33] R Savan A Aman K Sato R Yamaguchi and M Sakai ldquoDis-covery of a new class of immunoglobulin heavy chain fromfugurdquo European Journal of Immunology vol 35 no 11 pp 3320ndash3331 2005

[34] R Savan A AmanMNakao HWatanuki andM Sakai ldquoDis-covery of a novel immunoglobulin heavy chain gene chimerafrom common carp (Cyprinus carpio L)rdquo Immunogenetics vol57 no 6 pp 458ndash463 2005

[35] F Gambon-Deza C Sanchez-Espinel and S Magadan-Mompo ldquoPresence of an unique IgT on the IGH locus in three-spined stickleback fish (Gasterosteus aculeatus) and the veryrecent generation of a repertoire of VH genesrdquo Developmentaland Comparative Immunology vol 34 no 2 pp 114ndash122 2010

[36] T M Tadiso K K Lie and I Hordvik ldquoMolecular cloning ofIgT fromAtlantic salmon and analysis of the relative expression

16 ISRN Immunology

of 120591 120583 and 120575 in different tissuesrdquo Veterinary Immunology andImmunopathology vol 139 no 1 pp 17ndash26 2011

[37] S Mashoof C Pohlenz P L Chen et al ldquoExpressed IgH 120583and 120591 transcripts share diversity segment in ranched Thunnusorientalisrdquo Developmental and Comparative Immunology vol43 no 1 pp 76ndash86 2014

[38] Y-A Zhang I Salinas J Li et al ldquoIgT a primitive immunoglob-ulin class specialized in mucosal immunityrdquo Nature Immunol-ogy vol 11 no 9 pp 827ndash835 2010

[39] S Magadan-Mompo C Sanchez-Espinel and F Gambon-Deza ldquoImmunoglobulin heavy chains in medaka (Oryziaslatipes)rdquo BMC Evolutionary Biology vol 11 no 1 article 1652011

[40] C T Amemiya J Alfoldi A P Lee et al ldquoThe African coela-canth genome provides insights into tetrapod evolutionrdquoNature vol 496 no 7445 pp 311ndash316 2013

[41] T Ota J P Rast G W Litman and C T Amemiya ldquoLineage-restricted retention of a primitive immunoglobulin heavy chainisotype within the Dipnoi reveals an evolutionary paradoxrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 100 no 5 pp 2501ndash2506 2003

[42] Y Sun Z Wei N Li and Y Zhao ldquoA comparative overview ofimmunoglobulin genes and the generation of their diversity intetrapodsrdquo Developmental and Comparative Immunology vol39 no 1-2 pp 103ndash109 2013

[43] I Hadji-Azimi ldquoAnuran immunoglobulins a reviewrdquo Develop-mental and Comparative Immunology vol 3 no 2 pp 223ndash2431979

[44] E Hsu M F Flajnik and L du Pasquier ldquoA third immunoglob-ulin class in amphibiansrdquo The Journal of Immunology vol 135no 3 pp 1998ndash2004 1985

[45] C T Amemiya R N Haire and G W Litman ldquoNucleotidesequence of a cDNA encoding a third distinct Xenopusimmunoglobulin heavy chain isotyperdquo Nucleic Acids Researchvol 17 no 13 p 5388 1989

[46] R Muszligmann M Wilson A Marcuz M Courtet and L duPasquier ldquoMembrane exon sequences of the three Xenopus Igclasses explain the evolutionary origin of mammalian isotypesrdquoEuropean Journal of Immunology vol 26 no 2 pp 409ndash4141996

[47] R Muszligmann L du Pasquier and E Hsu ldquoIs Xenopus IgX ananalog of IgArdquo European Journal of Immunology vol 26 no12 pp 2823ndash2830 1996

[48] B Schaerlinger and J-P Frippiat ldquoIgX antibodies in the urodeleamphibian Ambystoma mexicanumrdquo Developmental and Com-parative Immunology vol 32 no 8 pp 908ndash915 2008

[49] B Schaerlinger M Bascove and J-P Frippiat ldquoA new isotypeof immunoglobulin heavy chain in the urodele amphibianPleurodeles waltl predominantly expressed in larvaerdquoMolecularImmunology vol 45 no 3 pp 776ndash786 2008

[50] S Mashoof A Goodroe C C Du et al ldquoAncient T-independence of mucosal IgXA gut microbiota unaffected bylarval thymectomy in Xenopus laevisrdquo Mucosal Immunologyvol 6 no 2 pp 358ndash368 2013

[51] J P Vaerman J Picard and J F Heremans ldquoStructural dataon chicken IgA and failure to identify the IgA of the tortoiserdquoin Immunologic Phylogeny vol 64 of Advances in ExperimentalMedicine and Biology pp 185ndash195 Springer New York NYUSA 1975

[52] J L Portis and J E Coe ldquoIgM the secretory immunoglobulinof reptiles and amphibiansrdquo Nature vol 258 no 5535 pp 547ndash548 1975

[53] J E Coe D Leong J L Portis and L A Thomas ldquoImmuneresponse in the garter snake (Thamnophis ordinoides)rdquo Immu-nology vol 31 no 3 pp 417ndash424 1976

[54] D Hadge and H Ambrosius ldquoEvolution of low molecularweight immunoglobulinsmdashIV IgY-like immunoglobulins ofbirds reptiles and amphibians precursors of mammalian IgArdquoMolecular Immunology vol 21 no 8 pp 699ndash707 1984

[55] D Hadge and H Ambrosius ldquoEvolution of low molecularweight immunoglobulins V Degree of antigenic relationshipbetween the 7S immunoglobulins ofmammals birds and lowervertebrates to the turkey IgYrdquo Developmental and ComparativeImmunology vol 10 no 3 pp 377ndash385 1986

[56] S Magadan-Mompo C Sanchez-Espinel and F Gambon-Deza ldquoImmunoglobulin genes of the turtlesrdquo Immunogeneticsvol 65 no 3 pp 227ndash237 2013

[57] Z Wei Q Wu L Ren et al ldquoExpression of IgM IgD and IgYin a reptile Anolis carolinensisrdquoThe Journal of Immunology vol183 no 6 pp 3858ndash3864 2009

[58] F Gambon-Deza C Sanchez-Espinel and J V Beneitez ldquoAnovel IgA-like immunoglobulin in the reptile Eublepharis mac-ulariusrdquo Developmental and Comparative Immunology vol 31no 6 pp 596ndash605 2007

[59] G Cheng Y Gao T Wang et al ldquoExtensive diversification ofIgH subclass-encoding genes and IgM subclass switching incrocodiliansrdquo Nature Communications vol 4 article 1337 2013

[60] S Magadan-Mompo C Sanchez-Espinel and F Gambon-Deza ldquoIgH loci of American alligator and saltwater crocodileshed light on IgA evolutionrdquo Immunogenetics vol 65 no 7 pp531ndash541 2013

[61] E Orlans and M E Rose ldquoAn IgA-like immunoglobulin in thefowlrdquo Immunochemistry vol 9 no 8 pp 833ndash838 1972

[62] G A Leslie and L N Martin ldquoStudies on the secretory immu-nologic system of fowl 3 Serum and secretory IgA of thechickenrdquoThe Journal of Immunology vol 110 no 1 pp 1ndash9 1973

[63] J Bienenstock D Y Perey J Gauldie and B J UnderdownldquoChicken 120574A physicochemical and immunochemical charac-teristicsrdquoThe Journal of Immunology vol 110 no 2 pp 524ndash5331973

[64] A M Lebacq-Verheyden J P Vaerman and J F HeremansldquoQuantification and distribution of chicken immunoglobulinsIgA IgM and IgG in serum and secretionsrdquo Immunology vol27 no 4 pp 683ndash692 1974

[65] J Goudswaard A Noordzij R H van Dam J A vanderDonk and J P Vaerman ldquoThe immunoglobulins of the turkey(Meleagris gallopavo) Isolation and characterization of IgGIgM and IgA in body fluids eggs and intraocular tissuesrdquoPoultry science vol 56 no 6 pp 1847ndash1851 1977

[66] D Hadge and H Ambrosius ldquoComparative studies on thestructure of biliary immunoglobulins of some avian speciesII Antigenic properties of the biliary immunoglobulins ofchicken turkey duck and gooserdquo Developmental and Compar-ative Immunology vol 12 no 2 pp 319ndash329 1988

[67] J Goudswaard J P Vaerman and J F Heremans ldquoThreeimmunoglobulin classes in the pigeon (Columbia livia)rdquo Inter-national Archives of Allergy andApplied Immunology vol 53 no5 pp 409ndash419 1977

[68] P L K Ng and D A Higgins ldquoBile immunoglobulin of theduck (Anas platyrhynchos) I Preliminary characterization andontogenyrdquo Immunology vol 58 no 2 pp 323ndash327 1986

[69] K E Magor G W Warr Y Bando D L Middleton and DA Higgins ldquoSecretory immune system of the duck (Anas

ISRN Immunology 17

platyrhynchos) Identification and expression of the genesencoding IgA and IgM heavy chainsrdquo European Journal ofImmunology vol 28 no 3 pp 1063ndash1068 1998

[70] Y Zhao H Rabbani A Shimizu and L Hammarstrom ldquoMap-ping of the chicken immunoglobulin heavy-chain constantregion gene locus reveals an inverted 120572 gene upstream of acondensed 120592 generdquo Immunology vol 101 no 3 pp 348ndash3532000

[71] M L Lundqvist D L Middleton S Hazard and G W WarrldquoThe immunoglobulin heavy chain locus of the duck genomicorganization and expression of D J and C region genesrdquo TheJournal of Biological Chemistry vol 276 no 50 pp 46729ndash46736 2001

[72] T HuangM Zhang ZWei et al ldquoAnalysis of immunoglobulintranscripts in the ostrich Struthio camelus a primitive avianspeciesrdquo PLoS ONE vol 7 no 3 Article ID e34346 2012

[73] K H Roux ldquoImmunoglobulin structure and function asrevealed by electron microscopyrdquo International Archives ofAllergy and Immunology vol 120 no 2 pp 85ndash99 1999

[74] F Gambon-Deza C Sanchez-Espinel and S Magadan-Mompo ldquoThe immunoglobulin heavy chain locus in the platy-pus (Ornithorhynchus anatinus)rdquo Molecular Immunology vol46 no 13 pp 2515ndash2523 2009

[75] Y Zhao H Cui C M Whittington et al ldquoOrnithorhynchusanatinus (platypus) links the evolution of immunoglobulingenes in eutherian mammals and nonmammalian tetrapodsrdquoThe Journal of Immunology vol 183 no 5 pp 3285ndash3293 2009

[76] M Aveskogh and L Hellman ldquoEvidence for an early appear-ance of modern post-switch isotypes in mammalian evolutioncloning of IgE IgG and IgA from the marsupial Monodelphisdomesticardquo European Journal of Immunology vol 28 no 9 pp2738ndash2750 1998

[77] K Belov G A Harrison and DW Cooper ldquoMolecular cloningof the cDNA encoding the constant region of the immunoglob-ulin a heavy chain (C120572) from amarsupialTrichosurus vulpecula(common brushtail possum)rdquo Immunology Letters vol 60 no2-3 pp 165ndash170 1998

[78] K Belov K R Zenger L Hellman and DW Cooper ldquoEchidnaIgA supports mammalian unity and traditional Therian rela-tionshiprdquo Mammalian Genome vol 13 no 11 pp 656ndash6632002

[79] K Belov and L Hellman ldquoImmunoglobulin genetics of Orni-thorhynchus anatinus (platypus) and Tachyglossus aculeatus(short-beaked echidna)rdquo Comparative Biochemistry and Phys-iology vol 136 no 4 pp 811ndash819 2003

[80] M VernerssonM Aveskogh BMunday and L Hellman ldquoEvi-dence for an early appearance of modern post-switch immu-noglobulin isotypes in mammalian evolution (II) cloning ofIgE IgG1 and IgG2 fromamonotreme the duck-billed platypusOrnithorhynchus anatinusrdquo European Journal of Immunologyvol 32 no 8 pp 2145ndash2155 2002

[81] C Auffray R Nageotte and J L Sikorav ldquoMouse immunoglob-ulin A nucleotide sequence of the structural gene for the 120572heavy chain derived from cloned cDNAsrdquo Gene vol 13 no 4pp 365ndash374 1981

[82] T Ukaji D Sumiyama and O Kai ldquoSequence determinationof the heavy-chain constant region in four immunoglobulinclasses of Mongolian gerbils (Meriones unguiculatus)rdquo Experi-mental Animals vol 61 no 2 pp 99ndash107 2012

[83] R C Burnett W C Hanly S K Zhai and K L Knight ldquoTheIgA heavy chain gene family in rabbit cloning and sequence

analysis of 13 C120572 genesrdquo The EMBO Journal vol 8 no 13 pp4041ndash4047 1989

[84] D K Lanning S-K Zhai and K L Knight ldquoAnalysis of the 31015840C120583 region of the rabbit Ig heavy chain locusrdquoGene vol 309 no2 pp 135ndash144 2003

[85] F Ros J Puels N Reichenberger W van Schooten R Buelowand J Platzer ldquoSequence analysis of 05Mb of the rabbitgermline immunoglobulin heavy chain locusrdquo Gene vol 330no 1-2 pp 49ndash59 2004

[86] M Patel D Selinger G E Mark G J Hickey and G FHollis ldquoSequence of the dog immunoglobulin alpha and epsilonconstant region genesrdquo Immunogenetics vol 41 no 5 pp 282ndash286 1995

[87] Z Zhao Y Zhao Q Pan-Hammarstrom et al ldquoPhysical map-ping of the giant panda immunoglobulin heavy chain constantregion genesrdquo Developmental and Comparative Immunologyvol 31 no 10 pp 1034ndash1049 2007

[88] W R Brown and J E Butler ldquoCharacterization of a C120572 gene ofswinerdquoMolecular Immunology vol 31 no 8 pp 633ndash642 1994

[89] W R Brown H Rabbani J E Butler and L HammarstromldquoCharacterization of the bovine C120572 generdquo Immunology vol 91no 1 pp 1ndash6 1997

[90] G PWhite P Roche M R Brandon S E Newton and E N TMeeusen ldquoCloning and characterization of sheep (Ovis aries)immunoglobulin 120572 chainrdquo Immunogenetics vol 48 no 5 pp359ndash362 1998

[91] AMancia T A Romano H A Gefroh et al ldquoCharacterizationof the immunoglobulin A heavy chain gene of the Atlantic bot-tlenose dolphin (Tursiops truncatus)rdquo Veterinary Immunologyand Immunopathology vol 118 no 3-4 pp 304ndash309 2007

[92] B Wagner I Greiser-Wilke and D F Antczak ldquoCharacteriza-tion of the horse [Equus caballus] IGHA generdquo Immunogeneticsvol 55 no 8 pp 552ndash560 2003

[93] N Takahashi S Ueda and M Obata ldquoStructure of humanimmunoglobulin gamma genes implications for evolution of agene familyrdquo Cell vol 29 no 2 pp 671ndash679 1982

[94] J G Flanagan M-P Lefranc and T H Rabbitts ldquoMechanismsof divergence and convergence of the human immunoglobulin1205721 and 1205722 constant region gene sequencesrdquo Cell vol 36 no 3pp 681ndash688 1984

[95] S Kawamura K Omoto and S Ueda ldquoEvolutionary hypervari-ability in the hinge region of the immunoglobulin alpha generdquoJournal of Molecular Biology vol 215 no 2 pp 201ndash206 1990

[96] F Scinicariello F Masseoud L Jayashankar and R AttanasioldquoSooty mangabey (Cercocebus torquatus atys) IGHG and IGHAgenesrdquo Immunogenetics vol 58 no 12 pp 955ndash965 2006

[97] K A Rogers L Jayashankar F Scinicariello and R AttanasioldquoNonhuman primate IgA genetic heterogeneity and interac-tions with CD89rdquoThe Journal of Immunology vol 180 no 7 pp4816ndash4824 2008

[98] S Kawamura N Saitou and S Ueda ldquoConcerted evolution ofthe primate immunoglobulin 120572-gene through gene conversionrdquoThe Journal of Biological Chemistry vol 267 no 11 pp 7359ndash7367 1992

[99] S Kawamura and S Ueda ldquoImmunoglobulin C119867gene family in

hominoids and its evolutionary historyrdquo Genomics vol 13 no1 pp 194ndash200 1992

[100] A Brusco U Cariota A Bottaro et al ldquoStructural andimmunologic analysis of gene triplications in the Ig heavy chainconstant region locusrdquoThe Journal of Immunology vol 152 no1 pp 129ndash135 1994

18 ISRN Immunology

[101] H Rabbani Q Pan N Kondo C I E Smith and L Ham-marstrom ldquoDuplications and deletions of the human IGHClocus evolutionary implicationsrdquo Immunogenetics vol 45 no2 pp 136ndash141 1996

[102] P F Weinheimer J Mestecky and R T Acton ldquoSpecies distri-bution of J chainrdquoThe Journal of Immunology vol 107 no 4 pp1211ndash1212 1971

[103] F P Inman and J Mestecky ldquoThe J chain of polymeric immu-noglobulinsrdquo inContemporary Topics inMolecular Immunologyvol 3 pp 111ndash141 Springer New York NY USA 1974

[104] P Brandtzaeg ldquoPresence of J chain in human immunocytescontaining various immunoglobulin classesrdquo Nature vol 252no 5482 pp 418ndash420 1974

[105] L Tacchi E Larragoite and I Salinas ldquoDiscovery of J chain inAfrican lungfish (Protopterus dolloi Sarcopterygii) using highthroughput transcriptome sequencing implications in mucosalimmunityrdquo PLoS ONE vol 8 no 8 Article ID e70650 2013

[106] I K Zarkadis D Mastellos and J D Lambris ldquoPhylogeneticaspects of the complement systemrdquo Developmental and Com-parative Immunology vol 25 no 8-9 pp 745ndash762 2001

[107] A P West Jr A B Herr and P J Bjorkman ldquoThe chickenyolk sac IgY receptor a functional equivalent of themammalianMHC-related Fc receptor is a phospholipase A

2receptor

homologrdquo Immunity vol 20 no 5 pp 601ndash610 2004[108] D B Tesar E J Cheung and P J Bjorkman ldquoThe chicken

yolk sac IgY receptor a mammalian mannose receptor familymember transcytoses IgY across polarized epithelial cellsrdquoMolecular Biology of the Cell vol 19 no 4 pp 1587ndash1593 2008

[109] A I Taylor R L Beavil B J Sutton and R A Calvert ldquoAmonomeric chicken IgY receptor binds IgY with 21 stoichiom-etryrdquo The Journal of Biological Chemistry vol 284 no 36 pp24168ndash24175 2009

[110] K Baker S-W Qiao T Kuo et al ldquoImmune and non-immunefunctions of the (not so) neonatal Fc receptor FcRnrdquo Seminarsin Immunopathology vol 31 no 2 pp 223ndash236 2009

[111] K Baker R S Blumberg and C S Kaetzel ldquoImmunoglob-ulin transport and immunoglobulin receptorsrdquo in MucosalImmunology J Mestecky W Strober H Cheroutre B KelsallB N Lambrecht andMW Russell Eds chapter 20 AcademicPressElsevier Waltham Mass USA 2014

[112] C S Kaetzel ldquoThepolymeric immunoglobulin receptorrdquo in eLSJohn Wiley amp Sons Chichester UK 2013

[113] N J Mantis N Rol and B Corthesy ldquoSecretory IgArsquos complexroles in immunity andmucosal homeostasis in the gutrdquoMucosalImmunology vol 4 no 6 pp 603ndash611 2011

[114] J V Peppard M E Rose and P Hesketh ldquoA functional homo-logue of mammalian secretory component exists in chickensrdquoEuropean Journal of Immunology vol 13 no 7 pp 566ndash5701983

[115] K E Mostov M Friedlander and G Blobel ldquoThe receptorfor transepithelial transport of IgA and IgM contains multipleimmunoglobulin-like domainsrdquo Nature vol 308 no 5954 pp37ndash43 1984

[116] P Krajci R Solberg M Sandberg O Oyen T Jahnsen and PBrandtzaeg ldquoMolecular cloning of the human transmembranesecretory component (poly-Ig receptor) and its mRNA expres-sion in human tissuesrdquo Biochemical and Biophysical ResearchCommunications vol 158 no 3 pp 783ndash789 1989

[117] P Krajci D Kvale K Tasken and P Brandtzaeg ldquoMolecularcloning and exon-intron mapping of the gene encoding humantransmembrane secretory component (the poly-Ig receptor)rdquo

European Journal of Immunology vol 22 no 9 pp 2309ndash23151992

[118] J F Piskurich J A France C M Tamer C A Willmer CS Kaetzel and D M Kaetzel ldquoInterferon-120574 induces polymericimmunoglobulin receptormRNA in human intestinal epithelialcells by a protein synthesis dependent mechanismrdquo MolecularImmunology vol 30 no 4 pp 413ndash421 1993

[119] J F Piskurich M H Blanchard K R Youngman J A Franceand C S Kaetzel ldquoMolecular cloning of the mouse polymericIg receptor functional regions of the molecule are conservedamong five mammalian speciesrdquo The Journal of Immunologyvol 154 no 4 pp 1735ndash1747 1995

[120] M A Kulseth P Krajci O Myklebost and S RogneldquoCloning and characterization of two forms of bovine polymericimmunoglobulin receptor cDNArdquo DNA and Cell Biology vol14 no 3 pp 251ndash256 1995

[121] K S Koch A S Gleiberman T Aoki et al ldquoDiscordant expres-sion and variable numbers of neighboring GGA- and GAA-richtriplet repeats in the 31015840 untranslated regions of two groups ofmessenger RNAs encoded by the rat polymeric immunoglob-ulin receptor generdquo Nucleic Acids Research vol 23 no 7 pp1098ndash1112 1995

[122] F M Adamski and J Demmer ldquoTwo stages of increased IgAtransfer during lactation in themarsupialTrichosurus vulpecula(brushtail possum)rdquoThe Journal of Immunology vol 162 no 10pp 6009ndash6015 1999

[123] H Kumura T Sone K-I Shimazaki and E KobayashildquoSequence analysis of porcine polymeric immunoglobulinreceptor from mammary epithelial cells present in colostrumrdquoThe Journal of Dairy Research vol 67 no 4 pp 631ndash636 2000

[124] C L Taylor G A Harrison C M Watson and E M DeaneldquocDNA cloning of the polymeric immunoglobulin receptor ofthe marsupial Macropus eugenii (tammar wallaby)rdquo EuropeanJournal of Immunogenetics vol 29 no 2 pp 87ndash93 2002

[125] R Braathen V S Hohman P Brandtzaeg and F-E JohansenldquoSecretory antibody formation conserved binding interactionsbetween J chain and polymeric Ig receptor from humans andamphibiansrdquo The Journal of Immunology vol 178 no 3 pp1589ndash1597 2007

[126] M J Lewis BWagner R M Irvine and J MWoof ldquoIgA in thehorse cloning of equine polymeric Ig receptor and J chain andcharacterization of recombinant forms of equine IgArdquoMucosalImmunology vol 3 no 6 pp 610ndash621 2010

[127] A J Leon D Banner L Xu et al ldquoSequencing annotation andcharacterization of the influenza ferret infectomerdquo Journal ofVirology vol 87 no 4 pp 1957ndash1966 2013

[128] W H Wieland D Orzaez A Lammers H K ParmentierM W A Verstegen and A Schots ldquoA functional polymericimmunoglobulin receptor in chicken (Gallus gallus) indicatesancient role of secretory IgA inmucosal immunityrdquoBiochemicalJournal vol 380 no 3 pp 669ndash676 2004

[129] K Hamuro H Suetake N R Saha K Kikuchi and YSuzuki ldquoA teleost polymeric Ig receptor exhibiting two Ig-likedomains transports tetrameric IgM into the skinrdquo The Journalof Immunology vol 178 no 9 pp 5682ndash5689 2007

[130] J H W M Rombout S J L van der Tuin G Yang et alldquoExpression of the polymeric immunoglobulin receptor (pIgR)in mucosal tissues of common carp (Cyprinus carpio L)rdquo Fishand Shellfish Immunology vol 24 no 5 pp 620ndash628 2008

[131] L-N Feng D-Q Lu J-X Bei et al ldquoMolecular cloning andfunctional analysis of polymeric immunoglobulin receptor gene

ISRN Immunology 19

in orange-spotted grouper (Epinephelus coioides)rdquo ComparativeBiochemistry and Physiology B vol 154 no 3 pp 282ndash289 2009

[132] A E Oslashstergaard S A M Martin T Wang R J M Stet andC J Secombes ldquoRainbow trout (Oncorhynchus mykiss) pos-sessmultiple novel immunoglobulin-like transcripts containingeither an ITAM or ITIMsrdquo Developmental and ComparativeImmunology vol 33 no 4 pp 525ndash532 2009

[133] H Eiffert E Quentin and J Decker ldquoThe primary structureof the human free secretory component and the arrangementof disulfide bondsrdquo Hoppe-Seylerrsquos Zeitschrift fur PhysiologischeChemie vol 365 no 12 pp 1489ndash1495 1984

[134] E Fallgreen-Gebauer W Gebauer A Bastian et al ldquoThe cova-lent linkage of secretory component to IgA Structure of sIgArdquoBiological Chemistry Hoppe-Seyler vol 374 no 11 pp 1023ndash1028 1993

[135] J MWoof ldquoThe structure of IgArdquo inMucosal Immune DefenseImmunoglobulin A C S Kaetzel Ed chapter 1 pp 1ndash24Springer New York NY USA 2007

[136] A Bonner A Almogren P B Furtado M A Kerr and S JPerkins ldquoLocation of secretory component on the Fc edge ofdimeric IgA1 reveals insight into the role of secretory IgA1 inmucosal immunityrdquoMucosal Immunology vol 2 no 1 pp 74ndash84 2009

[137] A Bonner A Almogren P B Furtado M A Kerr and S JPerkins ldquoThe nonplanar secretory IgA2 and near planar secre-tory IgA1 solution structures rationalize their different mucosalimmune responsesrdquo The Journal of Biological Chemistry vol284 no 8 pp 5077ndash5087 2009

[138] J Johansen B Braathen and P Brandtzaeg ldquoRole of J chain insecretory immunoglobulin formationrdquo Scandinavian Journal ofImmunology vol 52 no 3 pp 240ndash248 2000

[139] B A Hendrickson D A Conner D J Ladd et al ldquoAlteredhepatic transport of immunoglobulin A in mice lacking the Jchainrdquo Journal of Experimental Medicine vol 182 no 6 pp1905ndash1911 1995

[140] B A Hendrickson L Rindisbacher B Corthesy et al ldquoLackof association of secretory component with IgA in J chain-deficient micerdquo The Journal of Immunology vol 157 no 2 pp750ndash754 1996

[141] N Lycke L Erlandsson L Ekman K Schon and T Lean-derson ldquoLack of J chain inhibits the transport of gut IgA andabrogates the development of intestinal antitoxic protectionrdquoThe Journal of Immunology vol 163 no 2 pp 913ndash919 1999

[142] F-E Johansen R Braathen and P Brandtzaeg ldquoThe J chainis essential for polymeric Ig receptor-mediated epithelial trans-port of IgArdquoThe Journal of Immunology vol 167 no 9 pp 5185ndash5192 2001

[143] R E Ley D A Peterson and J I Gordon ldquoEcological andevolutionary forces shaping microbial diversity in the humanintestinerdquo Cell vol 124 no 4 pp 837ndash848 2006

[144] M McFall-Ngai ldquoAdaptive immunity care for the communityrdquoNature vol 445 no 7124 p 153 2007

[145] A J Macpherson K D McCoy F-E Johansen and PBrandtzaeg ldquoThe immune geography of IgA induction andfunctionrdquoMucosal Immunology vol 1 no 1 pp 11ndash22 2008

[146] D Kvale and P Brandtzaeg ldquoConstitutive and cytokine inducedexpression of HLA molecules secretory component and inter-cellular adhesion molecule-1 is modulated by butyrate in thecolonic epithelial cell line HT-29rdquo Gut vol 36 no 5 pp 737ndash742 1995

[147] L VHooperMHWong AThelin L Hansson P G Falk andJ I Gordon ldquoMolecular analysis of commensal host-microbialrelationships in the intestinerdquo Science vol 291 no 5505 pp 881ndash884 2001

[148] S Hapfelmeier M A E Lawson E Slack et al ldquoReversiblemicrobial colonization of germ-free mice reveals the dynamicsof IgA immune responsesrdquo Science vol 328 no 5986 pp 1705ndash1709 2010

[149] DH ReikvamMDerrien R Islam et al ldquoEpithelial-microbialcross-talk in polymeric Ig receptor deficient micerdquo EuropeanJournal of Immunology vol 42 no 11 pp 2959ndash2970 2012

[150] EW Rogier A L Frantz M E C Bruno et al ldquoSecretory anti-bodies in breast milk promote long-term intestinal homeostasisby regulating the gut microbiota and host gene expressionrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 111 no 8 pp 3074ndash3079 2014

[151] G M Barton and R Medzhitov ldquoToll-like receptor signalingpathwaysrdquo Science vol 300 no 5625 pp 1524ndash1525 2003

[152] K Takeda and S Akira ldquoToll receptors and pathogen resis-tancerdquo Cellular Microbiology vol 5 no 3 pp 143ndash153 2003

[153] E Cario andD K Podolsky ldquoDifferential alteration in intestinalepithelial cell expression of Toll-like receptor 3 (TLR3) andTLR4 in inflammatory bowel diseaserdquo Infection and Immunityvol 68 no 12 pp 7010ndash7017 2000

[154] M Hausmann S Kiessling S Mestermann et al ldquoToll-likereceptors 2 and 4 are up-regulated during intestinal inflamma-tionrdquo Gastroenterology vol 122 no 7 pp 1987ndash2000 2002

[155] M T Abreu L S Thomas S Y Tesfay et al ldquoRegulation ofTLR4 and MD-2 in the intestinal epithelium evidence for dys-regulated LPS signaling in human inflammatory bowel diseaserdquoin Proceedings of the 90th Annual Meeting of the AmericanAssociation for Immunologists Abstract 3634 Denver ColoUSA 2003

[156] T A Schneeman M E C Bruno H Schjerven F-E JohansenL Chady and C S Kaetzel ldquoRegulation of the polymeric Igreceptor by signaling through TLRs 3 and 4 linking innate andadaptive immune responsesrdquo The Journal of Immunology vol175 no 1 pp 376ndash384 2005

[157] M E C Bruno A L Frantz E W Rogier F-E Johansen andC S Kaetzel ldquoRegulation of the polymeric immunoglobulinreceptor by the classical and alternative NF-120581B pathways inintestinal epithelial cellsrdquoMucosal Immunology vol 4 no 4 pp468ndash478 2011

[158] M E C Bruno E W Rogier A L Frantz A T Stefka SN Thompson and C S Kaetzel ldquoRegulation of the poly-meric immunoglobulin receptor in intestinal epithelial cellsby Enterobacteriaceae implications for mucosal homeostasisrdquoImmunological Investigations vol 39 no 4-5 pp 356ndash382 2010

[159] A L Frantz E W Rogier C R Weber et al ldquoTargeted deletionof MyD88 in intestinal epithelial cells results in compromisedantibacterial immunity associatedwith downregulation of poly-meric immunoglobulin receptor mucin-2 and antibacterialpeptidesrdquoMucosal Immunology vol 5 no 5 pp 501ndash512 2012

[160] E W Rogier A L Frantz M E C Bruno and C S KaetzelldquoSecretory IgA is concentrated in the outer layer of intestinalmucus along with gut bacteriardquo Pathogens In press

[161] M B Geuking K D McCoy and A J Macpherson ldquoThe func-tion of secretory IgA in the context of the intestinal continuumof adaptive immune responses in host-microbial mutualismrdquoSeminars in Immunology vol 24 no 1 pp 36ndash42 2012

20 ISRN Immunology

[162] L VHooper D R Littman andA JMacpherson ldquoInteractionsbetween the microbiota and the immune systemrdquo Science vol336 no 6086 pp 1268ndash1273 2012

[163] A J Macpherson M B Geuking E Slack S Hapfelmeierand K D McCoy ldquoThe habitat double life citizenship andforgetfulness of IgArdquo Immunological Reviews vol 245 no 1 pp132ndash146 2012

Submit your manuscripts athttpwwwhindawicom

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Behavioural Neurology

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Disease Markers

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OncologyJournal of

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Oxidative Medicine and Cellular Longevity

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The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

ISRN Immunology 13

study from the laboratory of Finn-Eirik Johansen demon-strated that diversity of the bacterial community in the cecallumen was reduced in pIgR-knockoutmice supporting a rolefor SIgA in limiting overgrowth of selected species [149] Incontrast the community of bacteria adherent to the epithelialsurface was more diverse in pIgR-knockout mice than inwild-typemice and these adherent bacteria caused enhancedexpression of several epithelial antimicrobial peptides Thesefindings suggest that bacteria-specific SIgA anchored in themucus layer restricts adhesion of bacteria to the epithelialsurface and limits bacterial stimulation of host epithelial cellsA recent study from the authorrsquos laboratory employing abreeding scheme in which119875119894119892119903minusminus damswere bred to119875119894119892119903+minusmales and vice versa demonstrated that SIgA antibodiesin breast milk promote long-term intestinal homeostasis byregulating the gut microbiota and gene expression in colonicepithelial cells [150]

A direct role for commensal andor pathogenic bacteriain the regulation of pIgR expression suggests that the innateimmune system may ldquoprimerdquo epithelial cells for transportof polymeric Ig produced during the adaptive immuneresponse Host cells mediate innate immune responses tomicrobial components through toll-like receptor (TLR) sig-naling (reviewed in [151 152]) Intestinal epithelial cells havebeen shown to express a wide variety of TLRs the expressionof which is upregulated during intestinal inflammation [153ndash155] Significantly expression of pIgR was shown to beupregulated in the HT-29 human intestinal epithelial cellline by bacterial LPS a ligand for TLR4 [156 157] Similarinduction of PIGR gene transcription was seen followingdirect binding of bacteria of the family Enterobacteriaceaewhich express a form of LPS that stimulates TLR4 [158]A recent study from the authorrsquos laboratory demonstratedthat shRNA-mediated knockdown of myeloid differentiationprimary response protein 88 (MyD88) a cytoplasmic adapterprotein that transduces signals from cell surface TLR4blocked the induction of PIGR gene transcription by LPS inHT-29 cells [159] The in vivo significance was confirmed bythe finding that mice with a targeted deletion of the Myd88gene only in intestinal epithelial cells had reduced expressionof pIgR compared to wild-type littermates [159] Mice withtargeted depletion of MyD88 in intestinal epithelial cells alsoexhibited reduced expression of mucin-2 the major compo-nent of the intestinal mucus layer and several antimicrobialpeptides and decreased transmucosal electrical resistanceThese alterations in epithelial barrier function were accom-panied by significant changes in the composition of the fecalmicrobiota increased numbers of bacteria adherent to theintestinal mucus layer and a dramatic increase in transloca-tion of gut bacteria into the drainingmesenteric lymphnodesincluding the opportunistic pathogen Klebsiella pneumoniaeThese findings demonstrate that MyD88-mediated crosstalkbetween the gut microbiota and intestinal epithelial cells iscrucial for optimal expression of pIgR production of SIgAdevelopment of a healthy gut microbiota and maintenanceof intestinal homeostasis

A model can be proposed in which continuous stimu-lation of intestinal epithelial cells by gut bacteria regulates

Lumen

Mucus

Epithelium

Lamina

PIGR

TLRs

MyD88

Bacteria

Plasma cells

propria

Polymeric Ig

Polymeric Ig receptor

Secretory component

Figure 8 Crosstalk between the polymeric immunoglobulin recep-tor secretory immunoglobulins and the gut microbiotaThe single-layered epithelium that lines the gastrointestinal tract is coveredwith a thick mucus layer which physically excludes members ofthe resident microbiota but allows diffusion of shed components ofmicrobial cells Stimulation of epithelial toll-like receptors (TLRs)with microbial products engages the cytoplasmic adaptor proteinMyD88 and initiates NF120581B-dependent signaling pathways Translo-cation of activated NF120581B and other transcription factors to thenucleus enhances transcription of thePIGR gene Activation of TLRsmay also stimulate pIgR transcytosis Polymeric Igs secreted bylamina propria plasma cells bind to pIgRon the basolateral surface ofepithelial cells and are transcytosed to the apical surface along withunoccupied pIgR Proteolytic cleavage of pIgR at the apical surfacereleases secretory SIg and free secretory component (SC) Binding ofSIg and SC to luminal bacteria promotes association with themucuslayer and prevents direct access of bacteria to the epithelial surfaceOver time the continuous crosstalk with SIg shapes the compositionof the gut microbiota Modified from [17] under terms of authorrsquoscopyright with Nature Publishing Group

pIgR expression and transport of SIgA and promotes immuneexclusion of resident and pathogenic bacteria (Figure 8) Adense layer of mucus which increases in thickness fromthe proximal to the distal colon serves to separate bacteriafrom direct contact with the epithelial surface Secretionof microbial-associated molecular patterns (MAMPs) bycommensal bacteria stimulates MyD88-dependent TLR sig-naling leading to enhanced expression of pIgR and antimi-crobial peptides and increased mucus production Bindingof pIgA to pIgR and possibly also signaling via MAMPs

14 ISRN Immunology

enhances transcytosis of pIgA pIgA-containing immunecomplexes and unoccupied pIgR which promotes clearanceof antigens and pathogens from the lamina propria intra-cellular neutralization and release of SIgA and SC at theluminal surface SIgA and SC serve to trap bacteria in themucus layer limiting their access to the epithelial surface Inmice with a targeted deletion of the Muc2 gene which havea severely depleted mucus layer in the colon SIgA and SCfail to associate with the surface of colonic epithelial cells[160] The presence of SIgA in the intestinal lumen whetherderived passively frommaternalmilk or actively via epithelialtranscytosis shapes the composition of the gut microbiotaand modulates intestinal epithelial gene expression

9 Concluding Remarks

The first microbes that emerged on Earth almost 4 billionyears ago encountered a hostile world where nutrients werescarce hazards were everywhere and life was short Withthe evolution of multicellular organisms about 3 billion yearslater a select group ofmicrobes chose to sacrifice an indepen-dent existence for the benefits of a mutualistic relationshipwith eukaryotic hosts Prokaryotic-eukaryotic mutualismreached its apex some 500 million years ago with theemergence of primitive vertebrates whose gastrointestinaltracts were populated by an abundant and diverse commensalmicrobiota In humans the large intestine is home to some100 trillion microorganisms 10 times more than the totalnumber of eukaryotic cells in the entire body The microbesthat inhabit the vertebrate GI tract provide many benefitsto the eukaryotic host including digestion of complex foodmolecules synthesis of vitamins and production of solublefactors that enhance the development of the host immunesystem In return the eukaryotic host provides the microbeswith a warm moist place to live abundant food low oxygentension and a soft bed of mucus on which to form biofilmsWhen this mutually beneficial arrangement is challenged bypathogenicmicrobes the eukaryotic host and the commensalmicrobiota join forces to battle the pathogens and protectthe body from invasion The vertebrate immune system isequipped with a well-trained army of immune cells and asophisticated arsenal of weapons (cell surface molecules andsecreted factors) that protect the host from all but the mostvirulent pathogens This immune ldquoarmyrdquo also serves as aconstant reminder to the commensal microbes that whilethey are free to enjoy the amenities of the mucosal surfacesthey are not welcome in the body proper The emergence ofantigen-specific Igs and T-cell receptors in jawed vertebratesbegan a process of immunological diversification that led tothe development of a specialized mucosal immune systemin higher vertebrates in which secretory Igs play a centralrole The relationship between host and microbiota is clearlyreciprocal the mucosal Igs that evolved in response toselective pressure from the commensal microbiota play acentral role throughout life in shaping the compositiongenetics andmetabolic activity of themicrobiota [1 161 162]

The epithelial layer lining mucosal surfaces provides aphysical and innate immune barrier against penetration of

the body proper by microbes undigested food antigens andpotentially noxious environmental substances The evolu-tionary challenge of transporting mucosal Igs into externalsecretions without compromising the epithelial barrier wasmet by the emergence of the PIGR gene in an ancestor ofbony fishes encoding an epithelial-specific transmembraneprotein that actively transports polymeric Igs across mucosaland glandular epithelia (Figure 4) Structural similaritiesbetween Igs and the extracellular Ig-binding domains of pIgR(Figure 6) suggest that duplication and diversification of agene encoding primordial Ig-like domain may have givenrise to the PIGR gene in a primitive vertebrate ancestorParallel refinement of the structures of mucosal Igs andpIgR during tetrapod evolution (Figures 6 and 7) culminatedin the evolution of the multifunctional SIgA molecule inmammals in which the pIgR-derived SC subunit providesinnate immune functions and protects the antigen-bindingIgA polymer from proteolytic degradation In addition toacting as a powerful force during vertebrate evolution thereciprocal relationship between pIgR mucosal Igs and thecommensal microbiota provides benefits throughout thelife of the individual Microbial colonization of newbornvertebrates stimulates development of mucosal B cells andclass switching to mucosal Ig isotypes [1 163] Microbialfactors upregulate expression of pIgR enhancing transportof mucosal Igs into external secretions where they in turnregulate the microbiotaThis beautifully orchestrated processallows us to maintain a healthy relationship with our resi-dent microbiota while providing mutual protection againstpathogens

Conflict of Interests

The author declares that there is no conflict of interestsregarding the publication of this paper

Acknowledgments

This work was supported by Grant no AI069027 from theNational Institutes of Health of the United States of America(and an associatedAmerican Recovery andReinvestmentActsupplement) and a Senior Research Award from the Crohnrsquosand Colitis Foundation of America

References

[1] C L Maynard C O Elson R D Hatton and C T WeaverldquoReciprocal interactions of the intestinal microbiota andimmune systemrdquo Nature vol 489 no 7415 pp 231ndash241 2012

[2] M F Flajnik and M Kasahara ldquoOrigin and evolution of theadaptive immune system genetic events and selective pres-suresrdquo Nature Reviews Genetics vol 11 no 1 pp 47ndash59 2010

[3] M F Flajnik and L du Pasquier ldquoEvolution of the immunesystemrdquo in Fundamental Immunology W E Paul Ed chapter4 pp 67ndash128 Lippincott Williams ampWilkins Philadelphia PaUSA 2012

[4] M Hirano S Das P Guo and M D Cooper ldquoThe evolutionof adaptive immunity in vertebratesrdquo Advances in Immunologyvol 109 pp 125ndash157 2011

ISRN Immunology 15

[5] T BoehmNMcCurley Y SutohM SchorppMKasahara andM D Cooper ldquoVLR-based adaptive immunityrdquo Annual Reviewof Immunology vol 30 pp 203ndash220 2012

[6] T Hunkapiller and L Hood ldquoImmunology the growing immu-noglobulin gene superfamilyrdquoNature vol 323 no 6083 pp 15ndash16 1986

[7] P Bork L Holm and C Sander ldquoThe immunoglobulin foldstructural classification sequence patterns and common corerdquoJournal of Molecular Biology vol 242 no 4 pp 309ndash320 1994

[8] C S Kaetzel and M W Russell ldquoPhylogeny and comparativephysiology of IgArdquo in Mucosal Immunology J Mestecky WStrober H Cheroutre B Kelsall B N Lambrecht and M WRussell Eds chapter 19 Academic PressElsevier WalthamMass USA 2014

[9] Y He and P J Bjorkman ldquoStructure of FcRY an avian immu-noglobulin receptor related to mammalian mannose receptorsand its complex with IgYrdquo Proceedings of the National Academyof Sciences of the United States of America vol 108 no 30 pp12431ndash12436 2011

[10] J M Woof and D R Burton ldquoHuman antibody-Fc receptorinteractions illuminated by crystal structuresrdquo Nature ReviewsImmunology vol 4 no 2 pp 89ndash99 2004

[11] W L Martin A P West Jr L Gan and P J Bjorkman ldquoCrystalstructure at 28 A of an FcRnheterodimeric Fc complexmechanism of pH-dependent bindingrdquo Molecular Cell vol 7no 4 pp 867ndash877 2001

[12] E S Ward ldquoAcquiring maternal immunoglobulin differentreceptors similar functionsrdquo Immunity vol 20 no 5 pp 507ndash508 2004

[13] C S Kaetzel ldquoThe polymeric immunoglobulin receptor bridg-ing innate and adaptive immune responses atmucosal surfacesrdquoImmunological Reviews vol 206 no 1 pp 83ndash99 2005

[14] M Acharya G Borland A L Edkins et al ldquoCD23Fc120576RIImolecular multi-taskingrdquo Clinical and Experimental Immunol-ogy vol 162 no 1 pp 12ndash23 2010

[15] V B Klimovich ldquoIgM and its receptors structural and func-tional aspectsrdquo Biochemistry vol 76 no 5 pp 534ndash549 2011

[16] J MWoof andMW Russell ldquoStructure and function relation-ships in IgArdquo Mucosal Immunology vol 4 no 6 pp 590ndash5972011

[17] F-E Johansen and C S Kaetzel ldquoRegulation of the polymericimmunoglobulin receptor and IgA transport new advances inenvironmental factors that stimulate pIgR expression and itsrole in mucosal immunityrdquo Mucosal Immunology vol 4 no 6pp 598ndash602 2011

[18] F Kokubu K Hinds R Litman M J Shamblott and G WLitman ldquoExtensive families of constant region genes in a phy-logenetically primitive vertebrate indicate an additional levelof immunoglobulin complexityrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 84 no16 pp 5868ndash5872 1987

[19] A S Greenberg A L Hughes J Guo D Avila E CMcKinneyand M F Flajnik ldquoA novel ldquochimericrdquo antibody class in carti-laginous fish IgMmay not be the primordial immunoglobulinrdquoEuropean Journal of Immunology vol 26 no 5 pp 1123ndash11291996

[20] H Dooley and M F Flajnik ldquoShark immunity bites back affin-ity maturation and memory response in the nurse shark Ging-lymostoma cirratumrdquo European Journal of Immunology vol 35no 3 pp 936ndash945 2005

[21] S F Schluter R M Bernstein and J J Marchalonis ldquoMolecularorigins and evolution of immunoglobulin heavy-chain genes ofjawed vertebratesrdquo Immunology Today vol 18 no 11 pp 543ndash549 1997

[22] Y Ohta and M Flajnik ldquoIgD like IgM is a primordial immu-noglobulin class perpetuated in most jawed vertebratesrdquo Pro-ceedings of the National Academy of Sciences of the United Statesof America vol 103 no 28 pp 10723ndash10728 2006

[23] S Fillatreau A Six S Magadan R Castro J O Sunyer andP Boudinot ldquoThe astonishing diversity of Ig classes and B cellrepertoires in teleost fishrdquo Frontiers in Immunology vol 4 no28 2013

[24] W Harriman H Volk N Defranoux and M Wabl ldquoImmu-noglobulin class switch recombinationrdquo Annual Review ofImmunology vol 11 pp 361ndash384 1993

[25] J Stavnezer and C T Amemiya ldquoEvolution of isotype switch-ingrdquo Seminars in Immunology vol 16 no 4 pp 257ndash275 2004

[26] V M Barreto Q Pan-Hammarstrom Y Zhao L Ham-marstrom Z Misulovin and M C Nussenzweig ldquoAID frombony fish catalyzes class switch recombinationrdquo Journal ofExperimental Medicine vol 202 no 6 pp 733ndash738 2005

[27] T C Fletcher and AWhite ldquoAntibody production in the plaice(Pleuronectes platessa L) after oral and parenteral immuniza-tion with Vibrio anguillarum antigensrdquo Aquaculture vol 1 pp417ndash428 1972

[28] J W H M Rombout L J Blok C H J Lamers and E EgbertsldquoImmunization of carp (Cyprinus carpio) with a Vibrio anguil-larum bacterin indications for a common mucosal immunesystemrdquo Developmental and Comparative Immunology vol 10no 3 pp 341ndash351 1986

[29] U Georgopoulou and J-M Vernier ldquoLocal immunologicalresponse in the posterior intestinal segment of the rainbowtrout after oral administration of macromoleculesrdquo Develop-mental andComparative Immunology vol 10 no 4 pp 529ndash5371986

[30] C J Lobb ldquoSecretory immunity induced in catfish Ictaluruspunctatus following bath immunizationrdquo Developmental andComparative Immunology vol 11 no 4 pp 727ndash738 1987

[31] J D Hansen E D Landis and R B Phillips ldquoDiscovery ofa unique Ig heavy-chain (IgT) in rainbow trout implicationsfor a distinctive B cell developmental pathway in teleost fishrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 102 no 19 pp 6919ndash6924 2005

[32] N Danilova J Bussmann K Jekosch and L A Steiner ldquoTheimmunoglobulin heavy-chain locus in zebrafish identificationand expression of a previously unknown isotype immunoglob-ulin Zrdquo Nature Immunology vol 6 no 3 pp 295ndash302 2005

[33] R Savan A Aman K Sato R Yamaguchi and M Sakai ldquoDis-covery of a new class of immunoglobulin heavy chain fromfugurdquo European Journal of Immunology vol 35 no 11 pp 3320ndash3331 2005

[34] R Savan A AmanMNakao HWatanuki andM Sakai ldquoDis-covery of a novel immunoglobulin heavy chain gene chimerafrom common carp (Cyprinus carpio L)rdquo Immunogenetics vol57 no 6 pp 458ndash463 2005

[35] F Gambon-Deza C Sanchez-Espinel and S Magadan-Mompo ldquoPresence of an unique IgT on the IGH locus in three-spined stickleback fish (Gasterosteus aculeatus) and the veryrecent generation of a repertoire of VH genesrdquo Developmentaland Comparative Immunology vol 34 no 2 pp 114ndash122 2010

[36] T M Tadiso K K Lie and I Hordvik ldquoMolecular cloning ofIgT fromAtlantic salmon and analysis of the relative expression

16 ISRN Immunology

of 120591 120583 and 120575 in different tissuesrdquo Veterinary Immunology andImmunopathology vol 139 no 1 pp 17ndash26 2011

[37] S Mashoof C Pohlenz P L Chen et al ldquoExpressed IgH 120583and 120591 transcripts share diversity segment in ranched Thunnusorientalisrdquo Developmental and Comparative Immunology vol43 no 1 pp 76ndash86 2014

[38] Y-A Zhang I Salinas J Li et al ldquoIgT a primitive immunoglob-ulin class specialized in mucosal immunityrdquo Nature Immunol-ogy vol 11 no 9 pp 827ndash835 2010

[39] S Magadan-Mompo C Sanchez-Espinel and F Gambon-Deza ldquoImmunoglobulin heavy chains in medaka (Oryziaslatipes)rdquo BMC Evolutionary Biology vol 11 no 1 article 1652011

[40] C T Amemiya J Alfoldi A P Lee et al ldquoThe African coela-canth genome provides insights into tetrapod evolutionrdquoNature vol 496 no 7445 pp 311ndash316 2013

[41] T Ota J P Rast G W Litman and C T Amemiya ldquoLineage-restricted retention of a primitive immunoglobulin heavy chainisotype within the Dipnoi reveals an evolutionary paradoxrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 100 no 5 pp 2501ndash2506 2003

[42] Y Sun Z Wei N Li and Y Zhao ldquoA comparative overview ofimmunoglobulin genes and the generation of their diversity intetrapodsrdquo Developmental and Comparative Immunology vol39 no 1-2 pp 103ndash109 2013

[43] I Hadji-Azimi ldquoAnuran immunoglobulins a reviewrdquo Develop-mental and Comparative Immunology vol 3 no 2 pp 223ndash2431979

[44] E Hsu M F Flajnik and L du Pasquier ldquoA third immunoglob-ulin class in amphibiansrdquo The Journal of Immunology vol 135no 3 pp 1998ndash2004 1985

[45] C T Amemiya R N Haire and G W Litman ldquoNucleotidesequence of a cDNA encoding a third distinct Xenopusimmunoglobulin heavy chain isotyperdquo Nucleic Acids Researchvol 17 no 13 p 5388 1989

[46] R Muszligmann M Wilson A Marcuz M Courtet and L duPasquier ldquoMembrane exon sequences of the three Xenopus Igclasses explain the evolutionary origin of mammalian isotypesrdquoEuropean Journal of Immunology vol 26 no 2 pp 409ndash4141996

[47] R Muszligmann L du Pasquier and E Hsu ldquoIs Xenopus IgX ananalog of IgArdquo European Journal of Immunology vol 26 no12 pp 2823ndash2830 1996

[48] B Schaerlinger and J-P Frippiat ldquoIgX antibodies in the urodeleamphibian Ambystoma mexicanumrdquo Developmental and Com-parative Immunology vol 32 no 8 pp 908ndash915 2008

[49] B Schaerlinger M Bascove and J-P Frippiat ldquoA new isotypeof immunoglobulin heavy chain in the urodele amphibianPleurodeles waltl predominantly expressed in larvaerdquoMolecularImmunology vol 45 no 3 pp 776ndash786 2008

[50] S Mashoof A Goodroe C C Du et al ldquoAncient T-independence of mucosal IgXA gut microbiota unaffected bylarval thymectomy in Xenopus laevisrdquo Mucosal Immunologyvol 6 no 2 pp 358ndash368 2013

[51] J P Vaerman J Picard and J F Heremans ldquoStructural dataon chicken IgA and failure to identify the IgA of the tortoiserdquoin Immunologic Phylogeny vol 64 of Advances in ExperimentalMedicine and Biology pp 185ndash195 Springer New York NYUSA 1975

[52] J L Portis and J E Coe ldquoIgM the secretory immunoglobulinof reptiles and amphibiansrdquo Nature vol 258 no 5535 pp 547ndash548 1975

[53] J E Coe D Leong J L Portis and L A Thomas ldquoImmuneresponse in the garter snake (Thamnophis ordinoides)rdquo Immu-nology vol 31 no 3 pp 417ndash424 1976

[54] D Hadge and H Ambrosius ldquoEvolution of low molecularweight immunoglobulinsmdashIV IgY-like immunoglobulins ofbirds reptiles and amphibians precursors of mammalian IgArdquoMolecular Immunology vol 21 no 8 pp 699ndash707 1984

[55] D Hadge and H Ambrosius ldquoEvolution of low molecularweight immunoglobulins V Degree of antigenic relationshipbetween the 7S immunoglobulins ofmammals birds and lowervertebrates to the turkey IgYrdquo Developmental and ComparativeImmunology vol 10 no 3 pp 377ndash385 1986

[56] S Magadan-Mompo C Sanchez-Espinel and F Gambon-Deza ldquoImmunoglobulin genes of the turtlesrdquo Immunogeneticsvol 65 no 3 pp 227ndash237 2013

[57] Z Wei Q Wu L Ren et al ldquoExpression of IgM IgD and IgYin a reptile Anolis carolinensisrdquoThe Journal of Immunology vol183 no 6 pp 3858ndash3864 2009

[58] F Gambon-Deza C Sanchez-Espinel and J V Beneitez ldquoAnovel IgA-like immunoglobulin in the reptile Eublepharis mac-ulariusrdquo Developmental and Comparative Immunology vol 31no 6 pp 596ndash605 2007

[59] G Cheng Y Gao T Wang et al ldquoExtensive diversification ofIgH subclass-encoding genes and IgM subclass switching incrocodiliansrdquo Nature Communications vol 4 article 1337 2013

[60] S Magadan-Mompo C Sanchez-Espinel and F Gambon-Deza ldquoIgH loci of American alligator and saltwater crocodileshed light on IgA evolutionrdquo Immunogenetics vol 65 no 7 pp531ndash541 2013

[61] E Orlans and M E Rose ldquoAn IgA-like immunoglobulin in thefowlrdquo Immunochemistry vol 9 no 8 pp 833ndash838 1972

[62] G A Leslie and L N Martin ldquoStudies on the secretory immu-nologic system of fowl 3 Serum and secretory IgA of thechickenrdquoThe Journal of Immunology vol 110 no 1 pp 1ndash9 1973

[63] J Bienenstock D Y Perey J Gauldie and B J UnderdownldquoChicken 120574A physicochemical and immunochemical charac-teristicsrdquoThe Journal of Immunology vol 110 no 2 pp 524ndash5331973

[64] A M Lebacq-Verheyden J P Vaerman and J F HeremansldquoQuantification and distribution of chicken immunoglobulinsIgA IgM and IgG in serum and secretionsrdquo Immunology vol27 no 4 pp 683ndash692 1974

[65] J Goudswaard A Noordzij R H van Dam J A vanderDonk and J P Vaerman ldquoThe immunoglobulins of the turkey(Meleagris gallopavo) Isolation and characterization of IgGIgM and IgA in body fluids eggs and intraocular tissuesrdquoPoultry science vol 56 no 6 pp 1847ndash1851 1977

[66] D Hadge and H Ambrosius ldquoComparative studies on thestructure of biliary immunoglobulins of some avian speciesII Antigenic properties of the biliary immunoglobulins ofchicken turkey duck and gooserdquo Developmental and Compar-ative Immunology vol 12 no 2 pp 319ndash329 1988

[67] J Goudswaard J P Vaerman and J F Heremans ldquoThreeimmunoglobulin classes in the pigeon (Columbia livia)rdquo Inter-national Archives of Allergy andApplied Immunology vol 53 no5 pp 409ndash419 1977

[68] P L K Ng and D A Higgins ldquoBile immunoglobulin of theduck (Anas platyrhynchos) I Preliminary characterization andontogenyrdquo Immunology vol 58 no 2 pp 323ndash327 1986

[69] K E Magor G W Warr Y Bando D L Middleton and DA Higgins ldquoSecretory immune system of the duck (Anas

ISRN Immunology 17

platyrhynchos) Identification and expression of the genesencoding IgA and IgM heavy chainsrdquo European Journal ofImmunology vol 28 no 3 pp 1063ndash1068 1998

[70] Y Zhao H Rabbani A Shimizu and L Hammarstrom ldquoMap-ping of the chicken immunoglobulin heavy-chain constantregion gene locus reveals an inverted 120572 gene upstream of acondensed 120592 generdquo Immunology vol 101 no 3 pp 348ndash3532000

[71] M L Lundqvist D L Middleton S Hazard and G W WarrldquoThe immunoglobulin heavy chain locus of the duck genomicorganization and expression of D J and C region genesrdquo TheJournal of Biological Chemistry vol 276 no 50 pp 46729ndash46736 2001

[72] T HuangM Zhang ZWei et al ldquoAnalysis of immunoglobulintranscripts in the ostrich Struthio camelus a primitive avianspeciesrdquo PLoS ONE vol 7 no 3 Article ID e34346 2012

[73] K H Roux ldquoImmunoglobulin structure and function asrevealed by electron microscopyrdquo International Archives ofAllergy and Immunology vol 120 no 2 pp 85ndash99 1999

[74] F Gambon-Deza C Sanchez-Espinel and S Magadan-Mompo ldquoThe immunoglobulin heavy chain locus in the platy-pus (Ornithorhynchus anatinus)rdquo Molecular Immunology vol46 no 13 pp 2515ndash2523 2009

[75] Y Zhao H Cui C M Whittington et al ldquoOrnithorhynchusanatinus (platypus) links the evolution of immunoglobulingenes in eutherian mammals and nonmammalian tetrapodsrdquoThe Journal of Immunology vol 183 no 5 pp 3285ndash3293 2009

[76] M Aveskogh and L Hellman ldquoEvidence for an early appear-ance of modern post-switch isotypes in mammalian evolutioncloning of IgE IgG and IgA from the marsupial Monodelphisdomesticardquo European Journal of Immunology vol 28 no 9 pp2738ndash2750 1998

[77] K Belov G A Harrison and DW Cooper ldquoMolecular cloningof the cDNA encoding the constant region of the immunoglob-ulin a heavy chain (C120572) from amarsupialTrichosurus vulpecula(common brushtail possum)rdquo Immunology Letters vol 60 no2-3 pp 165ndash170 1998

[78] K Belov K R Zenger L Hellman and DW Cooper ldquoEchidnaIgA supports mammalian unity and traditional Therian rela-tionshiprdquo Mammalian Genome vol 13 no 11 pp 656ndash6632002

[79] K Belov and L Hellman ldquoImmunoglobulin genetics of Orni-thorhynchus anatinus (platypus) and Tachyglossus aculeatus(short-beaked echidna)rdquo Comparative Biochemistry and Phys-iology vol 136 no 4 pp 811ndash819 2003

[80] M VernerssonM Aveskogh BMunday and L Hellman ldquoEvi-dence for an early appearance of modern post-switch immu-noglobulin isotypes in mammalian evolution (II) cloning ofIgE IgG1 and IgG2 fromamonotreme the duck-billed platypusOrnithorhynchus anatinusrdquo European Journal of Immunologyvol 32 no 8 pp 2145ndash2155 2002

[81] C Auffray R Nageotte and J L Sikorav ldquoMouse immunoglob-ulin A nucleotide sequence of the structural gene for the 120572heavy chain derived from cloned cDNAsrdquo Gene vol 13 no 4pp 365ndash374 1981

[82] T Ukaji D Sumiyama and O Kai ldquoSequence determinationof the heavy-chain constant region in four immunoglobulinclasses of Mongolian gerbils (Meriones unguiculatus)rdquo Experi-mental Animals vol 61 no 2 pp 99ndash107 2012

[83] R C Burnett W C Hanly S K Zhai and K L Knight ldquoTheIgA heavy chain gene family in rabbit cloning and sequence

analysis of 13 C120572 genesrdquo The EMBO Journal vol 8 no 13 pp4041ndash4047 1989

[84] D K Lanning S-K Zhai and K L Knight ldquoAnalysis of the 31015840C120583 region of the rabbit Ig heavy chain locusrdquoGene vol 309 no2 pp 135ndash144 2003

[85] F Ros J Puels N Reichenberger W van Schooten R Buelowand J Platzer ldquoSequence analysis of 05Mb of the rabbitgermline immunoglobulin heavy chain locusrdquo Gene vol 330no 1-2 pp 49ndash59 2004

[86] M Patel D Selinger G E Mark G J Hickey and G FHollis ldquoSequence of the dog immunoglobulin alpha and epsilonconstant region genesrdquo Immunogenetics vol 41 no 5 pp 282ndash286 1995

[87] Z Zhao Y Zhao Q Pan-Hammarstrom et al ldquoPhysical map-ping of the giant panda immunoglobulin heavy chain constantregion genesrdquo Developmental and Comparative Immunologyvol 31 no 10 pp 1034ndash1049 2007

[88] W R Brown and J E Butler ldquoCharacterization of a C120572 gene ofswinerdquoMolecular Immunology vol 31 no 8 pp 633ndash642 1994

[89] W R Brown H Rabbani J E Butler and L HammarstromldquoCharacterization of the bovine C120572 generdquo Immunology vol 91no 1 pp 1ndash6 1997

[90] G PWhite P Roche M R Brandon S E Newton and E N TMeeusen ldquoCloning and characterization of sheep (Ovis aries)immunoglobulin 120572 chainrdquo Immunogenetics vol 48 no 5 pp359ndash362 1998

[91] AMancia T A Romano H A Gefroh et al ldquoCharacterizationof the immunoglobulin A heavy chain gene of the Atlantic bot-tlenose dolphin (Tursiops truncatus)rdquo Veterinary Immunologyand Immunopathology vol 118 no 3-4 pp 304ndash309 2007

[92] B Wagner I Greiser-Wilke and D F Antczak ldquoCharacteriza-tion of the horse [Equus caballus] IGHA generdquo Immunogeneticsvol 55 no 8 pp 552ndash560 2003

[93] N Takahashi S Ueda and M Obata ldquoStructure of humanimmunoglobulin gamma genes implications for evolution of agene familyrdquo Cell vol 29 no 2 pp 671ndash679 1982

[94] J G Flanagan M-P Lefranc and T H Rabbitts ldquoMechanismsof divergence and convergence of the human immunoglobulin1205721 and 1205722 constant region gene sequencesrdquo Cell vol 36 no 3pp 681ndash688 1984

[95] S Kawamura K Omoto and S Ueda ldquoEvolutionary hypervari-ability in the hinge region of the immunoglobulin alpha generdquoJournal of Molecular Biology vol 215 no 2 pp 201ndash206 1990

[96] F Scinicariello F Masseoud L Jayashankar and R AttanasioldquoSooty mangabey (Cercocebus torquatus atys) IGHG and IGHAgenesrdquo Immunogenetics vol 58 no 12 pp 955ndash965 2006

[97] K A Rogers L Jayashankar F Scinicariello and R AttanasioldquoNonhuman primate IgA genetic heterogeneity and interac-tions with CD89rdquoThe Journal of Immunology vol 180 no 7 pp4816ndash4824 2008

[98] S Kawamura N Saitou and S Ueda ldquoConcerted evolution ofthe primate immunoglobulin 120572-gene through gene conversionrdquoThe Journal of Biological Chemistry vol 267 no 11 pp 7359ndash7367 1992

[99] S Kawamura and S Ueda ldquoImmunoglobulin C119867gene family in

hominoids and its evolutionary historyrdquo Genomics vol 13 no1 pp 194ndash200 1992

[100] A Brusco U Cariota A Bottaro et al ldquoStructural andimmunologic analysis of gene triplications in the Ig heavy chainconstant region locusrdquoThe Journal of Immunology vol 152 no1 pp 129ndash135 1994

18 ISRN Immunology

[101] H Rabbani Q Pan N Kondo C I E Smith and L Ham-marstrom ldquoDuplications and deletions of the human IGHClocus evolutionary implicationsrdquo Immunogenetics vol 45 no2 pp 136ndash141 1996

[102] P F Weinheimer J Mestecky and R T Acton ldquoSpecies distri-bution of J chainrdquoThe Journal of Immunology vol 107 no 4 pp1211ndash1212 1971

[103] F P Inman and J Mestecky ldquoThe J chain of polymeric immu-noglobulinsrdquo inContemporary Topics inMolecular Immunologyvol 3 pp 111ndash141 Springer New York NY USA 1974

[104] P Brandtzaeg ldquoPresence of J chain in human immunocytescontaining various immunoglobulin classesrdquo Nature vol 252no 5482 pp 418ndash420 1974

[105] L Tacchi E Larragoite and I Salinas ldquoDiscovery of J chain inAfrican lungfish (Protopterus dolloi Sarcopterygii) using highthroughput transcriptome sequencing implications in mucosalimmunityrdquo PLoS ONE vol 8 no 8 Article ID e70650 2013

[106] I K Zarkadis D Mastellos and J D Lambris ldquoPhylogeneticaspects of the complement systemrdquo Developmental and Com-parative Immunology vol 25 no 8-9 pp 745ndash762 2001

[107] A P West Jr A B Herr and P J Bjorkman ldquoThe chickenyolk sac IgY receptor a functional equivalent of themammalianMHC-related Fc receptor is a phospholipase A

2receptor

homologrdquo Immunity vol 20 no 5 pp 601ndash610 2004[108] D B Tesar E J Cheung and P J Bjorkman ldquoThe chicken

yolk sac IgY receptor a mammalian mannose receptor familymember transcytoses IgY across polarized epithelial cellsrdquoMolecular Biology of the Cell vol 19 no 4 pp 1587ndash1593 2008

[109] A I Taylor R L Beavil B J Sutton and R A Calvert ldquoAmonomeric chicken IgY receptor binds IgY with 21 stoichiom-etryrdquo The Journal of Biological Chemistry vol 284 no 36 pp24168ndash24175 2009

[110] K Baker S-W Qiao T Kuo et al ldquoImmune and non-immunefunctions of the (not so) neonatal Fc receptor FcRnrdquo Seminarsin Immunopathology vol 31 no 2 pp 223ndash236 2009

[111] K Baker R S Blumberg and C S Kaetzel ldquoImmunoglob-ulin transport and immunoglobulin receptorsrdquo in MucosalImmunology J Mestecky W Strober H Cheroutre B KelsallB N Lambrecht andMW Russell Eds chapter 20 AcademicPressElsevier Waltham Mass USA 2014

[112] C S Kaetzel ldquoThepolymeric immunoglobulin receptorrdquo in eLSJohn Wiley amp Sons Chichester UK 2013

[113] N J Mantis N Rol and B Corthesy ldquoSecretory IgArsquos complexroles in immunity andmucosal homeostasis in the gutrdquoMucosalImmunology vol 4 no 6 pp 603ndash611 2011

[114] J V Peppard M E Rose and P Hesketh ldquoA functional homo-logue of mammalian secretory component exists in chickensrdquoEuropean Journal of Immunology vol 13 no 7 pp 566ndash5701983

[115] K E Mostov M Friedlander and G Blobel ldquoThe receptorfor transepithelial transport of IgA and IgM contains multipleimmunoglobulin-like domainsrdquo Nature vol 308 no 5954 pp37ndash43 1984

[116] P Krajci R Solberg M Sandberg O Oyen T Jahnsen and PBrandtzaeg ldquoMolecular cloning of the human transmembranesecretory component (poly-Ig receptor) and its mRNA expres-sion in human tissuesrdquo Biochemical and Biophysical ResearchCommunications vol 158 no 3 pp 783ndash789 1989

[117] P Krajci D Kvale K Tasken and P Brandtzaeg ldquoMolecularcloning and exon-intron mapping of the gene encoding humantransmembrane secretory component (the poly-Ig receptor)rdquo

European Journal of Immunology vol 22 no 9 pp 2309ndash23151992

[118] J F Piskurich J A France C M Tamer C A Willmer CS Kaetzel and D M Kaetzel ldquoInterferon-120574 induces polymericimmunoglobulin receptormRNA in human intestinal epithelialcells by a protein synthesis dependent mechanismrdquo MolecularImmunology vol 30 no 4 pp 413ndash421 1993

[119] J F Piskurich M H Blanchard K R Youngman J A Franceand C S Kaetzel ldquoMolecular cloning of the mouse polymericIg receptor functional regions of the molecule are conservedamong five mammalian speciesrdquo The Journal of Immunologyvol 154 no 4 pp 1735ndash1747 1995

[120] M A Kulseth P Krajci O Myklebost and S RogneldquoCloning and characterization of two forms of bovine polymericimmunoglobulin receptor cDNArdquo DNA and Cell Biology vol14 no 3 pp 251ndash256 1995

[121] K S Koch A S Gleiberman T Aoki et al ldquoDiscordant expres-sion and variable numbers of neighboring GGA- and GAA-richtriplet repeats in the 31015840 untranslated regions of two groups ofmessenger RNAs encoded by the rat polymeric immunoglob-ulin receptor generdquo Nucleic Acids Research vol 23 no 7 pp1098ndash1112 1995

[122] F M Adamski and J Demmer ldquoTwo stages of increased IgAtransfer during lactation in themarsupialTrichosurus vulpecula(brushtail possum)rdquoThe Journal of Immunology vol 162 no 10pp 6009ndash6015 1999

[123] H Kumura T Sone K-I Shimazaki and E KobayashildquoSequence analysis of porcine polymeric immunoglobulinreceptor from mammary epithelial cells present in colostrumrdquoThe Journal of Dairy Research vol 67 no 4 pp 631ndash636 2000

[124] C L Taylor G A Harrison C M Watson and E M DeaneldquocDNA cloning of the polymeric immunoglobulin receptor ofthe marsupial Macropus eugenii (tammar wallaby)rdquo EuropeanJournal of Immunogenetics vol 29 no 2 pp 87ndash93 2002

[125] R Braathen V S Hohman P Brandtzaeg and F-E JohansenldquoSecretory antibody formation conserved binding interactionsbetween J chain and polymeric Ig receptor from humans andamphibiansrdquo The Journal of Immunology vol 178 no 3 pp1589ndash1597 2007

[126] M J Lewis BWagner R M Irvine and J MWoof ldquoIgA in thehorse cloning of equine polymeric Ig receptor and J chain andcharacterization of recombinant forms of equine IgArdquoMucosalImmunology vol 3 no 6 pp 610ndash621 2010

[127] A J Leon D Banner L Xu et al ldquoSequencing annotation andcharacterization of the influenza ferret infectomerdquo Journal ofVirology vol 87 no 4 pp 1957ndash1966 2013

[128] W H Wieland D Orzaez A Lammers H K ParmentierM W A Verstegen and A Schots ldquoA functional polymericimmunoglobulin receptor in chicken (Gallus gallus) indicatesancient role of secretory IgA inmucosal immunityrdquoBiochemicalJournal vol 380 no 3 pp 669ndash676 2004

[129] K Hamuro H Suetake N R Saha K Kikuchi and YSuzuki ldquoA teleost polymeric Ig receptor exhibiting two Ig-likedomains transports tetrameric IgM into the skinrdquo The Journalof Immunology vol 178 no 9 pp 5682ndash5689 2007

[130] J H W M Rombout S J L van der Tuin G Yang et alldquoExpression of the polymeric immunoglobulin receptor (pIgR)in mucosal tissues of common carp (Cyprinus carpio L)rdquo Fishand Shellfish Immunology vol 24 no 5 pp 620ndash628 2008

[131] L-N Feng D-Q Lu J-X Bei et al ldquoMolecular cloning andfunctional analysis of polymeric immunoglobulin receptor gene

ISRN Immunology 19

in orange-spotted grouper (Epinephelus coioides)rdquo ComparativeBiochemistry and Physiology B vol 154 no 3 pp 282ndash289 2009

[132] A E Oslashstergaard S A M Martin T Wang R J M Stet andC J Secombes ldquoRainbow trout (Oncorhynchus mykiss) pos-sessmultiple novel immunoglobulin-like transcripts containingeither an ITAM or ITIMsrdquo Developmental and ComparativeImmunology vol 33 no 4 pp 525ndash532 2009

[133] H Eiffert E Quentin and J Decker ldquoThe primary structureof the human free secretory component and the arrangementof disulfide bondsrdquo Hoppe-Seylerrsquos Zeitschrift fur PhysiologischeChemie vol 365 no 12 pp 1489ndash1495 1984

[134] E Fallgreen-Gebauer W Gebauer A Bastian et al ldquoThe cova-lent linkage of secretory component to IgA Structure of sIgArdquoBiological Chemistry Hoppe-Seyler vol 374 no 11 pp 1023ndash1028 1993

[135] J MWoof ldquoThe structure of IgArdquo inMucosal Immune DefenseImmunoglobulin A C S Kaetzel Ed chapter 1 pp 1ndash24Springer New York NY USA 2007

[136] A Bonner A Almogren P B Furtado M A Kerr and S JPerkins ldquoLocation of secretory component on the Fc edge ofdimeric IgA1 reveals insight into the role of secretory IgA1 inmucosal immunityrdquoMucosal Immunology vol 2 no 1 pp 74ndash84 2009

[137] A Bonner A Almogren P B Furtado M A Kerr and S JPerkins ldquoThe nonplanar secretory IgA2 and near planar secre-tory IgA1 solution structures rationalize their different mucosalimmune responsesrdquo The Journal of Biological Chemistry vol284 no 8 pp 5077ndash5087 2009

[138] J Johansen B Braathen and P Brandtzaeg ldquoRole of J chain insecretory immunoglobulin formationrdquo Scandinavian Journal ofImmunology vol 52 no 3 pp 240ndash248 2000

[139] B A Hendrickson D A Conner D J Ladd et al ldquoAlteredhepatic transport of immunoglobulin A in mice lacking the Jchainrdquo Journal of Experimental Medicine vol 182 no 6 pp1905ndash1911 1995

[140] B A Hendrickson L Rindisbacher B Corthesy et al ldquoLackof association of secretory component with IgA in J chain-deficient micerdquo The Journal of Immunology vol 157 no 2 pp750ndash754 1996

[141] N Lycke L Erlandsson L Ekman K Schon and T Lean-derson ldquoLack of J chain inhibits the transport of gut IgA andabrogates the development of intestinal antitoxic protectionrdquoThe Journal of Immunology vol 163 no 2 pp 913ndash919 1999

[142] F-E Johansen R Braathen and P Brandtzaeg ldquoThe J chainis essential for polymeric Ig receptor-mediated epithelial trans-port of IgArdquoThe Journal of Immunology vol 167 no 9 pp 5185ndash5192 2001

[143] R E Ley D A Peterson and J I Gordon ldquoEcological andevolutionary forces shaping microbial diversity in the humanintestinerdquo Cell vol 124 no 4 pp 837ndash848 2006

[144] M McFall-Ngai ldquoAdaptive immunity care for the communityrdquoNature vol 445 no 7124 p 153 2007

[145] A J Macpherson K D McCoy F-E Johansen and PBrandtzaeg ldquoThe immune geography of IgA induction andfunctionrdquoMucosal Immunology vol 1 no 1 pp 11ndash22 2008

[146] D Kvale and P Brandtzaeg ldquoConstitutive and cytokine inducedexpression of HLA molecules secretory component and inter-cellular adhesion molecule-1 is modulated by butyrate in thecolonic epithelial cell line HT-29rdquo Gut vol 36 no 5 pp 737ndash742 1995

[147] L VHooperMHWong AThelin L Hansson P G Falk andJ I Gordon ldquoMolecular analysis of commensal host-microbialrelationships in the intestinerdquo Science vol 291 no 5505 pp 881ndash884 2001

[148] S Hapfelmeier M A E Lawson E Slack et al ldquoReversiblemicrobial colonization of germ-free mice reveals the dynamicsof IgA immune responsesrdquo Science vol 328 no 5986 pp 1705ndash1709 2010

[149] DH ReikvamMDerrien R Islam et al ldquoEpithelial-microbialcross-talk in polymeric Ig receptor deficient micerdquo EuropeanJournal of Immunology vol 42 no 11 pp 2959ndash2970 2012

[150] EW Rogier A L Frantz M E C Bruno et al ldquoSecretory anti-bodies in breast milk promote long-term intestinal homeostasisby regulating the gut microbiota and host gene expressionrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 111 no 8 pp 3074ndash3079 2014

[151] G M Barton and R Medzhitov ldquoToll-like receptor signalingpathwaysrdquo Science vol 300 no 5625 pp 1524ndash1525 2003

[152] K Takeda and S Akira ldquoToll receptors and pathogen resis-tancerdquo Cellular Microbiology vol 5 no 3 pp 143ndash153 2003

[153] E Cario andD K Podolsky ldquoDifferential alteration in intestinalepithelial cell expression of Toll-like receptor 3 (TLR3) andTLR4 in inflammatory bowel diseaserdquo Infection and Immunityvol 68 no 12 pp 7010ndash7017 2000

[154] M Hausmann S Kiessling S Mestermann et al ldquoToll-likereceptors 2 and 4 are up-regulated during intestinal inflamma-tionrdquo Gastroenterology vol 122 no 7 pp 1987ndash2000 2002

[155] M T Abreu L S Thomas S Y Tesfay et al ldquoRegulation ofTLR4 and MD-2 in the intestinal epithelium evidence for dys-regulated LPS signaling in human inflammatory bowel diseaserdquoin Proceedings of the 90th Annual Meeting of the AmericanAssociation for Immunologists Abstract 3634 Denver ColoUSA 2003

[156] T A Schneeman M E C Bruno H Schjerven F-E JohansenL Chady and C S Kaetzel ldquoRegulation of the polymeric Igreceptor by signaling through TLRs 3 and 4 linking innate andadaptive immune responsesrdquo The Journal of Immunology vol175 no 1 pp 376ndash384 2005

[157] M E C Bruno A L Frantz E W Rogier F-E Johansen andC S Kaetzel ldquoRegulation of the polymeric immunoglobulinreceptor by the classical and alternative NF-120581B pathways inintestinal epithelial cellsrdquoMucosal Immunology vol 4 no 4 pp468ndash478 2011

[158] M E C Bruno E W Rogier A L Frantz A T Stefka SN Thompson and C S Kaetzel ldquoRegulation of the poly-meric immunoglobulin receptor in intestinal epithelial cellsby Enterobacteriaceae implications for mucosal homeostasisrdquoImmunological Investigations vol 39 no 4-5 pp 356ndash382 2010

[159] A L Frantz E W Rogier C R Weber et al ldquoTargeted deletionof MyD88 in intestinal epithelial cells results in compromisedantibacterial immunity associatedwith downregulation of poly-meric immunoglobulin receptor mucin-2 and antibacterialpeptidesrdquoMucosal Immunology vol 5 no 5 pp 501ndash512 2012

[160] E W Rogier A L Frantz M E C Bruno and C S KaetzelldquoSecretory IgA is concentrated in the outer layer of intestinalmucus along with gut bacteriardquo Pathogens In press

[161] M B Geuking K D McCoy and A J Macpherson ldquoThe func-tion of secretory IgA in the context of the intestinal continuumof adaptive immune responses in host-microbial mutualismrdquoSeminars in Immunology vol 24 no 1 pp 36ndash42 2012

20 ISRN Immunology

[162] L VHooper D R Littman andA JMacpherson ldquoInteractionsbetween the microbiota and the immune systemrdquo Science vol336 no 6086 pp 1268ndash1273 2012

[163] A J Macpherson M B Geuking E Slack S Hapfelmeierand K D McCoy ldquoThe habitat double life citizenship andforgetfulness of IgArdquo Immunological Reviews vol 245 no 1 pp132ndash146 2012

Submit your manuscripts athttpwwwhindawicom

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Behavioural Neurology

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Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

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Oxidative Medicine and Cellular Longevity

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The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

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Research and TreatmentAIDS

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Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

14 ISRN Immunology

enhances transcytosis of pIgA pIgA-containing immunecomplexes and unoccupied pIgR which promotes clearanceof antigens and pathogens from the lamina propria intra-cellular neutralization and release of SIgA and SC at theluminal surface SIgA and SC serve to trap bacteria in themucus layer limiting their access to the epithelial surface Inmice with a targeted deletion of the Muc2 gene which havea severely depleted mucus layer in the colon SIgA and SCfail to associate with the surface of colonic epithelial cells[160] The presence of SIgA in the intestinal lumen whetherderived passively frommaternalmilk or actively via epithelialtranscytosis shapes the composition of the gut microbiotaand modulates intestinal epithelial gene expression

9 Concluding Remarks

The first microbes that emerged on Earth almost 4 billionyears ago encountered a hostile world where nutrients werescarce hazards were everywhere and life was short Withthe evolution of multicellular organisms about 3 billion yearslater a select group ofmicrobes chose to sacrifice an indepen-dent existence for the benefits of a mutualistic relationshipwith eukaryotic hosts Prokaryotic-eukaryotic mutualismreached its apex some 500 million years ago with theemergence of primitive vertebrates whose gastrointestinaltracts were populated by an abundant and diverse commensalmicrobiota In humans the large intestine is home to some100 trillion microorganisms 10 times more than the totalnumber of eukaryotic cells in the entire body The microbesthat inhabit the vertebrate GI tract provide many benefitsto the eukaryotic host including digestion of complex foodmolecules synthesis of vitamins and production of solublefactors that enhance the development of the host immunesystem In return the eukaryotic host provides the microbeswith a warm moist place to live abundant food low oxygentension and a soft bed of mucus on which to form biofilmsWhen this mutually beneficial arrangement is challenged bypathogenicmicrobes the eukaryotic host and the commensalmicrobiota join forces to battle the pathogens and protectthe body from invasion The vertebrate immune system isequipped with a well-trained army of immune cells and asophisticated arsenal of weapons (cell surface molecules andsecreted factors) that protect the host from all but the mostvirulent pathogens This immune ldquoarmyrdquo also serves as aconstant reminder to the commensal microbes that whilethey are free to enjoy the amenities of the mucosal surfacesthey are not welcome in the body proper The emergence ofantigen-specific Igs and T-cell receptors in jawed vertebratesbegan a process of immunological diversification that led tothe development of a specialized mucosal immune systemin higher vertebrates in which secretory Igs play a centralrole The relationship between host and microbiota is clearlyreciprocal the mucosal Igs that evolved in response toselective pressure from the commensal microbiota play acentral role throughout life in shaping the compositiongenetics andmetabolic activity of themicrobiota [1 161 162]

The epithelial layer lining mucosal surfaces provides aphysical and innate immune barrier against penetration of

the body proper by microbes undigested food antigens andpotentially noxious environmental substances The evolu-tionary challenge of transporting mucosal Igs into externalsecretions without compromising the epithelial barrier wasmet by the emergence of the PIGR gene in an ancestor ofbony fishes encoding an epithelial-specific transmembraneprotein that actively transports polymeric Igs across mucosaland glandular epithelia (Figure 4) Structural similaritiesbetween Igs and the extracellular Ig-binding domains of pIgR(Figure 6) suggest that duplication and diversification of agene encoding primordial Ig-like domain may have givenrise to the PIGR gene in a primitive vertebrate ancestorParallel refinement of the structures of mucosal Igs andpIgR during tetrapod evolution (Figures 6 and 7) culminatedin the evolution of the multifunctional SIgA molecule inmammals in which the pIgR-derived SC subunit providesinnate immune functions and protects the antigen-bindingIgA polymer from proteolytic degradation In addition toacting as a powerful force during vertebrate evolution thereciprocal relationship between pIgR mucosal Igs and thecommensal microbiota provides benefits throughout thelife of the individual Microbial colonization of newbornvertebrates stimulates development of mucosal B cells andclass switching to mucosal Ig isotypes [1 163] Microbialfactors upregulate expression of pIgR enhancing transportof mucosal Igs into external secretions where they in turnregulate the microbiotaThis beautifully orchestrated processallows us to maintain a healthy relationship with our resi-dent microbiota while providing mutual protection againstpathogens

Conflict of Interests

The author declares that there is no conflict of interestsregarding the publication of this paper

Acknowledgments

This work was supported by Grant no AI069027 from theNational Institutes of Health of the United States of America(and an associatedAmerican Recovery andReinvestmentActsupplement) and a Senior Research Award from the Crohnrsquosand Colitis Foundation of America

References

[1] C L Maynard C O Elson R D Hatton and C T WeaverldquoReciprocal interactions of the intestinal microbiota andimmune systemrdquo Nature vol 489 no 7415 pp 231ndash241 2012

[2] M F Flajnik and M Kasahara ldquoOrigin and evolution of theadaptive immune system genetic events and selective pres-suresrdquo Nature Reviews Genetics vol 11 no 1 pp 47ndash59 2010

[3] M F Flajnik and L du Pasquier ldquoEvolution of the immunesystemrdquo in Fundamental Immunology W E Paul Ed chapter4 pp 67ndash128 Lippincott Williams ampWilkins Philadelphia PaUSA 2012

[4] M Hirano S Das P Guo and M D Cooper ldquoThe evolutionof adaptive immunity in vertebratesrdquo Advances in Immunologyvol 109 pp 125ndash157 2011

ISRN Immunology 15

[5] T BoehmNMcCurley Y SutohM SchorppMKasahara andM D Cooper ldquoVLR-based adaptive immunityrdquo Annual Reviewof Immunology vol 30 pp 203ndash220 2012

[6] T Hunkapiller and L Hood ldquoImmunology the growing immu-noglobulin gene superfamilyrdquoNature vol 323 no 6083 pp 15ndash16 1986

[7] P Bork L Holm and C Sander ldquoThe immunoglobulin foldstructural classification sequence patterns and common corerdquoJournal of Molecular Biology vol 242 no 4 pp 309ndash320 1994

[8] C S Kaetzel and M W Russell ldquoPhylogeny and comparativephysiology of IgArdquo in Mucosal Immunology J Mestecky WStrober H Cheroutre B Kelsall B N Lambrecht and M WRussell Eds chapter 19 Academic PressElsevier WalthamMass USA 2014

[9] Y He and P J Bjorkman ldquoStructure of FcRY an avian immu-noglobulin receptor related to mammalian mannose receptorsand its complex with IgYrdquo Proceedings of the National Academyof Sciences of the United States of America vol 108 no 30 pp12431ndash12436 2011

[10] J M Woof and D R Burton ldquoHuman antibody-Fc receptorinteractions illuminated by crystal structuresrdquo Nature ReviewsImmunology vol 4 no 2 pp 89ndash99 2004

[11] W L Martin A P West Jr L Gan and P J Bjorkman ldquoCrystalstructure at 28 A of an FcRnheterodimeric Fc complexmechanism of pH-dependent bindingrdquo Molecular Cell vol 7no 4 pp 867ndash877 2001

[12] E S Ward ldquoAcquiring maternal immunoglobulin differentreceptors similar functionsrdquo Immunity vol 20 no 5 pp 507ndash508 2004

[13] C S Kaetzel ldquoThe polymeric immunoglobulin receptor bridg-ing innate and adaptive immune responses atmucosal surfacesrdquoImmunological Reviews vol 206 no 1 pp 83ndash99 2005

[14] M Acharya G Borland A L Edkins et al ldquoCD23Fc120576RIImolecular multi-taskingrdquo Clinical and Experimental Immunol-ogy vol 162 no 1 pp 12ndash23 2010

[15] V B Klimovich ldquoIgM and its receptors structural and func-tional aspectsrdquo Biochemistry vol 76 no 5 pp 534ndash549 2011

[16] J MWoof andMW Russell ldquoStructure and function relation-ships in IgArdquo Mucosal Immunology vol 4 no 6 pp 590ndash5972011

[17] F-E Johansen and C S Kaetzel ldquoRegulation of the polymericimmunoglobulin receptor and IgA transport new advances inenvironmental factors that stimulate pIgR expression and itsrole in mucosal immunityrdquo Mucosal Immunology vol 4 no 6pp 598ndash602 2011

[18] F Kokubu K Hinds R Litman M J Shamblott and G WLitman ldquoExtensive families of constant region genes in a phy-logenetically primitive vertebrate indicate an additional levelof immunoglobulin complexityrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 84 no16 pp 5868ndash5872 1987

[19] A S Greenberg A L Hughes J Guo D Avila E CMcKinneyand M F Flajnik ldquoA novel ldquochimericrdquo antibody class in carti-laginous fish IgMmay not be the primordial immunoglobulinrdquoEuropean Journal of Immunology vol 26 no 5 pp 1123ndash11291996

[20] H Dooley and M F Flajnik ldquoShark immunity bites back affin-ity maturation and memory response in the nurse shark Ging-lymostoma cirratumrdquo European Journal of Immunology vol 35no 3 pp 936ndash945 2005

[21] S F Schluter R M Bernstein and J J Marchalonis ldquoMolecularorigins and evolution of immunoglobulin heavy-chain genes ofjawed vertebratesrdquo Immunology Today vol 18 no 11 pp 543ndash549 1997

[22] Y Ohta and M Flajnik ldquoIgD like IgM is a primordial immu-noglobulin class perpetuated in most jawed vertebratesrdquo Pro-ceedings of the National Academy of Sciences of the United Statesof America vol 103 no 28 pp 10723ndash10728 2006

[23] S Fillatreau A Six S Magadan R Castro J O Sunyer andP Boudinot ldquoThe astonishing diversity of Ig classes and B cellrepertoires in teleost fishrdquo Frontiers in Immunology vol 4 no28 2013

[24] W Harriman H Volk N Defranoux and M Wabl ldquoImmu-noglobulin class switch recombinationrdquo Annual Review ofImmunology vol 11 pp 361ndash384 1993

[25] J Stavnezer and C T Amemiya ldquoEvolution of isotype switch-ingrdquo Seminars in Immunology vol 16 no 4 pp 257ndash275 2004

[26] V M Barreto Q Pan-Hammarstrom Y Zhao L Ham-marstrom Z Misulovin and M C Nussenzweig ldquoAID frombony fish catalyzes class switch recombinationrdquo Journal ofExperimental Medicine vol 202 no 6 pp 733ndash738 2005

[27] T C Fletcher and AWhite ldquoAntibody production in the plaice(Pleuronectes platessa L) after oral and parenteral immuniza-tion with Vibrio anguillarum antigensrdquo Aquaculture vol 1 pp417ndash428 1972

[28] J W H M Rombout L J Blok C H J Lamers and E EgbertsldquoImmunization of carp (Cyprinus carpio) with a Vibrio anguil-larum bacterin indications for a common mucosal immunesystemrdquo Developmental and Comparative Immunology vol 10no 3 pp 341ndash351 1986

[29] U Georgopoulou and J-M Vernier ldquoLocal immunologicalresponse in the posterior intestinal segment of the rainbowtrout after oral administration of macromoleculesrdquo Develop-mental andComparative Immunology vol 10 no 4 pp 529ndash5371986

[30] C J Lobb ldquoSecretory immunity induced in catfish Ictaluruspunctatus following bath immunizationrdquo Developmental andComparative Immunology vol 11 no 4 pp 727ndash738 1987

[31] J D Hansen E D Landis and R B Phillips ldquoDiscovery ofa unique Ig heavy-chain (IgT) in rainbow trout implicationsfor a distinctive B cell developmental pathway in teleost fishrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 102 no 19 pp 6919ndash6924 2005

[32] N Danilova J Bussmann K Jekosch and L A Steiner ldquoTheimmunoglobulin heavy-chain locus in zebrafish identificationand expression of a previously unknown isotype immunoglob-ulin Zrdquo Nature Immunology vol 6 no 3 pp 295ndash302 2005

[33] R Savan A Aman K Sato R Yamaguchi and M Sakai ldquoDis-covery of a new class of immunoglobulin heavy chain fromfugurdquo European Journal of Immunology vol 35 no 11 pp 3320ndash3331 2005

[34] R Savan A AmanMNakao HWatanuki andM Sakai ldquoDis-covery of a novel immunoglobulin heavy chain gene chimerafrom common carp (Cyprinus carpio L)rdquo Immunogenetics vol57 no 6 pp 458ndash463 2005

[35] F Gambon-Deza C Sanchez-Espinel and S Magadan-Mompo ldquoPresence of an unique IgT on the IGH locus in three-spined stickleback fish (Gasterosteus aculeatus) and the veryrecent generation of a repertoire of VH genesrdquo Developmentaland Comparative Immunology vol 34 no 2 pp 114ndash122 2010

[36] T M Tadiso K K Lie and I Hordvik ldquoMolecular cloning ofIgT fromAtlantic salmon and analysis of the relative expression

16 ISRN Immunology

of 120591 120583 and 120575 in different tissuesrdquo Veterinary Immunology andImmunopathology vol 139 no 1 pp 17ndash26 2011

[37] S Mashoof C Pohlenz P L Chen et al ldquoExpressed IgH 120583and 120591 transcripts share diversity segment in ranched Thunnusorientalisrdquo Developmental and Comparative Immunology vol43 no 1 pp 76ndash86 2014

[38] Y-A Zhang I Salinas J Li et al ldquoIgT a primitive immunoglob-ulin class specialized in mucosal immunityrdquo Nature Immunol-ogy vol 11 no 9 pp 827ndash835 2010

[39] S Magadan-Mompo C Sanchez-Espinel and F Gambon-Deza ldquoImmunoglobulin heavy chains in medaka (Oryziaslatipes)rdquo BMC Evolutionary Biology vol 11 no 1 article 1652011

[40] C T Amemiya J Alfoldi A P Lee et al ldquoThe African coela-canth genome provides insights into tetrapod evolutionrdquoNature vol 496 no 7445 pp 311ndash316 2013

[41] T Ota J P Rast G W Litman and C T Amemiya ldquoLineage-restricted retention of a primitive immunoglobulin heavy chainisotype within the Dipnoi reveals an evolutionary paradoxrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 100 no 5 pp 2501ndash2506 2003

[42] Y Sun Z Wei N Li and Y Zhao ldquoA comparative overview ofimmunoglobulin genes and the generation of their diversity intetrapodsrdquo Developmental and Comparative Immunology vol39 no 1-2 pp 103ndash109 2013

[43] I Hadji-Azimi ldquoAnuran immunoglobulins a reviewrdquo Develop-mental and Comparative Immunology vol 3 no 2 pp 223ndash2431979

[44] E Hsu M F Flajnik and L du Pasquier ldquoA third immunoglob-ulin class in amphibiansrdquo The Journal of Immunology vol 135no 3 pp 1998ndash2004 1985

[45] C T Amemiya R N Haire and G W Litman ldquoNucleotidesequence of a cDNA encoding a third distinct Xenopusimmunoglobulin heavy chain isotyperdquo Nucleic Acids Researchvol 17 no 13 p 5388 1989

[46] R Muszligmann M Wilson A Marcuz M Courtet and L duPasquier ldquoMembrane exon sequences of the three Xenopus Igclasses explain the evolutionary origin of mammalian isotypesrdquoEuropean Journal of Immunology vol 26 no 2 pp 409ndash4141996

[47] R Muszligmann L du Pasquier and E Hsu ldquoIs Xenopus IgX ananalog of IgArdquo European Journal of Immunology vol 26 no12 pp 2823ndash2830 1996

[48] B Schaerlinger and J-P Frippiat ldquoIgX antibodies in the urodeleamphibian Ambystoma mexicanumrdquo Developmental and Com-parative Immunology vol 32 no 8 pp 908ndash915 2008

[49] B Schaerlinger M Bascove and J-P Frippiat ldquoA new isotypeof immunoglobulin heavy chain in the urodele amphibianPleurodeles waltl predominantly expressed in larvaerdquoMolecularImmunology vol 45 no 3 pp 776ndash786 2008

[50] S Mashoof A Goodroe C C Du et al ldquoAncient T-independence of mucosal IgXA gut microbiota unaffected bylarval thymectomy in Xenopus laevisrdquo Mucosal Immunologyvol 6 no 2 pp 358ndash368 2013

[51] J P Vaerman J Picard and J F Heremans ldquoStructural dataon chicken IgA and failure to identify the IgA of the tortoiserdquoin Immunologic Phylogeny vol 64 of Advances in ExperimentalMedicine and Biology pp 185ndash195 Springer New York NYUSA 1975

[52] J L Portis and J E Coe ldquoIgM the secretory immunoglobulinof reptiles and amphibiansrdquo Nature vol 258 no 5535 pp 547ndash548 1975

[53] J E Coe D Leong J L Portis and L A Thomas ldquoImmuneresponse in the garter snake (Thamnophis ordinoides)rdquo Immu-nology vol 31 no 3 pp 417ndash424 1976

[54] D Hadge and H Ambrosius ldquoEvolution of low molecularweight immunoglobulinsmdashIV IgY-like immunoglobulins ofbirds reptiles and amphibians precursors of mammalian IgArdquoMolecular Immunology vol 21 no 8 pp 699ndash707 1984

[55] D Hadge and H Ambrosius ldquoEvolution of low molecularweight immunoglobulins V Degree of antigenic relationshipbetween the 7S immunoglobulins ofmammals birds and lowervertebrates to the turkey IgYrdquo Developmental and ComparativeImmunology vol 10 no 3 pp 377ndash385 1986

[56] S Magadan-Mompo C Sanchez-Espinel and F Gambon-Deza ldquoImmunoglobulin genes of the turtlesrdquo Immunogeneticsvol 65 no 3 pp 227ndash237 2013

[57] Z Wei Q Wu L Ren et al ldquoExpression of IgM IgD and IgYin a reptile Anolis carolinensisrdquoThe Journal of Immunology vol183 no 6 pp 3858ndash3864 2009

[58] F Gambon-Deza C Sanchez-Espinel and J V Beneitez ldquoAnovel IgA-like immunoglobulin in the reptile Eublepharis mac-ulariusrdquo Developmental and Comparative Immunology vol 31no 6 pp 596ndash605 2007

[59] G Cheng Y Gao T Wang et al ldquoExtensive diversification ofIgH subclass-encoding genes and IgM subclass switching incrocodiliansrdquo Nature Communications vol 4 article 1337 2013

[60] S Magadan-Mompo C Sanchez-Espinel and F Gambon-Deza ldquoIgH loci of American alligator and saltwater crocodileshed light on IgA evolutionrdquo Immunogenetics vol 65 no 7 pp531ndash541 2013

[61] E Orlans and M E Rose ldquoAn IgA-like immunoglobulin in thefowlrdquo Immunochemistry vol 9 no 8 pp 833ndash838 1972

[62] G A Leslie and L N Martin ldquoStudies on the secretory immu-nologic system of fowl 3 Serum and secretory IgA of thechickenrdquoThe Journal of Immunology vol 110 no 1 pp 1ndash9 1973

[63] J Bienenstock D Y Perey J Gauldie and B J UnderdownldquoChicken 120574A physicochemical and immunochemical charac-teristicsrdquoThe Journal of Immunology vol 110 no 2 pp 524ndash5331973

[64] A M Lebacq-Verheyden J P Vaerman and J F HeremansldquoQuantification and distribution of chicken immunoglobulinsIgA IgM and IgG in serum and secretionsrdquo Immunology vol27 no 4 pp 683ndash692 1974

[65] J Goudswaard A Noordzij R H van Dam J A vanderDonk and J P Vaerman ldquoThe immunoglobulins of the turkey(Meleagris gallopavo) Isolation and characterization of IgGIgM and IgA in body fluids eggs and intraocular tissuesrdquoPoultry science vol 56 no 6 pp 1847ndash1851 1977

[66] D Hadge and H Ambrosius ldquoComparative studies on thestructure of biliary immunoglobulins of some avian speciesII Antigenic properties of the biliary immunoglobulins ofchicken turkey duck and gooserdquo Developmental and Compar-ative Immunology vol 12 no 2 pp 319ndash329 1988

[67] J Goudswaard J P Vaerman and J F Heremans ldquoThreeimmunoglobulin classes in the pigeon (Columbia livia)rdquo Inter-national Archives of Allergy andApplied Immunology vol 53 no5 pp 409ndash419 1977

[68] P L K Ng and D A Higgins ldquoBile immunoglobulin of theduck (Anas platyrhynchos) I Preliminary characterization andontogenyrdquo Immunology vol 58 no 2 pp 323ndash327 1986

[69] K E Magor G W Warr Y Bando D L Middleton and DA Higgins ldquoSecretory immune system of the duck (Anas

ISRN Immunology 17

platyrhynchos) Identification and expression of the genesencoding IgA and IgM heavy chainsrdquo European Journal ofImmunology vol 28 no 3 pp 1063ndash1068 1998

[70] Y Zhao H Rabbani A Shimizu and L Hammarstrom ldquoMap-ping of the chicken immunoglobulin heavy-chain constantregion gene locus reveals an inverted 120572 gene upstream of acondensed 120592 generdquo Immunology vol 101 no 3 pp 348ndash3532000

[71] M L Lundqvist D L Middleton S Hazard and G W WarrldquoThe immunoglobulin heavy chain locus of the duck genomicorganization and expression of D J and C region genesrdquo TheJournal of Biological Chemistry vol 276 no 50 pp 46729ndash46736 2001

[72] T HuangM Zhang ZWei et al ldquoAnalysis of immunoglobulintranscripts in the ostrich Struthio camelus a primitive avianspeciesrdquo PLoS ONE vol 7 no 3 Article ID e34346 2012

[73] K H Roux ldquoImmunoglobulin structure and function asrevealed by electron microscopyrdquo International Archives ofAllergy and Immunology vol 120 no 2 pp 85ndash99 1999

[74] F Gambon-Deza C Sanchez-Espinel and S Magadan-Mompo ldquoThe immunoglobulin heavy chain locus in the platy-pus (Ornithorhynchus anatinus)rdquo Molecular Immunology vol46 no 13 pp 2515ndash2523 2009

[75] Y Zhao H Cui C M Whittington et al ldquoOrnithorhynchusanatinus (platypus) links the evolution of immunoglobulingenes in eutherian mammals and nonmammalian tetrapodsrdquoThe Journal of Immunology vol 183 no 5 pp 3285ndash3293 2009

[76] M Aveskogh and L Hellman ldquoEvidence for an early appear-ance of modern post-switch isotypes in mammalian evolutioncloning of IgE IgG and IgA from the marsupial Monodelphisdomesticardquo European Journal of Immunology vol 28 no 9 pp2738ndash2750 1998

[77] K Belov G A Harrison and DW Cooper ldquoMolecular cloningof the cDNA encoding the constant region of the immunoglob-ulin a heavy chain (C120572) from amarsupialTrichosurus vulpecula(common brushtail possum)rdquo Immunology Letters vol 60 no2-3 pp 165ndash170 1998

[78] K Belov K R Zenger L Hellman and DW Cooper ldquoEchidnaIgA supports mammalian unity and traditional Therian rela-tionshiprdquo Mammalian Genome vol 13 no 11 pp 656ndash6632002

[79] K Belov and L Hellman ldquoImmunoglobulin genetics of Orni-thorhynchus anatinus (platypus) and Tachyglossus aculeatus(short-beaked echidna)rdquo Comparative Biochemistry and Phys-iology vol 136 no 4 pp 811ndash819 2003

[80] M VernerssonM Aveskogh BMunday and L Hellman ldquoEvi-dence for an early appearance of modern post-switch immu-noglobulin isotypes in mammalian evolution (II) cloning ofIgE IgG1 and IgG2 fromamonotreme the duck-billed platypusOrnithorhynchus anatinusrdquo European Journal of Immunologyvol 32 no 8 pp 2145ndash2155 2002

[81] C Auffray R Nageotte and J L Sikorav ldquoMouse immunoglob-ulin A nucleotide sequence of the structural gene for the 120572heavy chain derived from cloned cDNAsrdquo Gene vol 13 no 4pp 365ndash374 1981

[82] T Ukaji D Sumiyama and O Kai ldquoSequence determinationof the heavy-chain constant region in four immunoglobulinclasses of Mongolian gerbils (Meriones unguiculatus)rdquo Experi-mental Animals vol 61 no 2 pp 99ndash107 2012

[83] R C Burnett W C Hanly S K Zhai and K L Knight ldquoTheIgA heavy chain gene family in rabbit cloning and sequence

analysis of 13 C120572 genesrdquo The EMBO Journal vol 8 no 13 pp4041ndash4047 1989

[84] D K Lanning S-K Zhai and K L Knight ldquoAnalysis of the 31015840C120583 region of the rabbit Ig heavy chain locusrdquoGene vol 309 no2 pp 135ndash144 2003

[85] F Ros J Puels N Reichenberger W van Schooten R Buelowand J Platzer ldquoSequence analysis of 05Mb of the rabbitgermline immunoglobulin heavy chain locusrdquo Gene vol 330no 1-2 pp 49ndash59 2004

[86] M Patel D Selinger G E Mark G J Hickey and G FHollis ldquoSequence of the dog immunoglobulin alpha and epsilonconstant region genesrdquo Immunogenetics vol 41 no 5 pp 282ndash286 1995

[87] Z Zhao Y Zhao Q Pan-Hammarstrom et al ldquoPhysical map-ping of the giant panda immunoglobulin heavy chain constantregion genesrdquo Developmental and Comparative Immunologyvol 31 no 10 pp 1034ndash1049 2007

[88] W R Brown and J E Butler ldquoCharacterization of a C120572 gene ofswinerdquoMolecular Immunology vol 31 no 8 pp 633ndash642 1994

[89] W R Brown H Rabbani J E Butler and L HammarstromldquoCharacterization of the bovine C120572 generdquo Immunology vol 91no 1 pp 1ndash6 1997

[90] G PWhite P Roche M R Brandon S E Newton and E N TMeeusen ldquoCloning and characterization of sheep (Ovis aries)immunoglobulin 120572 chainrdquo Immunogenetics vol 48 no 5 pp359ndash362 1998

[91] AMancia T A Romano H A Gefroh et al ldquoCharacterizationof the immunoglobulin A heavy chain gene of the Atlantic bot-tlenose dolphin (Tursiops truncatus)rdquo Veterinary Immunologyand Immunopathology vol 118 no 3-4 pp 304ndash309 2007

[92] B Wagner I Greiser-Wilke and D F Antczak ldquoCharacteriza-tion of the horse [Equus caballus] IGHA generdquo Immunogeneticsvol 55 no 8 pp 552ndash560 2003

[93] N Takahashi S Ueda and M Obata ldquoStructure of humanimmunoglobulin gamma genes implications for evolution of agene familyrdquo Cell vol 29 no 2 pp 671ndash679 1982

[94] J G Flanagan M-P Lefranc and T H Rabbitts ldquoMechanismsof divergence and convergence of the human immunoglobulin1205721 and 1205722 constant region gene sequencesrdquo Cell vol 36 no 3pp 681ndash688 1984

[95] S Kawamura K Omoto and S Ueda ldquoEvolutionary hypervari-ability in the hinge region of the immunoglobulin alpha generdquoJournal of Molecular Biology vol 215 no 2 pp 201ndash206 1990

[96] F Scinicariello F Masseoud L Jayashankar and R AttanasioldquoSooty mangabey (Cercocebus torquatus atys) IGHG and IGHAgenesrdquo Immunogenetics vol 58 no 12 pp 955ndash965 2006

[97] K A Rogers L Jayashankar F Scinicariello and R AttanasioldquoNonhuman primate IgA genetic heterogeneity and interac-tions with CD89rdquoThe Journal of Immunology vol 180 no 7 pp4816ndash4824 2008

[98] S Kawamura N Saitou and S Ueda ldquoConcerted evolution ofthe primate immunoglobulin 120572-gene through gene conversionrdquoThe Journal of Biological Chemistry vol 267 no 11 pp 7359ndash7367 1992

[99] S Kawamura and S Ueda ldquoImmunoglobulin C119867gene family in

hominoids and its evolutionary historyrdquo Genomics vol 13 no1 pp 194ndash200 1992

[100] A Brusco U Cariota A Bottaro et al ldquoStructural andimmunologic analysis of gene triplications in the Ig heavy chainconstant region locusrdquoThe Journal of Immunology vol 152 no1 pp 129ndash135 1994

18 ISRN Immunology

[101] H Rabbani Q Pan N Kondo C I E Smith and L Ham-marstrom ldquoDuplications and deletions of the human IGHClocus evolutionary implicationsrdquo Immunogenetics vol 45 no2 pp 136ndash141 1996

[102] P F Weinheimer J Mestecky and R T Acton ldquoSpecies distri-bution of J chainrdquoThe Journal of Immunology vol 107 no 4 pp1211ndash1212 1971

[103] F P Inman and J Mestecky ldquoThe J chain of polymeric immu-noglobulinsrdquo inContemporary Topics inMolecular Immunologyvol 3 pp 111ndash141 Springer New York NY USA 1974

[104] P Brandtzaeg ldquoPresence of J chain in human immunocytescontaining various immunoglobulin classesrdquo Nature vol 252no 5482 pp 418ndash420 1974

[105] L Tacchi E Larragoite and I Salinas ldquoDiscovery of J chain inAfrican lungfish (Protopterus dolloi Sarcopterygii) using highthroughput transcriptome sequencing implications in mucosalimmunityrdquo PLoS ONE vol 8 no 8 Article ID e70650 2013

[106] I K Zarkadis D Mastellos and J D Lambris ldquoPhylogeneticaspects of the complement systemrdquo Developmental and Com-parative Immunology vol 25 no 8-9 pp 745ndash762 2001

[107] A P West Jr A B Herr and P J Bjorkman ldquoThe chickenyolk sac IgY receptor a functional equivalent of themammalianMHC-related Fc receptor is a phospholipase A

2receptor

homologrdquo Immunity vol 20 no 5 pp 601ndash610 2004[108] D B Tesar E J Cheung and P J Bjorkman ldquoThe chicken

yolk sac IgY receptor a mammalian mannose receptor familymember transcytoses IgY across polarized epithelial cellsrdquoMolecular Biology of the Cell vol 19 no 4 pp 1587ndash1593 2008

[109] A I Taylor R L Beavil B J Sutton and R A Calvert ldquoAmonomeric chicken IgY receptor binds IgY with 21 stoichiom-etryrdquo The Journal of Biological Chemistry vol 284 no 36 pp24168ndash24175 2009

[110] K Baker S-W Qiao T Kuo et al ldquoImmune and non-immunefunctions of the (not so) neonatal Fc receptor FcRnrdquo Seminarsin Immunopathology vol 31 no 2 pp 223ndash236 2009

[111] K Baker R S Blumberg and C S Kaetzel ldquoImmunoglob-ulin transport and immunoglobulin receptorsrdquo in MucosalImmunology J Mestecky W Strober H Cheroutre B KelsallB N Lambrecht andMW Russell Eds chapter 20 AcademicPressElsevier Waltham Mass USA 2014

[112] C S Kaetzel ldquoThepolymeric immunoglobulin receptorrdquo in eLSJohn Wiley amp Sons Chichester UK 2013

[113] N J Mantis N Rol and B Corthesy ldquoSecretory IgArsquos complexroles in immunity andmucosal homeostasis in the gutrdquoMucosalImmunology vol 4 no 6 pp 603ndash611 2011

[114] J V Peppard M E Rose and P Hesketh ldquoA functional homo-logue of mammalian secretory component exists in chickensrdquoEuropean Journal of Immunology vol 13 no 7 pp 566ndash5701983

[115] K E Mostov M Friedlander and G Blobel ldquoThe receptorfor transepithelial transport of IgA and IgM contains multipleimmunoglobulin-like domainsrdquo Nature vol 308 no 5954 pp37ndash43 1984

[116] P Krajci R Solberg M Sandberg O Oyen T Jahnsen and PBrandtzaeg ldquoMolecular cloning of the human transmembranesecretory component (poly-Ig receptor) and its mRNA expres-sion in human tissuesrdquo Biochemical and Biophysical ResearchCommunications vol 158 no 3 pp 783ndash789 1989

[117] P Krajci D Kvale K Tasken and P Brandtzaeg ldquoMolecularcloning and exon-intron mapping of the gene encoding humantransmembrane secretory component (the poly-Ig receptor)rdquo

European Journal of Immunology vol 22 no 9 pp 2309ndash23151992

[118] J F Piskurich J A France C M Tamer C A Willmer CS Kaetzel and D M Kaetzel ldquoInterferon-120574 induces polymericimmunoglobulin receptormRNA in human intestinal epithelialcells by a protein synthesis dependent mechanismrdquo MolecularImmunology vol 30 no 4 pp 413ndash421 1993

[119] J F Piskurich M H Blanchard K R Youngman J A Franceand C S Kaetzel ldquoMolecular cloning of the mouse polymericIg receptor functional regions of the molecule are conservedamong five mammalian speciesrdquo The Journal of Immunologyvol 154 no 4 pp 1735ndash1747 1995

[120] M A Kulseth P Krajci O Myklebost and S RogneldquoCloning and characterization of two forms of bovine polymericimmunoglobulin receptor cDNArdquo DNA and Cell Biology vol14 no 3 pp 251ndash256 1995

[121] K S Koch A S Gleiberman T Aoki et al ldquoDiscordant expres-sion and variable numbers of neighboring GGA- and GAA-richtriplet repeats in the 31015840 untranslated regions of two groups ofmessenger RNAs encoded by the rat polymeric immunoglob-ulin receptor generdquo Nucleic Acids Research vol 23 no 7 pp1098ndash1112 1995

[122] F M Adamski and J Demmer ldquoTwo stages of increased IgAtransfer during lactation in themarsupialTrichosurus vulpecula(brushtail possum)rdquoThe Journal of Immunology vol 162 no 10pp 6009ndash6015 1999

[123] H Kumura T Sone K-I Shimazaki and E KobayashildquoSequence analysis of porcine polymeric immunoglobulinreceptor from mammary epithelial cells present in colostrumrdquoThe Journal of Dairy Research vol 67 no 4 pp 631ndash636 2000

[124] C L Taylor G A Harrison C M Watson and E M DeaneldquocDNA cloning of the polymeric immunoglobulin receptor ofthe marsupial Macropus eugenii (tammar wallaby)rdquo EuropeanJournal of Immunogenetics vol 29 no 2 pp 87ndash93 2002

[125] R Braathen V S Hohman P Brandtzaeg and F-E JohansenldquoSecretory antibody formation conserved binding interactionsbetween J chain and polymeric Ig receptor from humans andamphibiansrdquo The Journal of Immunology vol 178 no 3 pp1589ndash1597 2007

[126] M J Lewis BWagner R M Irvine and J MWoof ldquoIgA in thehorse cloning of equine polymeric Ig receptor and J chain andcharacterization of recombinant forms of equine IgArdquoMucosalImmunology vol 3 no 6 pp 610ndash621 2010

[127] A J Leon D Banner L Xu et al ldquoSequencing annotation andcharacterization of the influenza ferret infectomerdquo Journal ofVirology vol 87 no 4 pp 1957ndash1966 2013

[128] W H Wieland D Orzaez A Lammers H K ParmentierM W A Verstegen and A Schots ldquoA functional polymericimmunoglobulin receptor in chicken (Gallus gallus) indicatesancient role of secretory IgA inmucosal immunityrdquoBiochemicalJournal vol 380 no 3 pp 669ndash676 2004

[129] K Hamuro H Suetake N R Saha K Kikuchi and YSuzuki ldquoA teleost polymeric Ig receptor exhibiting two Ig-likedomains transports tetrameric IgM into the skinrdquo The Journalof Immunology vol 178 no 9 pp 5682ndash5689 2007

[130] J H W M Rombout S J L van der Tuin G Yang et alldquoExpression of the polymeric immunoglobulin receptor (pIgR)in mucosal tissues of common carp (Cyprinus carpio L)rdquo Fishand Shellfish Immunology vol 24 no 5 pp 620ndash628 2008

[131] L-N Feng D-Q Lu J-X Bei et al ldquoMolecular cloning andfunctional analysis of polymeric immunoglobulin receptor gene

ISRN Immunology 19

in orange-spotted grouper (Epinephelus coioides)rdquo ComparativeBiochemistry and Physiology B vol 154 no 3 pp 282ndash289 2009

[132] A E Oslashstergaard S A M Martin T Wang R J M Stet andC J Secombes ldquoRainbow trout (Oncorhynchus mykiss) pos-sessmultiple novel immunoglobulin-like transcripts containingeither an ITAM or ITIMsrdquo Developmental and ComparativeImmunology vol 33 no 4 pp 525ndash532 2009

[133] H Eiffert E Quentin and J Decker ldquoThe primary structureof the human free secretory component and the arrangementof disulfide bondsrdquo Hoppe-Seylerrsquos Zeitschrift fur PhysiologischeChemie vol 365 no 12 pp 1489ndash1495 1984

[134] E Fallgreen-Gebauer W Gebauer A Bastian et al ldquoThe cova-lent linkage of secretory component to IgA Structure of sIgArdquoBiological Chemistry Hoppe-Seyler vol 374 no 11 pp 1023ndash1028 1993

[135] J MWoof ldquoThe structure of IgArdquo inMucosal Immune DefenseImmunoglobulin A C S Kaetzel Ed chapter 1 pp 1ndash24Springer New York NY USA 2007

[136] A Bonner A Almogren P B Furtado M A Kerr and S JPerkins ldquoLocation of secretory component on the Fc edge ofdimeric IgA1 reveals insight into the role of secretory IgA1 inmucosal immunityrdquoMucosal Immunology vol 2 no 1 pp 74ndash84 2009

[137] A Bonner A Almogren P B Furtado M A Kerr and S JPerkins ldquoThe nonplanar secretory IgA2 and near planar secre-tory IgA1 solution structures rationalize their different mucosalimmune responsesrdquo The Journal of Biological Chemistry vol284 no 8 pp 5077ndash5087 2009

[138] J Johansen B Braathen and P Brandtzaeg ldquoRole of J chain insecretory immunoglobulin formationrdquo Scandinavian Journal ofImmunology vol 52 no 3 pp 240ndash248 2000

[139] B A Hendrickson D A Conner D J Ladd et al ldquoAlteredhepatic transport of immunoglobulin A in mice lacking the Jchainrdquo Journal of Experimental Medicine vol 182 no 6 pp1905ndash1911 1995

[140] B A Hendrickson L Rindisbacher B Corthesy et al ldquoLackof association of secretory component with IgA in J chain-deficient micerdquo The Journal of Immunology vol 157 no 2 pp750ndash754 1996

[141] N Lycke L Erlandsson L Ekman K Schon and T Lean-derson ldquoLack of J chain inhibits the transport of gut IgA andabrogates the development of intestinal antitoxic protectionrdquoThe Journal of Immunology vol 163 no 2 pp 913ndash919 1999

[142] F-E Johansen R Braathen and P Brandtzaeg ldquoThe J chainis essential for polymeric Ig receptor-mediated epithelial trans-port of IgArdquoThe Journal of Immunology vol 167 no 9 pp 5185ndash5192 2001

[143] R E Ley D A Peterson and J I Gordon ldquoEcological andevolutionary forces shaping microbial diversity in the humanintestinerdquo Cell vol 124 no 4 pp 837ndash848 2006

[144] M McFall-Ngai ldquoAdaptive immunity care for the communityrdquoNature vol 445 no 7124 p 153 2007

[145] A J Macpherson K D McCoy F-E Johansen and PBrandtzaeg ldquoThe immune geography of IgA induction andfunctionrdquoMucosal Immunology vol 1 no 1 pp 11ndash22 2008

[146] D Kvale and P Brandtzaeg ldquoConstitutive and cytokine inducedexpression of HLA molecules secretory component and inter-cellular adhesion molecule-1 is modulated by butyrate in thecolonic epithelial cell line HT-29rdquo Gut vol 36 no 5 pp 737ndash742 1995

[147] L VHooperMHWong AThelin L Hansson P G Falk andJ I Gordon ldquoMolecular analysis of commensal host-microbialrelationships in the intestinerdquo Science vol 291 no 5505 pp 881ndash884 2001

[148] S Hapfelmeier M A E Lawson E Slack et al ldquoReversiblemicrobial colonization of germ-free mice reveals the dynamicsof IgA immune responsesrdquo Science vol 328 no 5986 pp 1705ndash1709 2010

[149] DH ReikvamMDerrien R Islam et al ldquoEpithelial-microbialcross-talk in polymeric Ig receptor deficient micerdquo EuropeanJournal of Immunology vol 42 no 11 pp 2959ndash2970 2012

[150] EW Rogier A L Frantz M E C Bruno et al ldquoSecretory anti-bodies in breast milk promote long-term intestinal homeostasisby regulating the gut microbiota and host gene expressionrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 111 no 8 pp 3074ndash3079 2014

[151] G M Barton and R Medzhitov ldquoToll-like receptor signalingpathwaysrdquo Science vol 300 no 5625 pp 1524ndash1525 2003

[152] K Takeda and S Akira ldquoToll receptors and pathogen resis-tancerdquo Cellular Microbiology vol 5 no 3 pp 143ndash153 2003

[153] E Cario andD K Podolsky ldquoDifferential alteration in intestinalepithelial cell expression of Toll-like receptor 3 (TLR3) andTLR4 in inflammatory bowel diseaserdquo Infection and Immunityvol 68 no 12 pp 7010ndash7017 2000

[154] M Hausmann S Kiessling S Mestermann et al ldquoToll-likereceptors 2 and 4 are up-regulated during intestinal inflamma-tionrdquo Gastroenterology vol 122 no 7 pp 1987ndash2000 2002

[155] M T Abreu L S Thomas S Y Tesfay et al ldquoRegulation ofTLR4 and MD-2 in the intestinal epithelium evidence for dys-regulated LPS signaling in human inflammatory bowel diseaserdquoin Proceedings of the 90th Annual Meeting of the AmericanAssociation for Immunologists Abstract 3634 Denver ColoUSA 2003

[156] T A Schneeman M E C Bruno H Schjerven F-E JohansenL Chady and C S Kaetzel ldquoRegulation of the polymeric Igreceptor by signaling through TLRs 3 and 4 linking innate andadaptive immune responsesrdquo The Journal of Immunology vol175 no 1 pp 376ndash384 2005

[157] M E C Bruno A L Frantz E W Rogier F-E Johansen andC S Kaetzel ldquoRegulation of the polymeric immunoglobulinreceptor by the classical and alternative NF-120581B pathways inintestinal epithelial cellsrdquoMucosal Immunology vol 4 no 4 pp468ndash478 2011

[158] M E C Bruno E W Rogier A L Frantz A T Stefka SN Thompson and C S Kaetzel ldquoRegulation of the poly-meric immunoglobulin receptor in intestinal epithelial cellsby Enterobacteriaceae implications for mucosal homeostasisrdquoImmunological Investigations vol 39 no 4-5 pp 356ndash382 2010

[159] A L Frantz E W Rogier C R Weber et al ldquoTargeted deletionof MyD88 in intestinal epithelial cells results in compromisedantibacterial immunity associatedwith downregulation of poly-meric immunoglobulin receptor mucin-2 and antibacterialpeptidesrdquoMucosal Immunology vol 5 no 5 pp 501ndash512 2012

[160] E W Rogier A L Frantz M E C Bruno and C S KaetzelldquoSecretory IgA is concentrated in the outer layer of intestinalmucus along with gut bacteriardquo Pathogens In press

[161] M B Geuking K D McCoy and A J Macpherson ldquoThe func-tion of secretory IgA in the context of the intestinal continuumof adaptive immune responses in host-microbial mutualismrdquoSeminars in Immunology vol 24 no 1 pp 36ndash42 2012

20 ISRN Immunology

[162] L VHooper D R Littman andA JMacpherson ldquoInteractionsbetween the microbiota and the immune systemrdquo Science vol336 no 6086 pp 1268ndash1273 2012

[163] A J Macpherson M B Geuking E Slack S Hapfelmeierand K D McCoy ldquoThe habitat double life citizenship andforgetfulness of IgArdquo Immunological Reviews vol 245 no 1 pp132ndash146 2012

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

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Oxidative Medicine and Cellular Longevity

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PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

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Diabetes ResearchJournal of

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

ISRN Immunology 15

[5] T BoehmNMcCurley Y SutohM SchorppMKasahara andM D Cooper ldquoVLR-based adaptive immunityrdquo Annual Reviewof Immunology vol 30 pp 203ndash220 2012

[6] T Hunkapiller and L Hood ldquoImmunology the growing immu-noglobulin gene superfamilyrdquoNature vol 323 no 6083 pp 15ndash16 1986

[7] P Bork L Holm and C Sander ldquoThe immunoglobulin foldstructural classification sequence patterns and common corerdquoJournal of Molecular Biology vol 242 no 4 pp 309ndash320 1994

[8] C S Kaetzel and M W Russell ldquoPhylogeny and comparativephysiology of IgArdquo in Mucosal Immunology J Mestecky WStrober H Cheroutre B Kelsall B N Lambrecht and M WRussell Eds chapter 19 Academic PressElsevier WalthamMass USA 2014

[9] Y He and P J Bjorkman ldquoStructure of FcRY an avian immu-noglobulin receptor related to mammalian mannose receptorsand its complex with IgYrdquo Proceedings of the National Academyof Sciences of the United States of America vol 108 no 30 pp12431ndash12436 2011

[10] J M Woof and D R Burton ldquoHuman antibody-Fc receptorinteractions illuminated by crystal structuresrdquo Nature ReviewsImmunology vol 4 no 2 pp 89ndash99 2004

[11] W L Martin A P West Jr L Gan and P J Bjorkman ldquoCrystalstructure at 28 A of an FcRnheterodimeric Fc complexmechanism of pH-dependent bindingrdquo Molecular Cell vol 7no 4 pp 867ndash877 2001

[12] E S Ward ldquoAcquiring maternal immunoglobulin differentreceptors similar functionsrdquo Immunity vol 20 no 5 pp 507ndash508 2004

[13] C S Kaetzel ldquoThe polymeric immunoglobulin receptor bridg-ing innate and adaptive immune responses atmucosal surfacesrdquoImmunological Reviews vol 206 no 1 pp 83ndash99 2005

[14] M Acharya G Borland A L Edkins et al ldquoCD23Fc120576RIImolecular multi-taskingrdquo Clinical and Experimental Immunol-ogy vol 162 no 1 pp 12ndash23 2010

[15] V B Klimovich ldquoIgM and its receptors structural and func-tional aspectsrdquo Biochemistry vol 76 no 5 pp 534ndash549 2011

[16] J MWoof andMW Russell ldquoStructure and function relation-ships in IgArdquo Mucosal Immunology vol 4 no 6 pp 590ndash5972011

[17] F-E Johansen and C S Kaetzel ldquoRegulation of the polymericimmunoglobulin receptor and IgA transport new advances inenvironmental factors that stimulate pIgR expression and itsrole in mucosal immunityrdquo Mucosal Immunology vol 4 no 6pp 598ndash602 2011

[18] F Kokubu K Hinds R Litman M J Shamblott and G WLitman ldquoExtensive families of constant region genes in a phy-logenetically primitive vertebrate indicate an additional levelof immunoglobulin complexityrdquo Proceedings of the NationalAcademy of Sciences of the United States of America vol 84 no16 pp 5868ndash5872 1987

[19] A S Greenberg A L Hughes J Guo D Avila E CMcKinneyand M F Flajnik ldquoA novel ldquochimericrdquo antibody class in carti-laginous fish IgMmay not be the primordial immunoglobulinrdquoEuropean Journal of Immunology vol 26 no 5 pp 1123ndash11291996

[20] H Dooley and M F Flajnik ldquoShark immunity bites back affin-ity maturation and memory response in the nurse shark Ging-lymostoma cirratumrdquo European Journal of Immunology vol 35no 3 pp 936ndash945 2005

[21] S F Schluter R M Bernstein and J J Marchalonis ldquoMolecularorigins and evolution of immunoglobulin heavy-chain genes ofjawed vertebratesrdquo Immunology Today vol 18 no 11 pp 543ndash549 1997

[22] Y Ohta and M Flajnik ldquoIgD like IgM is a primordial immu-noglobulin class perpetuated in most jawed vertebratesrdquo Pro-ceedings of the National Academy of Sciences of the United Statesof America vol 103 no 28 pp 10723ndash10728 2006

[23] S Fillatreau A Six S Magadan R Castro J O Sunyer andP Boudinot ldquoThe astonishing diversity of Ig classes and B cellrepertoires in teleost fishrdquo Frontiers in Immunology vol 4 no28 2013

[24] W Harriman H Volk N Defranoux and M Wabl ldquoImmu-noglobulin class switch recombinationrdquo Annual Review ofImmunology vol 11 pp 361ndash384 1993

[25] J Stavnezer and C T Amemiya ldquoEvolution of isotype switch-ingrdquo Seminars in Immunology vol 16 no 4 pp 257ndash275 2004

[26] V M Barreto Q Pan-Hammarstrom Y Zhao L Ham-marstrom Z Misulovin and M C Nussenzweig ldquoAID frombony fish catalyzes class switch recombinationrdquo Journal ofExperimental Medicine vol 202 no 6 pp 733ndash738 2005

[27] T C Fletcher and AWhite ldquoAntibody production in the plaice(Pleuronectes platessa L) after oral and parenteral immuniza-tion with Vibrio anguillarum antigensrdquo Aquaculture vol 1 pp417ndash428 1972

[28] J W H M Rombout L J Blok C H J Lamers and E EgbertsldquoImmunization of carp (Cyprinus carpio) with a Vibrio anguil-larum bacterin indications for a common mucosal immunesystemrdquo Developmental and Comparative Immunology vol 10no 3 pp 341ndash351 1986

[29] U Georgopoulou and J-M Vernier ldquoLocal immunologicalresponse in the posterior intestinal segment of the rainbowtrout after oral administration of macromoleculesrdquo Develop-mental andComparative Immunology vol 10 no 4 pp 529ndash5371986

[30] C J Lobb ldquoSecretory immunity induced in catfish Ictaluruspunctatus following bath immunizationrdquo Developmental andComparative Immunology vol 11 no 4 pp 727ndash738 1987

[31] J D Hansen E D Landis and R B Phillips ldquoDiscovery ofa unique Ig heavy-chain (IgT) in rainbow trout implicationsfor a distinctive B cell developmental pathway in teleost fishrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 102 no 19 pp 6919ndash6924 2005

[32] N Danilova J Bussmann K Jekosch and L A Steiner ldquoTheimmunoglobulin heavy-chain locus in zebrafish identificationand expression of a previously unknown isotype immunoglob-ulin Zrdquo Nature Immunology vol 6 no 3 pp 295ndash302 2005

[33] R Savan A Aman K Sato R Yamaguchi and M Sakai ldquoDis-covery of a new class of immunoglobulin heavy chain fromfugurdquo European Journal of Immunology vol 35 no 11 pp 3320ndash3331 2005

[34] R Savan A AmanMNakao HWatanuki andM Sakai ldquoDis-covery of a novel immunoglobulin heavy chain gene chimerafrom common carp (Cyprinus carpio L)rdquo Immunogenetics vol57 no 6 pp 458ndash463 2005

[35] F Gambon-Deza C Sanchez-Espinel and S Magadan-Mompo ldquoPresence of an unique IgT on the IGH locus in three-spined stickleback fish (Gasterosteus aculeatus) and the veryrecent generation of a repertoire of VH genesrdquo Developmentaland Comparative Immunology vol 34 no 2 pp 114ndash122 2010

[36] T M Tadiso K K Lie and I Hordvik ldquoMolecular cloning ofIgT fromAtlantic salmon and analysis of the relative expression

16 ISRN Immunology

of 120591 120583 and 120575 in different tissuesrdquo Veterinary Immunology andImmunopathology vol 139 no 1 pp 17ndash26 2011

[37] S Mashoof C Pohlenz P L Chen et al ldquoExpressed IgH 120583and 120591 transcripts share diversity segment in ranched Thunnusorientalisrdquo Developmental and Comparative Immunology vol43 no 1 pp 76ndash86 2014

[38] Y-A Zhang I Salinas J Li et al ldquoIgT a primitive immunoglob-ulin class specialized in mucosal immunityrdquo Nature Immunol-ogy vol 11 no 9 pp 827ndash835 2010

[39] S Magadan-Mompo C Sanchez-Espinel and F Gambon-Deza ldquoImmunoglobulin heavy chains in medaka (Oryziaslatipes)rdquo BMC Evolutionary Biology vol 11 no 1 article 1652011

[40] C T Amemiya J Alfoldi A P Lee et al ldquoThe African coela-canth genome provides insights into tetrapod evolutionrdquoNature vol 496 no 7445 pp 311ndash316 2013

[41] T Ota J P Rast G W Litman and C T Amemiya ldquoLineage-restricted retention of a primitive immunoglobulin heavy chainisotype within the Dipnoi reveals an evolutionary paradoxrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 100 no 5 pp 2501ndash2506 2003

[42] Y Sun Z Wei N Li and Y Zhao ldquoA comparative overview ofimmunoglobulin genes and the generation of their diversity intetrapodsrdquo Developmental and Comparative Immunology vol39 no 1-2 pp 103ndash109 2013

[43] I Hadji-Azimi ldquoAnuran immunoglobulins a reviewrdquo Develop-mental and Comparative Immunology vol 3 no 2 pp 223ndash2431979

[44] E Hsu M F Flajnik and L du Pasquier ldquoA third immunoglob-ulin class in amphibiansrdquo The Journal of Immunology vol 135no 3 pp 1998ndash2004 1985

[45] C T Amemiya R N Haire and G W Litman ldquoNucleotidesequence of a cDNA encoding a third distinct Xenopusimmunoglobulin heavy chain isotyperdquo Nucleic Acids Researchvol 17 no 13 p 5388 1989

[46] R Muszligmann M Wilson A Marcuz M Courtet and L duPasquier ldquoMembrane exon sequences of the three Xenopus Igclasses explain the evolutionary origin of mammalian isotypesrdquoEuropean Journal of Immunology vol 26 no 2 pp 409ndash4141996

[47] R Muszligmann L du Pasquier and E Hsu ldquoIs Xenopus IgX ananalog of IgArdquo European Journal of Immunology vol 26 no12 pp 2823ndash2830 1996

[48] B Schaerlinger and J-P Frippiat ldquoIgX antibodies in the urodeleamphibian Ambystoma mexicanumrdquo Developmental and Com-parative Immunology vol 32 no 8 pp 908ndash915 2008

[49] B Schaerlinger M Bascove and J-P Frippiat ldquoA new isotypeof immunoglobulin heavy chain in the urodele amphibianPleurodeles waltl predominantly expressed in larvaerdquoMolecularImmunology vol 45 no 3 pp 776ndash786 2008

[50] S Mashoof A Goodroe C C Du et al ldquoAncient T-independence of mucosal IgXA gut microbiota unaffected bylarval thymectomy in Xenopus laevisrdquo Mucosal Immunologyvol 6 no 2 pp 358ndash368 2013

[51] J P Vaerman J Picard and J F Heremans ldquoStructural dataon chicken IgA and failure to identify the IgA of the tortoiserdquoin Immunologic Phylogeny vol 64 of Advances in ExperimentalMedicine and Biology pp 185ndash195 Springer New York NYUSA 1975

[52] J L Portis and J E Coe ldquoIgM the secretory immunoglobulinof reptiles and amphibiansrdquo Nature vol 258 no 5535 pp 547ndash548 1975

[53] J E Coe D Leong J L Portis and L A Thomas ldquoImmuneresponse in the garter snake (Thamnophis ordinoides)rdquo Immu-nology vol 31 no 3 pp 417ndash424 1976

[54] D Hadge and H Ambrosius ldquoEvolution of low molecularweight immunoglobulinsmdashIV IgY-like immunoglobulins ofbirds reptiles and amphibians precursors of mammalian IgArdquoMolecular Immunology vol 21 no 8 pp 699ndash707 1984

[55] D Hadge and H Ambrosius ldquoEvolution of low molecularweight immunoglobulins V Degree of antigenic relationshipbetween the 7S immunoglobulins ofmammals birds and lowervertebrates to the turkey IgYrdquo Developmental and ComparativeImmunology vol 10 no 3 pp 377ndash385 1986

[56] S Magadan-Mompo C Sanchez-Espinel and F Gambon-Deza ldquoImmunoglobulin genes of the turtlesrdquo Immunogeneticsvol 65 no 3 pp 227ndash237 2013

[57] Z Wei Q Wu L Ren et al ldquoExpression of IgM IgD and IgYin a reptile Anolis carolinensisrdquoThe Journal of Immunology vol183 no 6 pp 3858ndash3864 2009

[58] F Gambon-Deza C Sanchez-Espinel and J V Beneitez ldquoAnovel IgA-like immunoglobulin in the reptile Eublepharis mac-ulariusrdquo Developmental and Comparative Immunology vol 31no 6 pp 596ndash605 2007

[59] G Cheng Y Gao T Wang et al ldquoExtensive diversification ofIgH subclass-encoding genes and IgM subclass switching incrocodiliansrdquo Nature Communications vol 4 article 1337 2013

[60] S Magadan-Mompo C Sanchez-Espinel and F Gambon-Deza ldquoIgH loci of American alligator and saltwater crocodileshed light on IgA evolutionrdquo Immunogenetics vol 65 no 7 pp531ndash541 2013

[61] E Orlans and M E Rose ldquoAn IgA-like immunoglobulin in thefowlrdquo Immunochemistry vol 9 no 8 pp 833ndash838 1972

[62] G A Leslie and L N Martin ldquoStudies on the secretory immu-nologic system of fowl 3 Serum and secretory IgA of thechickenrdquoThe Journal of Immunology vol 110 no 1 pp 1ndash9 1973

[63] J Bienenstock D Y Perey J Gauldie and B J UnderdownldquoChicken 120574A physicochemical and immunochemical charac-teristicsrdquoThe Journal of Immunology vol 110 no 2 pp 524ndash5331973

[64] A M Lebacq-Verheyden J P Vaerman and J F HeremansldquoQuantification and distribution of chicken immunoglobulinsIgA IgM and IgG in serum and secretionsrdquo Immunology vol27 no 4 pp 683ndash692 1974

[65] J Goudswaard A Noordzij R H van Dam J A vanderDonk and J P Vaerman ldquoThe immunoglobulins of the turkey(Meleagris gallopavo) Isolation and characterization of IgGIgM and IgA in body fluids eggs and intraocular tissuesrdquoPoultry science vol 56 no 6 pp 1847ndash1851 1977

[66] D Hadge and H Ambrosius ldquoComparative studies on thestructure of biliary immunoglobulins of some avian speciesII Antigenic properties of the biliary immunoglobulins ofchicken turkey duck and gooserdquo Developmental and Compar-ative Immunology vol 12 no 2 pp 319ndash329 1988

[67] J Goudswaard J P Vaerman and J F Heremans ldquoThreeimmunoglobulin classes in the pigeon (Columbia livia)rdquo Inter-national Archives of Allergy andApplied Immunology vol 53 no5 pp 409ndash419 1977

[68] P L K Ng and D A Higgins ldquoBile immunoglobulin of theduck (Anas platyrhynchos) I Preliminary characterization andontogenyrdquo Immunology vol 58 no 2 pp 323ndash327 1986

[69] K E Magor G W Warr Y Bando D L Middleton and DA Higgins ldquoSecretory immune system of the duck (Anas

ISRN Immunology 17

platyrhynchos) Identification and expression of the genesencoding IgA and IgM heavy chainsrdquo European Journal ofImmunology vol 28 no 3 pp 1063ndash1068 1998

[70] Y Zhao H Rabbani A Shimizu and L Hammarstrom ldquoMap-ping of the chicken immunoglobulin heavy-chain constantregion gene locus reveals an inverted 120572 gene upstream of acondensed 120592 generdquo Immunology vol 101 no 3 pp 348ndash3532000

[71] M L Lundqvist D L Middleton S Hazard and G W WarrldquoThe immunoglobulin heavy chain locus of the duck genomicorganization and expression of D J and C region genesrdquo TheJournal of Biological Chemistry vol 276 no 50 pp 46729ndash46736 2001

[72] T HuangM Zhang ZWei et al ldquoAnalysis of immunoglobulintranscripts in the ostrich Struthio camelus a primitive avianspeciesrdquo PLoS ONE vol 7 no 3 Article ID e34346 2012

[73] K H Roux ldquoImmunoglobulin structure and function asrevealed by electron microscopyrdquo International Archives ofAllergy and Immunology vol 120 no 2 pp 85ndash99 1999

[74] F Gambon-Deza C Sanchez-Espinel and S Magadan-Mompo ldquoThe immunoglobulin heavy chain locus in the platy-pus (Ornithorhynchus anatinus)rdquo Molecular Immunology vol46 no 13 pp 2515ndash2523 2009

[75] Y Zhao H Cui C M Whittington et al ldquoOrnithorhynchusanatinus (platypus) links the evolution of immunoglobulingenes in eutherian mammals and nonmammalian tetrapodsrdquoThe Journal of Immunology vol 183 no 5 pp 3285ndash3293 2009

[76] M Aveskogh and L Hellman ldquoEvidence for an early appear-ance of modern post-switch isotypes in mammalian evolutioncloning of IgE IgG and IgA from the marsupial Monodelphisdomesticardquo European Journal of Immunology vol 28 no 9 pp2738ndash2750 1998

[77] K Belov G A Harrison and DW Cooper ldquoMolecular cloningof the cDNA encoding the constant region of the immunoglob-ulin a heavy chain (C120572) from amarsupialTrichosurus vulpecula(common brushtail possum)rdquo Immunology Letters vol 60 no2-3 pp 165ndash170 1998

[78] K Belov K R Zenger L Hellman and DW Cooper ldquoEchidnaIgA supports mammalian unity and traditional Therian rela-tionshiprdquo Mammalian Genome vol 13 no 11 pp 656ndash6632002

[79] K Belov and L Hellman ldquoImmunoglobulin genetics of Orni-thorhynchus anatinus (platypus) and Tachyglossus aculeatus(short-beaked echidna)rdquo Comparative Biochemistry and Phys-iology vol 136 no 4 pp 811ndash819 2003

[80] M VernerssonM Aveskogh BMunday and L Hellman ldquoEvi-dence for an early appearance of modern post-switch immu-noglobulin isotypes in mammalian evolution (II) cloning ofIgE IgG1 and IgG2 fromamonotreme the duck-billed platypusOrnithorhynchus anatinusrdquo European Journal of Immunologyvol 32 no 8 pp 2145ndash2155 2002

[81] C Auffray R Nageotte and J L Sikorav ldquoMouse immunoglob-ulin A nucleotide sequence of the structural gene for the 120572heavy chain derived from cloned cDNAsrdquo Gene vol 13 no 4pp 365ndash374 1981

[82] T Ukaji D Sumiyama and O Kai ldquoSequence determinationof the heavy-chain constant region in four immunoglobulinclasses of Mongolian gerbils (Meriones unguiculatus)rdquo Experi-mental Animals vol 61 no 2 pp 99ndash107 2012

[83] R C Burnett W C Hanly S K Zhai and K L Knight ldquoTheIgA heavy chain gene family in rabbit cloning and sequence

analysis of 13 C120572 genesrdquo The EMBO Journal vol 8 no 13 pp4041ndash4047 1989

[84] D K Lanning S-K Zhai and K L Knight ldquoAnalysis of the 31015840C120583 region of the rabbit Ig heavy chain locusrdquoGene vol 309 no2 pp 135ndash144 2003

[85] F Ros J Puels N Reichenberger W van Schooten R Buelowand J Platzer ldquoSequence analysis of 05Mb of the rabbitgermline immunoglobulin heavy chain locusrdquo Gene vol 330no 1-2 pp 49ndash59 2004

[86] M Patel D Selinger G E Mark G J Hickey and G FHollis ldquoSequence of the dog immunoglobulin alpha and epsilonconstant region genesrdquo Immunogenetics vol 41 no 5 pp 282ndash286 1995

[87] Z Zhao Y Zhao Q Pan-Hammarstrom et al ldquoPhysical map-ping of the giant panda immunoglobulin heavy chain constantregion genesrdquo Developmental and Comparative Immunologyvol 31 no 10 pp 1034ndash1049 2007

[88] W R Brown and J E Butler ldquoCharacterization of a C120572 gene ofswinerdquoMolecular Immunology vol 31 no 8 pp 633ndash642 1994

[89] W R Brown H Rabbani J E Butler and L HammarstromldquoCharacterization of the bovine C120572 generdquo Immunology vol 91no 1 pp 1ndash6 1997

[90] G PWhite P Roche M R Brandon S E Newton and E N TMeeusen ldquoCloning and characterization of sheep (Ovis aries)immunoglobulin 120572 chainrdquo Immunogenetics vol 48 no 5 pp359ndash362 1998

[91] AMancia T A Romano H A Gefroh et al ldquoCharacterizationof the immunoglobulin A heavy chain gene of the Atlantic bot-tlenose dolphin (Tursiops truncatus)rdquo Veterinary Immunologyand Immunopathology vol 118 no 3-4 pp 304ndash309 2007

[92] B Wagner I Greiser-Wilke and D F Antczak ldquoCharacteriza-tion of the horse [Equus caballus] IGHA generdquo Immunogeneticsvol 55 no 8 pp 552ndash560 2003

[93] N Takahashi S Ueda and M Obata ldquoStructure of humanimmunoglobulin gamma genes implications for evolution of agene familyrdquo Cell vol 29 no 2 pp 671ndash679 1982

[94] J G Flanagan M-P Lefranc and T H Rabbitts ldquoMechanismsof divergence and convergence of the human immunoglobulin1205721 and 1205722 constant region gene sequencesrdquo Cell vol 36 no 3pp 681ndash688 1984

[95] S Kawamura K Omoto and S Ueda ldquoEvolutionary hypervari-ability in the hinge region of the immunoglobulin alpha generdquoJournal of Molecular Biology vol 215 no 2 pp 201ndash206 1990

[96] F Scinicariello F Masseoud L Jayashankar and R AttanasioldquoSooty mangabey (Cercocebus torquatus atys) IGHG and IGHAgenesrdquo Immunogenetics vol 58 no 12 pp 955ndash965 2006

[97] K A Rogers L Jayashankar F Scinicariello and R AttanasioldquoNonhuman primate IgA genetic heterogeneity and interac-tions with CD89rdquoThe Journal of Immunology vol 180 no 7 pp4816ndash4824 2008

[98] S Kawamura N Saitou and S Ueda ldquoConcerted evolution ofthe primate immunoglobulin 120572-gene through gene conversionrdquoThe Journal of Biological Chemistry vol 267 no 11 pp 7359ndash7367 1992

[99] S Kawamura and S Ueda ldquoImmunoglobulin C119867gene family in

hominoids and its evolutionary historyrdquo Genomics vol 13 no1 pp 194ndash200 1992

[100] A Brusco U Cariota A Bottaro et al ldquoStructural andimmunologic analysis of gene triplications in the Ig heavy chainconstant region locusrdquoThe Journal of Immunology vol 152 no1 pp 129ndash135 1994

18 ISRN Immunology

[101] H Rabbani Q Pan N Kondo C I E Smith and L Ham-marstrom ldquoDuplications and deletions of the human IGHClocus evolutionary implicationsrdquo Immunogenetics vol 45 no2 pp 136ndash141 1996

[102] P F Weinheimer J Mestecky and R T Acton ldquoSpecies distri-bution of J chainrdquoThe Journal of Immunology vol 107 no 4 pp1211ndash1212 1971

[103] F P Inman and J Mestecky ldquoThe J chain of polymeric immu-noglobulinsrdquo inContemporary Topics inMolecular Immunologyvol 3 pp 111ndash141 Springer New York NY USA 1974

[104] P Brandtzaeg ldquoPresence of J chain in human immunocytescontaining various immunoglobulin classesrdquo Nature vol 252no 5482 pp 418ndash420 1974

[105] L Tacchi E Larragoite and I Salinas ldquoDiscovery of J chain inAfrican lungfish (Protopterus dolloi Sarcopterygii) using highthroughput transcriptome sequencing implications in mucosalimmunityrdquo PLoS ONE vol 8 no 8 Article ID e70650 2013

[106] I K Zarkadis D Mastellos and J D Lambris ldquoPhylogeneticaspects of the complement systemrdquo Developmental and Com-parative Immunology vol 25 no 8-9 pp 745ndash762 2001

[107] A P West Jr A B Herr and P J Bjorkman ldquoThe chickenyolk sac IgY receptor a functional equivalent of themammalianMHC-related Fc receptor is a phospholipase A

2receptor

homologrdquo Immunity vol 20 no 5 pp 601ndash610 2004[108] D B Tesar E J Cheung and P J Bjorkman ldquoThe chicken

yolk sac IgY receptor a mammalian mannose receptor familymember transcytoses IgY across polarized epithelial cellsrdquoMolecular Biology of the Cell vol 19 no 4 pp 1587ndash1593 2008

[109] A I Taylor R L Beavil B J Sutton and R A Calvert ldquoAmonomeric chicken IgY receptor binds IgY with 21 stoichiom-etryrdquo The Journal of Biological Chemistry vol 284 no 36 pp24168ndash24175 2009

[110] K Baker S-W Qiao T Kuo et al ldquoImmune and non-immunefunctions of the (not so) neonatal Fc receptor FcRnrdquo Seminarsin Immunopathology vol 31 no 2 pp 223ndash236 2009

[111] K Baker R S Blumberg and C S Kaetzel ldquoImmunoglob-ulin transport and immunoglobulin receptorsrdquo in MucosalImmunology J Mestecky W Strober H Cheroutre B KelsallB N Lambrecht andMW Russell Eds chapter 20 AcademicPressElsevier Waltham Mass USA 2014

[112] C S Kaetzel ldquoThepolymeric immunoglobulin receptorrdquo in eLSJohn Wiley amp Sons Chichester UK 2013

[113] N J Mantis N Rol and B Corthesy ldquoSecretory IgArsquos complexroles in immunity andmucosal homeostasis in the gutrdquoMucosalImmunology vol 4 no 6 pp 603ndash611 2011

[114] J V Peppard M E Rose and P Hesketh ldquoA functional homo-logue of mammalian secretory component exists in chickensrdquoEuropean Journal of Immunology vol 13 no 7 pp 566ndash5701983

[115] K E Mostov M Friedlander and G Blobel ldquoThe receptorfor transepithelial transport of IgA and IgM contains multipleimmunoglobulin-like domainsrdquo Nature vol 308 no 5954 pp37ndash43 1984

[116] P Krajci R Solberg M Sandberg O Oyen T Jahnsen and PBrandtzaeg ldquoMolecular cloning of the human transmembranesecretory component (poly-Ig receptor) and its mRNA expres-sion in human tissuesrdquo Biochemical and Biophysical ResearchCommunications vol 158 no 3 pp 783ndash789 1989

[117] P Krajci D Kvale K Tasken and P Brandtzaeg ldquoMolecularcloning and exon-intron mapping of the gene encoding humantransmembrane secretory component (the poly-Ig receptor)rdquo

European Journal of Immunology vol 22 no 9 pp 2309ndash23151992

[118] J F Piskurich J A France C M Tamer C A Willmer CS Kaetzel and D M Kaetzel ldquoInterferon-120574 induces polymericimmunoglobulin receptormRNA in human intestinal epithelialcells by a protein synthesis dependent mechanismrdquo MolecularImmunology vol 30 no 4 pp 413ndash421 1993

[119] J F Piskurich M H Blanchard K R Youngman J A Franceand C S Kaetzel ldquoMolecular cloning of the mouse polymericIg receptor functional regions of the molecule are conservedamong five mammalian speciesrdquo The Journal of Immunologyvol 154 no 4 pp 1735ndash1747 1995

[120] M A Kulseth P Krajci O Myklebost and S RogneldquoCloning and characterization of two forms of bovine polymericimmunoglobulin receptor cDNArdquo DNA and Cell Biology vol14 no 3 pp 251ndash256 1995

[121] K S Koch A S Gleiberman T Aoki et al ldquoDiscordant expres-sion and variable numbers of neighboring GGA- and GAA-richtriplet repeats in the 31015840 untranslated regions of two groups ofmessenger RNAs encoded by the rat polymeric immunoglob-ulin receptor generdquo Nucleic Acids Research vol 23 no 7 pp1098ndash1112 1995

[122] F M Adamski and J Demmer ldquoTwo stages of increased IgAtransfer during lactation in themarsupialTrichosurus vulpecula(brushtail possum)rdquoThe Journal of Immunology vol 162 no 10pp 6009ndash6015 1999

[123] H Kumura T Sone K-I Shimazaki and E KobayashildquoSequence analysis of porcine polymeric immunoglobulinreceptor from mammary epithelial cells present in colostrumrdquoThe Journal of Dairy Research vol 67 no 4 pp 631ndash636 2000

[124] C L Taylor G A Harrison C M Watson and E M DeaneldquocDNA cloning of the polymeric immunoglobulin receptor ofthe marsupial Macropus eugenii (tammar wallaby)rdquo EuropeanJournal of Immunogenetics vol 29 no 2 pp 87ndash93 2002

[125] R Braathen V S Hohman P Brandtzaeg and F-E JohansenldquoSecretory antibody formation conserved binding interactionsbetween J chain and polymeric Ig receptor from humans andamphibiansrdquo The Journal of Immunology vol 178 no 3 pp1589ndash1597 2007

[126] M J Lewis BWagner R M Irvine and J MWoof ldquoIgA in thehorse cloning of equine polymeric Ig receptor and J chain andcharacterization of recombinant forms of equine IgArdquoMucosalImmunology vol 3 no 6 pp 610ndash621 2010

[127] A J Leon D Banner L Xu et al ldquoSequencing annotation andcharacterization of the influenza ferret infectomerdquo Journal ofVirology vol 87 no 4 pp 1957ndash1966 2013

[128] W H Wieland D Orzaez A Lammers H K ParmentierM W A Verstegen and A Schots ldquoA functional polymericimmunoglobulin receptor in chicken (Gallus gallus) indicatesancient role of secretory IgA inmucosal immunityrdquoBiochemicalJournal vol 380 no 3 pp 669ndash676 2004

[129] K Hamuro H Suetake N R Saha K Kikuchi and YSuzuki ldquoA teleost polymeric Ig receptor exhibiting two Ig-likedomains transports tetrameric IgM into the skinrdquo The Journalof Immunology vol 178 no 9 pp 5682ndash5689 2007

[130] J H W M Rombout S J L van der Tuin G Yang et alldquoExpression of the polymeric immunoglobulin receptor (pIgR)in mucosal tissues of common carp (Cyprinus carpio L)rdquo Fishand Shellfish Immunology vol 24 no 5 pp 620ndash628 2008

[131] L-N Feng D-Q Lu J-X Bei et al ldquoMolecular cloning andfunctional analysis of polymeric immunoglobulin receptor gene

ISRN Immunology 19

in orange-spotted grouper (Epinephelus coioides)rdquo ComparativeBiochemistry and Physiology B vol 154 no 3 pp 282ndash289 2009

[132] A E Oslashstergaard S A M Martin T Wang R J M Stet andC J Secombes ldquoRainbow trout (Oncorhynchus mykiss) pos-sessmultiple novel immunoglobulin-like transcripts containingeither an ITAM or ITIMsrdquo Developmental and ComparativeImmunology vol 33 no 4 pp 525ndash532 2009

[133] H Eiffert E Quentin and J Decker ldquoThe primary structureof the human free secretory component and the arrangementof disulfide bondsrdquo Hoppe-Seylerrsquos Zeitschrift fur PhysiologischeChemie vol 365 no 12 pp 1489ndash1495 1984

[134] E Fallgreen-Gebauer W Gebauer A Bastian et al ldquoThe cova-lent linkage of secretory component to IgA Structure of sIgArdquoBiological Chemistry Hoppe-Seyler vol 374 no 11 pp 1023ndash1028 1993

[135] J MWoof ldquoThe structure of IgArdquo inMucosal Immune DefenseImmunoglobulin A C S Kaetzel Ed chapter 1 pp 1ndash24Springer New York NY USA 2007

[136] A Bonner A Almogren P B Furtado M A Kerr and S JPerkins ldquoLocation of secretory component on the Fc edge ofdimeric IgA1 reveals insight into the role of secretory IgA1 inmucosal immunityrdquoMucosal Immunology vol 2 no 1 pp 74ndash84 2009

[137] A Bonner A Almogren P B Furtado M A Kerr and S JPerkins ldquoThe nonplanar secretory IgA2 and near planar secre-tory IgA1 solution structures rationalize their different mucosalimmune responsesrdquo The Journal of Biological Chemistry vol284 no 8 pp 5077ndash5087 2009

[138] J Johansen B Braathen and P Brandtzaeg ldquoRole of J chain insecretory immunoglobulin formationrdquo Scandinavian Journal ofImmunology vol 52 no 3 pp 240ndash248 2000

[139] B A Hendrickson D A Conner D J Ladd et al ldquoAlteredhepatic transport of immunoglobulin A in mice lacking the Jchainrdquo Journal of Experimental Medicine vol 182 no 6 pp1905ndash1911 1995

[140] B A Hendrickson L Rindisbacher B Corthesy et al ldquoLackof association of secretory component with IgA in J chain-deficient micerdquo The Journal of Immunology vol 157 no 2 pp750ndash754 1996

[141] N Lycke L Erlandsson L Ekman K Schon and T Lean-derson ldquoLack of J chain inhibits the transport of gut IgA andabrogates the development of intestinal antitoxic protectionrdquoThe Journal of Immunology vol 163 no 2 pp 913ndash919 1999

[142] F-E Johansen R Braathen and P Brandtzaeg ldquoThe J chainis essential for polymeric Ig receptor-mediated epithelial trans-port of IgArdquoThe Journal of Immunology vol 167 no 9 pp 5185ndash5192 2001

[143] R E Ley D A Peterson and J I Gordon ldquoEcological andevolutionary forces shaping microbial diversity in the humanintestinerdquo Cell vol 124 no 4 pp 837ndash848 2006

[144] M McFall-Ngai ldquoAdaptive immunity care for the communityrdquoNature vol 445 no 7124 p 153 2007

[145] A J Macpherson K D McCoy F-E Johansen and PBrandtzaeg ldquoThe immune geography of IgA induction andfunctionrdquoMucosal Immunology vol 1 no 1 pp 11ndash22 2008

[146] D Kvale and P Brandtzaeg ldquoConstitutive and cytokine inducedexpression of HLA molecules secretory component and inter-cellular adhesion molecule-1 is modulated by butyrate in thecolonic epithelial cell line HT-29rdquo Gut vol 36 no 5 pp 737ndash742 1995

[147] L VHooperMHWong AThelin L Hansson P G Falk andJ I Gordon ldquoMolecular analysis of commensal host-microbialrelationships in the intestinerdquo Science vol 291 no 5505 pp 881ndash884 2001

[148] S Hapfelmeier M A E Lawson E Slack et al ldquoReversiblemicrobial colonization of germ-free mice reveals the dynamicsof IgA immune responsesrdquo Science vol 328 no 5986 pp 1705ndash1709 2010

[149] DH ReikvamMDerrien R Islam et al ldquoEpithelial-microbialcross-talk in polymeric Ig receptor deficient micerdquo EuropeanJournal of Immunology vol 42 no 11 pp 2959ndash2970 2012

[150] EW Rogier A L Frantz M E C Bruno et al ldquoSecretory anti-bodies in breast milk promote long-term intestinal homeostasisby regulating the gut microbiota and host gene expressionrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 111 no 8 pp 3074ndash3079 2014

[151] G M Barton and R Medzhitov ldquoToll-like receptor signalingpathwaysrdquo Science vol 300 no 5625 pp 1524ndash1525 2003

[152] K Takeda and S Akira ldquoToll receptors and pathogen resis-tancerdquo Cellular Microbiology vol 5 no 3 pp 143ndash153 2003

[153] E Cario andD K Podolsky ldquoDifferential alteration in intestinalepithelial cell expression of Toll-like receptor 3 (TLR3) andTLR4 in inflammatory bowel diseaserdquo Infection and Immunityvol 68 no 12 pp 7010ndash7017 2000

[154] M Hausmann S Kiessling S Mestermann et al ldquoToll-likereceptors 2 and 4 are up-regulated during intestinal inflamma-tionrdquo Gastroenterology vol 122 no 7 pp 1987ndash2000 2002

[155] M T Abreu L S Thomas S Y Tesfay et al ldquoRegulation ofTLR4 and MD-2 in the intestinal epithelium evidence for dys-regulated LPS signaling in human inflammatory bowel diseaserdquoin Proceedings of the 90th Annual Meeting of the AmericanAssociation for Immunologists Abstract 3634 Denver ColoUSA 2003

[156] T A Schneeman M E C Bruno H Schjerven F-E JohansenL Chady and C S Kaetzel ldquoRegulation of the polymeric Igreceptor by signaling through TLRs 3 and 4 linking innate andadaptive immune responsesrdquo The Journal of Immunology vol175 no 1 pp 376ndash384 2005

[157] M E C Bruno A L Frantz E W Rogier F-E Johansen andC S Kaetzel ldquoRegulation of the polymeric immunoglobulinreceptor by the classical and alternative NF-120581B pathways inintestinal epithelial cellsrdquoMucosal Immunology vol 4 no 4 pp468ndash478 2011

[158] M E C Bruno E W Rogier A L Frantz A T Stefka SN Thompson and C S Kaetzel ldquoRegulation of the poly-meric immunoglobulin receptor in intestinal epithelial cellsby Enterobacteriaceae implications for mucosal homeostasisrdquoImmunological Investigations vol 39 no 4-5 pp 356ndash382 2010

[159] A L Frantz E W Rogier C R Weber et al ldquoTargeted deletionof MyD88 in intestinal epithelial cells results in compromisedantibacterial immunity associatedwith downregulation of poly-meric immunoglobulin receptor mucin-2 and antibacterialpeptidesrdquoMucosal Immunology vol 5 no 5 pp 501ndash512 2012

[160] E W Rogier A L Frantz M E C Bruno and C S KaetzelldquoSecretory IgA is concentrated in the outer layer of intestinalmucus along with gut bacteriardquo Pathogens In press

[161] M B Geuking K D McCoy and A J Macpherson ldquoThe func-tion of secretory IgA in the context of the intestinal continuumof adaptive immune responses in host-microbial mutualismrdquoSeminars in Immunology vol 24 no 1 pp 36ndash42 2012

20 ISRN Immunology

[162] L VHooper D R Littman andA JMacpherson ldquoInteractionsbetween the microbiota and the immune systemrdquo Science vol336 no 6086 pp 1268ndash1273 2012

[163] A J Macpherson M B Geuking E Slack S Hapfelmeierand K D McCoy ldquoThe habitat double life citizenship andforgetfulness of IgArdquo Immunological Reviews vol 245 no 1 pp132ndash146 2012

Submit your manuscripts athttpwwwhindawicom

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

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Behavioural Neurology

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Disease Markers

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BioMed Research International

OncologyJournal of

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Oxidative Medicine and Cellular Longevity

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The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

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Research and TreatmentAIDS

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Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

16 ISRN Immunology

of 120591 120583 and 120575 in different tissuesrdquo Veterinary Immunology andImmunopathology vol 139 no 1 pp 17ndash26 2011

[37] S Mashoof C Pohlenz P L Chen et al ldquoExpressed IgH 120583and 120591 transcripts share diversity segment in ranched Thunnusorientalisrdquo Developmental and Comparative Immunology vol43 no 1 pp 76ndash86 2014

[38] Y-A Zhang I Salinas J Li et al ldquoIgT a primitive immunoglob-ulin class specialized in mucosal immunityrdquo Nature Immunol-ogy vol 11 no 9 pp 827ndash835 2010

[39] S Magadan-Mompo C Sanchez-Espinel and F Gambon-Deza ldquoImmunoglobulin heavy chains in medaka (Oryziaslatipes)rdquo BMC Evolutionary Biology vol 11 no 1 article 1652011

[40] C T Amemiya J Alfoldi A P Lee et al ldquoThe African coela-canth genome provides insights into tetrapod evolutionrdquoNature vol 496 no 7445 pp 311ndash316 2013

[41] T Ota J P Rast G W Litman and C T Amemiya ldquoLineage-restricted retention of a primitive immunoglobulin heavy chainisotype within the Dipnoi reveals an evolutionary paradoxrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 100 no 5 pp 2501ndash2506 2003

[42] Y Sun Z Wei N Li and Y Zhao ldquoA comparative overview ofimmunoglobulin genes and the generation of their diversity intetrapodsrdquo Developmental and Comparative Immunology vol39 no 1-2 pp 103ndash109 2013

[43] I Hadji-Azimi ldquoAnuran immunoglobulins a reviewrdquo Develop-mental and Comparative Immunology vol 3 no 2 pp 223ndash2431979

[44] E Hsu M F Flajnik and L du Pasquier ldquoA third immunoglob-ulin class in amphibiansrdquo The Journal of Immunology vol 135no 3 pp 1998ndash2004 1985

[45] C T Amemiya R N Haire and G W Litman ldquoNucleotidesequence of a cDNA encoding a third distinct Xenopusimmunoglobulin heavy chain isotyperdquo Nucleic Acids Researchvol 17 no 13 p 5388 1989

[46] R Muszligmann M Wilson A Marcuz M Courtet and L duPasquier ldquoMembrane exon sequences of the three Xenopus Igclasses explain the evolutionary origin of mammalian isotypesrdquoEuropean Journal of Immunology vol 26 no 2 pp 409ndash4141996

[47] R Muszligmann L du Pasquier and E Hsu ldquoIs Xenopus IgX ananalog of IgArdquo European Journal of Immunology vol 26 no12 pp 2823ndash2830 1996

[48] B Schaerlinger and J-P Frippiat ldquoIgX antibodies in the urodeleamphibian Ambystoma mexicanumrdquo Developmental and Com-parative Immunology vol 32 no 8 pp 908ndash915 2008

[49] B Schaerlinger M Bascove and J-P Frippiat ldquoA new isotypeof immunoglobulin heavy chain in the urodele amphibianPleurodeles waltl predominantly expressed in larvaerdquoMolecularImmunology vol 45 no 3 pp 776ndash786 2008

[50] S Mashoof A Goodroe C C Du et al ldquoAncient T-independence of mucosal IgXA gut microbiota unaffected bylarval thymectomy in Xenopus laevisrdquo Mucosal Immunologyvol 6 no 2 pp 358ndash368 2013

[51] J P Vaerman J Picard and J F Heremans ldquoStructural dataon chicken IgA and failure to identify the IgA of the tortoiserdquoin Immunologic Phylogeny vol 64 of Advances in ExperimentalMedicine and Biology pp 185ndash195 Springer New York NYUSA 1975

[52] J L Portis and J E Coe ldquoIgM the secretory immunoglobulinof reptiles and amphibiansrdquo Nature vol 258 no 5535 pp 547ndash548 1975

[53] J E Coe D Leong J L Portis and L A Thomas ldquoImmuneresponse in the garter snake (Thamnophis ordinoides)rdquo Immu-nology vol 31 no 3 pp 417ndash424 1976

[54] D Hadge and H Ambrosius ldquoEvolution of low molecularweight immunoglobulinsmdashIV IgY-like immunoglobulins ofbirds reptiles and amphibians precursors of mammalian IgArdquoMolecular Immunology vol 21 no 8 pp 699ndash707 1984

[55] D Hadge and H Ambrosius ldquoEvolution of low molecularweight immunoglobulins V Degree of antigenic relationshipbetween the 7S immunoglobulins ofmammals birds and lowervertebrates to the turkey IgYrdquo Developmental and ComparativeImmunology vol 10 no 3 pp 377ndash385 1986

[56] S Magadan-Mompo C Sanchez-Espinel and F Gambon-Deza ldquoImmunoglobulin genes of the turtlesrdquo Immunogeneticsvol 65 no 3 pp 227ndash237 2013

[57] Z Wei Q Wu L Ren et al ldquoExpression of IgM IgD and IgYin a reptile Anolis carolinensisrdquoThe Journal of Immunology vol183 no 6 pp 3858ndash3864 2009

[58] F Gambon-Deza C Sanchez-Espinel and J V Beneitez ldquoAnovel IgA-like immunoglobulin in the reptile Eublepharis mac-ulariusrdquo Developmental and Comparative Immunology vol 31no 6 pp 596ndash605 2007

[59] G Cheng Y Gao T Wang et al ldquoExtensive diversification ofIgH subclass-encoding genes and IgM subclass switching incrocodiliansrdquo Nature Communications vol 4 article 1337 2013

[60] S Magadan-Mompo C Sanchez-Espinel and F Gambon-Deza ldquoIgH loci of American alligator and saltwater crocodileshed light on IgA evolutionrdquo Immunogenetics vol 65 no 7 pp531ndash541 2013

[61] E Orlans and M E Rose ldquoAn IgA-like immunoglobulin in thefowlrdquo Immunochemistry vol 9 no 8 pp 833ndash838 1972

[62] G A Leslie and L N Martin ldquoStudies on the secretory immu-nologic system of fowl 3 Serum and secretory IgA of thechickenrdquoThe Journal of Immunology vol 110 no 1 pp 1ndash9 1973

[63] J Bienenstock D Y Perey J Gauldie and B J UnderdownldquoChicken 120574A physicochemical and immunochemical charac-teristicsrdquoThe Journal of Immunology vol 110 no 2 pp 524ndash5331973

[64] A M Lebacq-Verheyden J P Vaerman and J F HeremansldquoQuantification and distribution of chicken immunoglobulinsIgA IgM and IgG in serum and secretionsrdquo Immunology vol27 no 4 pp 683ndash692 1974

[65] J Goudswaard A Noordzij R H van Dam J A vanderDonk and J P Vaerman ldquoThe immunoglobulins of the turkey(Meleagris gallopavo) Isolation and characterization of IgGIgM and IgA in body fluids eggs and intraocular tissuesrdquoPoultry science vol 56 no 6 pp 1847ndash1851 1977

[66] D Hadge and H Ambrosius ldquoComparative studies on thestructure of biliary immunoglobulins of some avian speciesII Antigenic properties of the biliary immunoglobulins ofchicken turkey duck and gooserdquo Developmental and Compar-ative Immunology vol 12 no 2 pp 319ndash329 1988

[67] J Goudswaard J P Vaerman and J F Heremans ldquoThreeimmunoglobulin classes in the pigeon (Columbia livia)rdquo Inter-national Archives of Allergy andApplied Immunology vol 53 no5 pp 409ndash419 1977

[68] P L K Ng and D A Higgins ldquoBile immunoglobulin of theduck (Anas platyrhynchos) I Preliminary characterization andontogenyrdquo Immunology vol 58 no 2 pp 323ndash327 1986

[69] K E Magor G W Warr Y Bando D L Middleton and DA Higgins ldquoSecretory immune system of the duck (Anas

ISRN Immunology 17

platyrhynchos) Identification and expression of the genesencoding IgA and IgM heavy chainsrdquo European Journal ofImmunology vol 28 no 3 pp 1063ndash1068 1998

[70] Y Zhao H Rabbani A Shimizu and L Hammarstrom ldquoMap-ping of the chicken immunoglobulin heavy-chain constantregion gene locus reveals an inverted 120572 gene upstream of acondensed 120592 generdquo Immunology vol 101 no 3 pp 348ndash3532000

[71] M L Lundqvist D L Middleton S Hazard and G W WarrldquoThe immunoglobulin heavy chain locus of the duck genomicorganization and expression of D J and C region genesrdquo TheJournal of Biological Chemistry vol 276 no 50 pp 46729ndash46736 2001

[72] T HuangM Zhang ZWei et al ldquoAnalysis of immunoglobulintranscripts in the ostrich Struthio camelus a primitive avianspeciesrdquo PLoS ONE vol 7 no 3 Article ID e34346 2012

[73] K H Roux ldquoImmunoglobulin structure and function asrevealed by electron microscopyrdquo International Archives ofAllergy and Immunology vol 120 no 2 pp 85ndash99 1999

[74] F Gambon-Deza C Sanchez-Espinel and S Magadan-Mompo ldquoThe immunoglobulin heavy chain locus in the platy-pus (Ornithorhynchus anatinus)rdquo Molecular Immunology vol46 no 13 pp 2515ndash2523 2009

[75] Y Zhao H Cui C M Whittington et al ldquoOrnithorhynchusanatinus (platypus) links the evolution of immunoglobulingenes in eutherian mammals and nonmammalian tetrapodsrdquoThe Journal of Immunology vol 183 no 5 pp 3285ndash3293 2009

[76] M Aveskogh and L Hellman ldquoEvidence for an early appear-ance of modern post-switch isotypes in mammalian evolutioncloning of IgE IgG and IgA from the marsupial Monodelphisdomesticardquo European Journal of Immunology vol 28 no 9 pp2738ndash2750 1998

[77] K Belov G A Harrison and DW Cooper ldquoMolecular cloningof the cDNA encoding the constant region of the immunoglob-ulin a heavy chain (C120572) from amarsupialTrichosurus vulpecula(common brushtail possum)rdquo Immunology Letters vol 60 no2-3 pp 165ndash170 1998

[78] K Belov K R Zenger L Hellman and DW Cooper ldquoEchidnaIgA supports mammalian unity and traditional Therian rela-tionshiprdquo Mammalian Genome vol 13 no 11 pp 656ndash6632002

[79] K Belov and L Hellman ldquoImmunoglobulin genetics of Orni-thorhynchus anatinus (platypus) and Tachyglossus aculeatus(short-beaked echidna)rdquo Comparative Biochemistry and Phys-iology vol 136 no 4 pp 811ndash819 2003

[80] M VernerssonM Aveskogh BMunday and L Hellman ldquoEvi-dence for an early appearance of modern post-switch immu-noglobulin isotypes in mammalian evolution (II) cloning ofIgE IgG1 and IgG2 fromamonotreme the duck-billed platypusOrnithorhynchus anatinusrdquo European Journal of Immunologyvol 32 no 8 pp 2145ndash2155 2002

[81] C Auffray R Nageotte and J L Sikorav ldquoMouse immunoglob-ulin A nucleotide sequence of the structural gene for the 120572heavy chain derived from cloned cDNAsrdquo Gene vol 13 no 4pp 365ndash374 1981

[82] T Ukaji D Sumiyama and O Kai ldquoSequence determinationof the heavy-chain constant region in four immunoglobulinclasses of Mongolian gerbils (Meriones unguiculatus)rdquo Experi-mental Animals vol 61 no 2 pp 99ndash107 2012

[83] R C Burnett W C Hanly S K Zhai and K L Knight ldquoTheIgA heavy chain gene family in rabbit cloning and sequence

analysis of 13 C120572 genesrdquo The EMBO Journal vol 8 no 13 pp4041ndash4047 1989

[84] D K Lanning S-K Zhai and K L Knight ldquoAnalysis of the 31015840C120583 region of the rabbit Ig heavy chain locusrdquoGene vol 309 no2 pp 135ndash144 2003

[85] F Ros J Puels N Reichenberger W van Schooten R Buelowand J Platzer ldquoSequence analysis of 05Mb of the rabbitgermline immunoglobulin heavy chain locusrdquo Gene vol 330no 1-2 pp 49ndash59 2004

[86] M Patel D Selinger G E Mark G J Hickey and G FHollis ldquoSequence of the dog immunoglobulin alpha and epsilonconstant region genesrdquo Immunogenetics vol 41 no 5 pp 282ndash286 1995

[87] Z Zhao Y Zhao Q Pan-Hammarstrom et al ldquoPhysical map-ping of the giant panda immunoglobulin heavy chain constantregion genesrdquo Developmental and Comparative Immunologyvol 31 no 10 pp 1034ndash1049 2007

[88] W R Brown and J E Butler ldquoCharacterization of a C120572 gene ofswinerdquoMolecular Immunology vol 31 no 8 pp 633ndash642 1994

[89] W R Brown H Rabbani J E Butler and L HammarstromldquoCharacterization of the bovine C120572 generdquo Immunology vol 91no 1 pp 1ndash6 1997

[90] G PWhite P Roche M R Brandon S E Newton and E N TMeeusen ldquoCloning and characterization of sheep (Ovis aries)immunoglobulin 120572 chainrdquo Immunogenetics vol 48 no 5 pp359ndash362 1998

[91] AMancia T A Romano H A Gefroh et al ldquoCharacterizationof the immunoglobulin A heavy chain gene of the Atlantic bot-tlenose dolphin (Tursiops truncatus)rdquo Veterinary Immunologyand Immunopathology vol 118 no 3-4 pp 304ndash309 2007

[92] B Wagner I Greiser-Wilke and D F Antczak ldquoCharacteriza-tion of the horse [Equus caballus] IGHA generdquo Immunogeneticsvol 55 no 8 pp 552ndash560 2003

[93] N Takahashi S Ueda and M Obata ldquoStructure of humanimmunoglobulin gamma genes implications for evolution of agene familyrdquo Cell vol 29 no 2 pp 671ndash679 1982

[94] J G Flanagan M-P Lefranc and T H Rabbitts ldquoMechanismsof divergence and convergence of the human immunoglobulin1205721 and 1205722 constant region gene sequencesrdquo Cell vol 36 no 3pp 681ndash688 1984

[95] S Kawamura K Omoto and S Ueda ldquoEvolutionary hypervari-ability in the hinge region of the immunoglobulin alpha generdquoJournal of Molecular Biology vol 215 no 2 pp 201ndash206 1990

[96] F Scinicariello F Masseoud L Jayashankar and R AttanasioldquoSooty mangabey (Cercocebus torquatus atys) IGHG and IGHAgenesrdquo Immunogenetics vol 58 no 12 pp 955ndash965 2006

[97] K A Rogers L Jayashankar F Scinicariello and R AttanasioldquoNonhuman primate IgA genetic heterogeneity and interac-tions with CD89rdquoThe Journal of Immunology vol 180 no 7 pp4816ndash4824 2008

[98] S Kawamura N Saitou and S Ueda ldquoConcerted evolution ofthe primate immunoglobulin 120572-gene through gene conversionrdquoThe Journal of Biological Chemistry vol 267 no 11 pp 7359ndash7367 1992

[99] S Kawamura and S Ueda ldquoImmunoglobulin C119867gene family in

hominoids and its evolutionary historyrdquo Genomics vol 13 no1 pp 194ndash200 1992

[100] A Brusco U Cariota A Bottaro et al ldquoStructural andimmunologic analysis of gene triplications in the Ig heavy chainconstant region locusrdquoThe Journal of Immunology vol 152 no1 pp 129ndash135 1994

18 ISRN Immunology

[101] H Rabbani Q Pan N Kondo C I E Smith and L Ham-marstrom ldquoDuplications and deletions of the human IGHClocus evolutionary implicationsrdquo Immunogenetics vol 45 no2 pp 136ndash141 1996

[102] P F Weinheimer J Mestecky and R T Acton ldquoSpecies distri-bution of J chainrdquoThe Journal of Immunology vol 107 no 4 pp1211ndash1212 1971

[103] F P Inman and J Mestecky ldquoThe J chain of polymeric immu-noglobulinsrdquo inContemporary Topics inMolecular Immunologyvol 3 pp 111ndash141 Springer New York NY USA 1974

[104] P Brandtzaeg ldquoPresence of J chain in human immunocytescontaining various immunoglobulin classesrdquo Nature vol 252no 5482 pp 418ndash420 1974

[105] L Tacchi E Larragoite and I Salinas ldquoDiscovery of J chain inAfrican lungfish (Protopterus dolloi Sarcopterygii) using highthroughput transcriptome sequencing implications in mucosalimmunityrdquo PLoS ONE vol 8 no 8 Article ID e70650 2013

[106] I K Zarkadis D Mastellos and J D Lambris ldquoPhylogeneticaspects of the complement systemrdquo Developmental and Com-parative Immunology vol 25 no 8-9 pp 745ndash762 2001

[107] A P West Jr A B Herr and P J Bjorkman ldquoThe chickenyolk sac IgY receptor a functional equivalent of themammalianMHC-related Fc receptor is a phospholipase A

2receptor

homologrdquo Immunity vol 20 no 5 pp 601ndash610 2004[108] D B Tesar E J Cheung and P J Bjorkman ldquoThe chicken

yolk sac IgY receptor a mammalian mannose receptor familymember transcytoses IgY across polarized epithelial cellsrdquoMolecular Biology of the Cell vol 19 no 4 pp 1587ndash1593 2008

[109] A I Taylor R L Beavil B J Sutton and R A Calvert ldquoAmonomeric chicken IgY receptor binds IgY with 21 stoichiom-etryrdquo The Journal of Biological Chemistry vol 284 no 36 pp24168ndash24175 2009

[110] K Baker S-W Qiao T Kuo et al ldquoImmune and non-immunefunctions of the (not so) neonatal Fc receptor FcRnrdquo Seminarsin Immunopathology vol 31 no 2 pp 223ndash236 2009

[111] K Baker R S Blumberg and C S Kaetzel ldquoImmunoglob-ulin transport and immunoglobulin receptorsrdquo in MucosalImmunology J Mestecky W Strober H Cheroutre B KelsallB N Lambrecht andMW Russell Eds chapter 20 AcademicPressElsevier Waltham Mass USA 2014

[112] C S Kaetzel ldquoThepolymeric immunoglobulin receptorrdquo in eLSJohn Wiley amp Sons Chichester UK 2013

[113] N J Mantis N Rol and B Corthesy ldquoSecretory IgArsquos complexroles in immunity andmucosal homeostasis in the gutrdquoMucosalImmunology vol 4 no 6 pp 603ndash611 2011

[114] J V Peppard M E Rose and P Hesketh ldquoA functional homo-logue of mammalian secretory component exists in chickensrdquoEuropean Journal of Immunology vol 13 no 7 pp 566ndash5701983

[115] K E Mostov M Friedlander and G Blobel ldquoThe receptorfor transepithelial transport of IgA and IgM contains multipleimmunoglobulin-like domainsrdquo Nature vol 308 no 5954 pp37ndash43 1984

[116] P Krajci R Solberg M Sandberg O Oyen T Jahnsen and PBrandtzaeg ldquoMolecular cloning of the human transmembranesecretory component (poly-Ig receptor) and its mRNA expres-sion in human tissuesrdquo Biochemical and Biophysical ResearchCommunications vol 158 no 3 pp 783ndash789 1989

[117] P Krajci D Kvale K Tasken and P Brandtzaeg ldquoMolecularcloning and exon-intron mapping of the gene encoding humantransmembrane secretory component (the poly-Ig receptor)rdquo

European Journal of Immunology vol 22 no 9 pp 2309ndash23151992

[118] J F Piskurich J A France C M Tamer C A Willmer CS Kaetzel and D M Kaetzel ldquoInterferon-120574 induces polymericimmunoglobulin receptormRNA in human intestinal epithelialcells by a protein synthesis dependent mechanismrdquo MolecularImmunology vol 30 no 4 pp 413ndash421 1993

[119] J F Piskurich M H Blanchard K R Youngman J A Franceand C S Kaetzel ldquoMolecular cloning of the mouse polymericIg receptor functional regions of the molecule are conservedamong five mammalian speciesrdquo The Journal of Immunologyvol 154 no 4 pp 1735ndash1747 1995

[120] M A Kulseth P Krajci O Myklebost and S RogneldquoCloning and characterization of two forms of bovine polymericimmunoglobulin receptor cDNArdquo DNA and Cell Biology vol14 no 3 pp 251ndash256 1995

[121] K S Koch A S Gleiberman T Aoki et al ldquoDiscordant expres-sion and variable numbers of neighboring GGA- and GAA-richtriplet repeats in the 31015840 untranslated regions of two groups ofmessenger RNAs encoded by the rat polymeric immunoglob-ulin receptor generdquo Nucleic Acids Research vol 23 no 7 pp1098ndash1112 1995

[122] F M Adamski and J Demmer ldquoTwo stages of increased IgAtransfer during lactation in themarsupialTrichosurus vulpecula(brushtail possum)rdquoThe Journal of Immunology vol 162 no 10pp 6009ndash6015 1999

[123] H Kumura T Sone K-I Shimazaki and E KobayashildquoSequence analysis of porcine polymeric immunoglobulinreceptor from mammary epithelial cells present in colostrumrdquoThe Journal of Dairy Research vol 67 no 4 pp 631ndash636 2000

[124] C L Taylor G A Harrison C M Watson and E M DeaneldquocDNA cloning of the polymeric immunoglobulin receptor ofthe marsupial Macropus eugenii (tammar wallaby)rdquo EuropeanJournal of Immunogenetics vol 29 no 2 pp 87ndash93 2002

[125] R Braathen V S Hohman P Brandtzaeg and F-E JohansenldquoSecretory antibody formation conserved binding interactionsbetween J chain and polymeric Ig receptor from humans andamphibiansrdquo The Journal of Immunology vol 178 no 3 pp1589ndash1597 2007

[126] M J Lewis BWagner R M Irvine and J MWoof ldquoIgA in thehorse cloning of equine polymeric Ig receptor and J chain andcharacterization of recombinant forms of equine IgArdquoMucosalImmunology vol 3 no 6 pp 610ndash621 2010

[127] A J Leon D Banner L Xu et al ldquoSequencing annotation andcharacterization of the influenza ferret infectomerdquo Journal ofVirology vol 87 no 4 pp 1957ndash1966 2013

[128] W H Wieland D Orzaez A Lammers H K ParmentierM W A Verstegen and A Schots ldquoA functional polymericimmunoglobulin receptor in chicken (Gallus gallus) indicatesancient role of secretory IgA inmucosal immunityrdquoBiochemicalJournal vol 380 no 3 pp 669ndash676 2004

[129] K Hamuro H Suetake N R Saha K Kikuchi and YSuzuki ldquoA teleost polymeric Ig receptor exhibiting two Ig-likedomains transports tetrameric IgM into the skinrdquo The Journalof Immunology vol 178 no 9 pp 5682ndash5689 2007

[130] J H W M Rombout S J L van der Tuin G Yang et alldquoExpression of the polymeric immunoglobulin receptor (pIgR)in mucosal tissues of common carp (Cyprinus carpio L)rdquo Fishand Shellfish Immunology vol 24 no 5 pp 620ndash628 2008

[131] L-N Feng D-Q Lu J-X Bei et al ldquoMolecular cloning andfunctional analysis of polymeric immunoglobulin receptor gene

ISRN Immunology 19

in orange-spotted grouper (Epinephelus coioides)rdquo ComparativeBiochemistry and Physiology B vol 154 no 3 pp 282ndash289 2009

[132] A E Oslashstergaard S A M Martin T Wang R J M Stet andC J Secombes ldquoRainbow trout (Oncorhynchus mykiss) pos-sessmultiple novel immunoglobulin-like transcripts containingeither an ITAM or ITIMsrdquo Developmental and ComparativeImmunology vol 33 no 4 pp 525ndash532 2009

[133] H Eiffert E Quentin and J Decker ldquoThe primary structureof the human free secretory component and the arrangementof disulfide bondsrdquo Hoppe-Seylerrsquos Zeitschrift fur PhysiologischeChemie vol 365 no 12 pp 1489ndash1495 1984

[134] E Fallgreen-Gebauer W Gebauer A Bastian et al ldquoThe cova-lent linkage of secretory component to IgA Structure of sIgArdquoBiological Chemistry Hoppe-Seyler vol 374 no 11 pp 1023ndash1028 1993

[135] J MWoof ldquoThe structure of IgArdquo inMucosal Immune DefenseImmunoglobulin A C S Kaetzel Ed chapter 1 pp 1ndash24Springer New York NY USA 2007

[136] A Bonner A Almogren P B Furtado M A Kerr and S JPerkins ldquoLocation of secretory component on the Fc edge ofdimeric IgA1 reveals insight into the role of secretory IgA1 inmucosal immunityrdquoMucosal Immunology vol 2 no 1 pp 74ndash84 2009

[137] A Bonner A Almogren P B Furtado M A Kerr and S JPerkins ldquoThe nonplanar secretory IgA2 and near planar secre-tory IgA1 solution structures rationalize their different mucosalimmune responsesrdquo The Journal of Biological Chemistry vol284 no 8 pp 5077ndash5087 2009

[138] J Johansen B Braathen and P Brandtzaeg ldquoRole of J chain insecretory immunoglobulin formationrdquo Scandinavian Journal ofImmunology vol 52 no 3 pp 240ndash248 2000

[139] B A Hendrickson D A Conner D J Ladd et al ldquoAlteredhepatic transport of immunoglobulin A in mice lacking the Jchainrdquo Journal of Experimental Medicine vol 182 no 6 pp1905ndash1911 1995

[140] B A Hendrickson L Rindisbacher B Corthesy et al ldquoLackof association of secretory component with IgA in J chain-deficient micerdquo The Journal of Immunology vol 157 no 2 pp750ndash754 1996

[141] N Lycke L Erlandsson L Ekman K Schon and T Lean-derson ldquoLack of J chain inhibits the transport of gut IgA andabrogates the development of intestinal antitoxic protectionrdquoThe Journal of Immunology vol 163 no 2 pp 913ndash919 1999

[142] F-E Johansen R Braathen and P Brandtzaeg ldquoThe J chainis essential for polymeric Ig receptor-mediated epithelial trans-port of IgArdquoThe Journal of Immunology vol 167 no 9 pp 5185ndash5192 2001

[143] R E Ley D A Peterson and J I Gordon ldquoEcological andevolutionary forces shaping microbial diversity in the humanintestinerdquo Cell vol 124 no 4 pp 837ndash848 2006

[144] M McFall-Ngai ldquoAdaptive immunity care for the communityrdquoNature vol 445 no 7124 p 153 2007

[145] A J Macpherson K D McCoy F-E Johansen and PBrandtzaeg ldquoThe immune geography of IgA induction andfunctionrdquoMucosal Immunology vol 1 no 1 pp 11ndash22 2008

[146] D Kvale and P Brandtzaeg ldquoConstitutive and cytokine inducedexpression of HLA molecules secretory component and inter-cellular adhesion molecule-1 is modulated by butyrate in thecolonic epithelial cell line HT-29rdquo Gut vol 36 no 5 pp 737ndash742 1995

[147] L VHooperMHWong AThelin L Hansson P G Falk andJ I Gordon ldquoMolecular analysis of commensal host-microbialrelationships in the intestinerdquo Science vol 291 no 5505 pp 881ndash884 2001

[148] S Hapfelmeier M A E Lawson E Slack et al ldquoReversiblemicrobial colonization of germ-free mice reveals the dynamicsof IgA immune responsesrdquo Science vol 328 no 5986 pp 1705ndash1709 2010

[149] DH ReikvamMDerrien R Islam et al ldquoEpithelial-microbialcross-talk in polymeric Ig receptor deficient micerdquo EuropeanJournal of Immunology vol 42 no 11 pp 2959ndash2970 2012

[150] EW Rogier A L Frantz M E C Bruno et al ldquoSecretory anti-bodies in breast milk promote long-term intestinal homeostasisby regulating the gut microbiota and host gene expressionrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 111 no 8 pp 3074ndash3079 2014

[151] G M Barton and R Medzhitov ldquoToll-like receptor signalingpathwaysrdquo Science vol 300 no 5625 pp 1524ndash1525 2003

[152] K Takeda and S Akira ldquoToll receptors and pathogen resis-tancerdquo Cellular Microbiology vol 5 no 3 pp 143ndash153 2003

[153] E Cario andD K Podolsky ldquoDifferential alteration in intestinalepithelial cell expression of Toll-like receptor 3 (TLR3) andTLR4 in inflammatory bowel diseaserdquo Infection and Immunityvol 68 no 12 pp 7010ndash7017 2000

[154] M Hausmann S Kiessling S Mestermann et al ldquoToll-likereceptors 2 and 4 are up-regulated during intestinal inflamma-tionrdquo Gastroenterology vol 122 no 7 pp 1987ndash2000 2002

[155] M T Abreu L S Thomas S Y Tesfay et al ldquoRegulation ofTLR4 and MD-2 in the intestinal epithelium evidence for dys-regulated LPS signaling in human inflammatory bowel diseaserdquoin Proceedings of the 90th Annual Meeting of the AmericanAssociation for Immunologists Abstract 3634 Denver ColoUSA 2003

[156] T A Schneeman M E C Bruno H Schjerven F-E JohansenL Chady and C S Kaetzel ldquoRegulation of the polymeric Igreceptor by signaling through TLRs 3 and 4 linking innate andadaptive immune responsesrdquo The Journal of Immunology vol175 no 1 pp 376ndash384 2005

[157] M E C Bruno A L Frantz E W Rogier F-E Johansen andC S Kaetzel ldquoRegulation of the polymeric immunoglobulinreceptor by the classical and alternative NF-120581B pathways inintestinal epithelial cellsrdquoMucosal Immunology vol 4 no 4 pp468ndash478 2011

[158] M E C Bruno E W Rogier A L Frantz A T Stefka SN Thompson and C S Kaetzel ldquoRegulation of the poly-meric immunoglobulin receptor in intestinal epithelial cellsby Enterobacteriaceae implications for mucosal homeostasisrdquoImmunological Investigations vol 39 no 4-5 pp 356ndash382 2010

[159] A L Frantz E W Rogier C R Weber et al ldquoTargeted deletionof MyD88 in intestinal epithelial cells results in compromisedantibacterial immunity associatedwith downregulation of poly-meric immunoglobulin receptor mucin-2 and antibacterialpeptidesrdquoMucosal Immunology vol 5 no 5 pp 501ndash512 2012

[160] E W Rogier A L Frantz M E C Bruno and C S KaetzelldquoSecretory IgA is concentrated in the outer layer of intestinalmucus along with gut bacteriardquo Pathogens In press

[161] M B Geuking K D McCoy and A J Macpherson ldquoThe func-tion of secretory IgA in the context of the intestinal continuumof adaptive immune responses in host-microbial mutualismrdquoSeminars in Immunology vol 24 no 1 pp 36ndash42 2012

20 ISRN Immunology

[162] L VHooper D R Littman andA JMacpherson ldquoInteractionsbetween the microbiota and the immune systemrdquo Science vol336 no 6086 pp 1268ndash1273 2012

[163] A J Macpherson M B Geuking E Slack S Hapfelmeierand K D McCoy ldquoThe habitat double life citizenship andforgetfulness of IgArdquo Immunological Reviews vol 245 no 1 pp132ndash146 2012

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

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Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

ISRN Immunology 17

platyrhynchos) Identification and expression of the genesencoding IgA and IgM heavy chainsrdquo European Journal ofImmunology vol 28 no 3 pp 1063ndash1068 1998

[70] Y Zhao H Rabbani A Shimizu and L Hammarstrom ldquoMap-ping of the chicken immunoglobulin heavy-chain constantregion gene locus reveals an inverted 120572 gene upstream of acondensed 120592 generdquo Immunology vol 101 no 3 pp 348ndash3532000

[71] M L Lundqvist D L Middleton S Hazard and G W WarrldquoThe immunoglobulin heavy chain locus of the duck genomicorganization and expression of D J and C region genesrdquo TheJournal of Biological Chemistry vol 276 no 50 pp 46729ndash46736 2001

[72] T HuangM Zhang ZWei et al ldquoAnalysis of immunoglobulintranscripts in the ostrich Struthio camelus a primitive avianspeciesrdquo PLoS ONE vol 7 no 3 Article ID e34346 2012

[73] K H Roux ldquoImmunoglobulin structure and function asrevealed by electron microscopyrdquo International Archives ofAllergy and Immunology vol 120 no 2 pp 85ndash99 1999

[74] F Gambon-Deza C Sanchez-Espinel and S Magadan-Mompo ldquoThe immunoglobulin heavy chain locus in the platy-pus (Ornithorhynchus anatinus)rdquo Molecular Immunology vol46 no 13 pp 2515ndash2523 2009

[75] Y Zhao H Cui C M Whittington et al ldquoOrnithorhynchusanatinus (platypus) links the evolution of immunoglobulingenes in eutherian mammals and nonmammalian tetrapodsrdquoThe Journal of Immunology vol 183 no 5 pp 3285ndash3293 2009

[76] M Aveskogh and L Hellman ldquoEvidence for an early appear-ance of modern post-switch isotypes in mammalian evolutioncloning of IgE IgG and IgA from the marsupial Monodelphisdomesticardquo European Journal of Immunology vol 28 no 9 pp2738ndash2750 1998

[77] K Belov G A Harrison and DW Cooper ldquoMolecular cloningof the cDNA encoding the constant region of the immunoglob-ulin a heavy chain (C120572) from amarsupialTrichosurus vulpecula(common brushtail possum)rdquo Immunology Letters vol 60 no2-3 pp 165ndash170 1998

[78] K Belov K R Zenger L Hellman and DW Cooper ldquoEchidnaIgA supports mammalian unity and traditional Therian rela-tionshiprdquo Mammalian Genome vol 13 no 11 pp 656ndash6632002

[79] K Belov and L Hellman ldquoImmunoglobulin genetics of Orni-thorhynchus anatinus (platypus) and Tachyglossus aculeatus(short-beaked echidna)rdquo Comparative Biochemistry and Phys-iology vol 136 no 4 pp 811ndash819 2003

[80] M VernerssonM Aveskogh BMunday and L Hellman ldquoEvi-dence for an early appearance of modern post-switch immu-noglobulin isotypes in mammalian evolution (II) cloning ofIgE IgG1 and IgG2 fromamonotreme the duck-billed platypusOrnithorhynchus anatinusrdquo European Journal of Immunologyvol 32 no 8 pp 2145ndash2155 2002

[81] C Auffray R Nageotte and J L Sikorav ldquoMouse immunoglob-ulin A nucleotide sequence of the structural gene for the 120572heavy chain derived from cloned cDNAsrdquo Gene vol 13 no 4pp 365ndash374 1981

[82] T Ukaji D Sumiyama and O Kai ldquoSequence determinationof the heavy-chain constant region in four immunoglobulinclasses of Mongolian gerbils (Meriones unguiculatus)rdquo Experi-mental Animals vol 61 no 2 pp 99ndash107 2012

[83] R C Burnett W C Hanly S K Zhai and K L Knight ldquoTheIgA heavy chain gene family in rabbit cloning and sequence

analysis of 13 C120572 genesrdquo The EMBO Journal vol 8 no 13 pp4041ndash4047 1989

[84] D K Lanning S-K Zhai and K L Knight ldquoAnalysis of the 31015840C120583 region of the rabbit Ig heavy chain locusrdquoGene vol 309 no2 pp 135ndash144 2003

[85] F Ros J Puels N Reichenberger W van Schooten R Buelowand J Platzer ldquoSequence analysis of 05Mb of the rabbitgermline immunoglobulin heavy chain locusrdquo Gene vol 330no 1-2 pp 49ndash59 2004

[86] M Patel D Selinger G E Mark G J Hickey and G FHollis ldquoSequence of the dog immunoglobulin alpha and epsilonconstant region genesrdquo Immunogenetics vol 41 no 5 pp 282ndash286 1995

[87] Z Zhao Y Zhao Q Pan-Hammarstrom et al ldquoPhysical map-ping of the giant panda immunoglobulin heavy chain constantregion genesrdquo Developmental and Comparative Immunologyvol 31 no 10 pp 1034ndash1049 2007

[88] W R Brown and J E Butler ldquoCharacterization of a C120572 gene ofswinerdquoMolecular Immunology vol 31 no 8 pp 633ndash642 1994

[89] W R Brown H Rabbani J E Butler and L HammarstromldquoCharacterization of the bovine C120572 generdquo Immunology vol 91no 1 pp 1ndash6 1997

[90] G PWhite P Roche M R Brandon S E Newton and E N TMeeusen ldquoCloning and characterization of sheep (Ovis aries)immunoglobulin 120572 chainrdquo Immunogenetics vol 48 no 5 pp359ndash362 1998

[91] AMancia T A Romano H A Gefroh et al ldquoCharacterizationof the immunoglobulin A heavy chain gene of the Atlantic bot-tlenose dolphin (Tursiops truncatus)rdquo Veterinary Immunologyand Immunopathology vol 118 no 3-4 pp 304ndash309 2007

[92] B Wagner I Greiser-Wilke and D F Antczak ldquoCharacteriza-tion of the horse [Equus caballus] IGHA generdquo Immunogeneticsvol 55 no 8 pp 552ndash560 2003

[93] N Takahashi S Ueda and M Obata ldquoStructure of humanimmunoglobulin gamma genes implications for evolution of agene familyrdquo Cell vol 29 no 2 pp 671ndash679 1982

[94] J G Flanagan M-P Lefranc and T H Rabbitts ldquoMechanismsof divergence and convergence of the human immunoglobulin1205721 and 1205722 constant region gene sequencesrdquo Cell vol 36 no 3pp 681ndash688 1984

[95] S Kawamura K Omoto and S Ueda ldquoEvolutionary hypervari-ability in the hinge region of the immunoglobulin alpha generdquoJournal of Molecular Biology vol 215 no 2 pp 201ndash206 1990

[96] F Scinicariello F Masseoud L Jayashankar and R AttanasioldquoSooty mangabey (Cercocebus torquatus atys) IGHG and IGHAgenesrdquo Immunogenetics vol 58 no 12 pp 955ndash965 2006

[97] K A Rogers L Jayashankar F Scinicariello and R AttanasioldquoNonhuman primate IgA genetic heterogeneity and interac-tions with CD89rdquoThe Journal of Immunology vol 180 no 7 pp4816ndash4824 2008

[98] S Kawamura N Saitou and S Ueda ldquoConcerted evolution ofthe primate immunoglobulin 120572-gene through gene conversionrdquoThe Journal of Biological Chemistry vol 267 no 11 pp 7359ndash7367 1992

[99] S Kawamura and S Ueda ldquoImmunoglobulin C119867gene family in

hominoids and its evolutionary historyrdquo Genomics vol 13 no1 pp 194ndash200 1992

[100] A Brusco U Cariota A Bottaro et al ldquoStructural andimmunologic analysis of gene triplications in the Ig heavy chainconstant region locusrdquoThe Journal of Immunology vol 152 no1 pp 129ndash135 1994

18 ISRN Immunology

[101] H Rabbani Q Pan N Kondo C I E Smith and L Ham-marstrom ldquoDuplications and deletions of the human IGHClocus evolutionary implicationsrdquo Immunogenetics vol 45 no2 pp 136ndash141 1996

[102] P F Weinheimer J Mestecky and R T Acton ldquoSpecies distri-bution of J chainrdquoThe Journal of Immunology vol 107 no 4 pp1211ndash1212 1971

[103] F P Inman and J Mestecky ldquoThe J chain of polymeric immu-noglobulinsrdquo inContemporary Topics inMolecular Immunologyvol 3 pp 111ndash141 Springer New York NY USA 1974

[104] P Brandtzaeg ldquoPresence of J chain in human immunocytescontaining various immunoglobulin classesrdquo Nature vol 252no 5482 pp 418ndash420 1974

[105] L Tacchi E Larragoite and I Salinas ldquoDiscovery of J chain inAfrican lungfish (Protopterus dolloi Sarcopterygii) using highthroughput transcriptome sequencing implications in mucosalimmunityrdquo PLoS ONE vol 8 no 8 Article ID e70650 2013

[106] I K Zarkadis D Mastellos and J D Lambris ldquoPhylogeneticaspects of the complement systemrdquo Developmental and Com-parative Immunology vol 25 no 8-9 pp 745ndash762 2001

[107] A P West Jr A B Herr and P J Bjorkman ldquoThe chickenyolk sac IgY receptor a functional equivalent of themammalianMHC-related Fc receptor is a phospholipase A

2receptor

homologrdquo Immunity vol 20 no 5 pp 601ndash610 2004[108] D B Tesar E J Cheung and P J Bjorkman ldquoThe chicken

yolk sac IgY receptor a mammalian mannose receptor familymember transcytoses IgY across polarized epithelial cellsrdquoMolecular Biology of the Cell vol 19 no 4 pp 1587ndash1593 2008

[109] A I Taylor R L Beavil B J Sutton and R A Calvert ldquoAmonomeric chicken IgY receptor binds IgY with 21 stoichiom-etryrdquo The Journal of Biological Chemistry vol 284 no 36 pp24168ndash24175 2009

[110] K Baker S-W Qiao T Kuo et al ldquoImmune and non-immunefunctions of the (not so) neonatal Fc receptor FcRnrdquo Seminarsin Immunopathology vol 31 no 2 pp 223ndash236 2009

[111] K Baker R S Blumberg and C S Kaetzel ldquoImmunoglob-ulin transport and immunoglobulin receptorsrdquo in MucosalImmunology J Mestecky W Strober H Cheroutre B KelsallB N Lambrecht andMW Russell Eds chapter 20 AcademicPressElsevier Waltham Mass USA 2014

[112] C S Kaetzel ldquoThepolymeric immunoglobulin receptorrdquo in eLSJohn Wiley amp Sons Chichester UK 2013

[113] N J Mantis N Rol and B Corthesy ldquoSecretory IgArsquos complexroles in immunity andmucosal homeostasis in the gutrdquoMucosalImmunology vol 4 no 6 pp 603ndash611 2011

[114] J V Peppard M E Rose and P Hesketh ldquoA functional homo-logue of mammalian secretory component exists in chickensrdquoEuropean Journal of Immunology vol 13 no 7 pp 566ndash5701983

[115] K E Mostov M Friedlander and G Blobel ldquoThe receptorfor transepithelial transport of IgA and IgM contains multipleimmunoglobulin-like domainsrdquo Nature vol 308 no 5954 pp37ndash43 1984

[116] P Krajci R Solberg M Sandberg O Oyen T Jahnsen and PBrandtzaeg ldquoMolecular cloning of the human transmembranesecretory component (poly-Ig receptor) and its mRNA expres-sion in human tissuesrdquo Biochemical and Biophysical ResearchCommunications vol 158 no 3 pp 783ndash789 1989

[117] P Krajci D Kvale K Tasken and P Brandtzaeg ldquoMolecularcloning and exon-intron mapping of the gene encoding humantransmembrane secretory component (the poly-Ig receptor)rdquo

European Journal of Immunology vol 22 no 9 pp 2309ndash23151992

[118] J F Piskurich J A France C M Tamer C A Willmer CS Kaetzel and D M Kaetzel ldquoInterferon-120574 induces polymericimmunoglobulin receptormRNA in human intestinal epithelialcells by a protein synthesis dependent mechanismrdquo MolecularImmunology vol 30 no 4 pp 413ndash421 1993

[119] J F Piskurich M H Blanchard K R Youngman J A Franceand C S Kaetzel ldquoMolecular cloning of the mouse polymericIg receptor functional regions of the molecule are conservedamong five mammalian speciesrdquo The Journal of Immunologyvol 154 no 4 pp 1735ndash1747 1995

[120] M A Kulseth P Krajci O Myklebost and S RogneldquoCloning and characterization of two forms of bovine polymericimmunoglobulin receptor cDNArdquo DNA and Cell Biology vol14 no 3 pp 251ndash256 1995

[121] K S Koch A S Gleiberman T Aoki et al ldquoDiscordant expres-sion and variable numbers of neighboring GGA- and GAA-richtriplet repeats in the 31015840 untranslated regions of two groups ofmessenger RNAs encoded by the rat polymeric immunoglob-ulin receptor generdquo Nucleic Acids Research vol 23 no 7 pp1098ndash1112 1995

[122] F M Adamski and J Demmer ldquoTwo stages of increased IgAtransfer during lactation in themarsupialTrichosurus vulpecula(brushtail possum)rdquoThe Journal of Immunology vol 162 no 10pp 6009ndash6015 1999

[123] H Kumura T Sone K-I Shimazaki and E KobayashildquoSequence analysis of porcine polymeric immunoglobulinreceptor from mammary epithelial cells present in colostrumrdquoThe Journal of Dairy Research vol 67 no 4 pp 631ndash636 2000

[124] C L Taylor G A Harrison C M Watson and E M DeaneldquocDNA cloning of the polymeric immunoglobulin receptor ofthe marsupial Macropus eugenii (tammar wallaby)rdquo EuropeanJournal of Immunogenetics vol 29 no 2 pp 87ndash93 2002

[125] R Braathen V S Hohman P Brandtzaeg and F-E JohansenldquoSecretory antibody formation conserved binding interactionsbetween J chain and polymeric Ig receptor from humans andamphibiansrdquo The Journal of Immunology vol 178 no 3 pp1589ndash1597 2007

[126] M J Lewis BWagner R M Irvine and J MWoof ldquoIgA in thehorse cloning of equine polymeric Ig receptor and J chain andcharacterization of recombinant forms of equine IgArdquoMucosalImmunology vol 3 no 6 pp 610ndash621 2010

[127] A J Leon D Banner L Xu et al ldquoSequencing annotation andcharacterization of the influenza ferret infectomerdquo Journal ofVirology vol 87 no 4 pp 1957ndash1966 2013

[128] W H Wieland D Orzaez A Lammers H K ParmentierM W A Verstegen and A Schots ldquoA functional polymericimmunoglobulin receptor in chicken (Gallus gallus) indicatesancient role of secretory IgA inmucosal immunityrdquoBiochemicalJournal vol 380 no 3 pp 669ndash676 2004

[129] K Hamuro H Suetake N R Saha K Kikuchi and YSuzuki ldquoA teleost polymeric Ig receptor exhibiting two Ig-likedomains transports tetrameric IgM into the skinrdquo The Journalof Immunology vol 178 no 9 pp 5682ndash5689 2007

[130] J H W M Rombout S J L van der Tuin G Yang et alldquoExpression of the polymeric immunoglobulin receptor (pIgR)in mucosal tissues of common carp (Cyprinus carpio L)rdquo Fishand Shellfish Immunology vol 24 no 5 pp 620ndash628 2008

[131] L-N Feng D-Q Lu J-X Bei et al ldquoMolecular cloning andfunctional analysis of polymeric immunoglobulin receptor gene

ISRN Immunology 19

in orange-spotted grouper (Epinephelus coioides)rdquo ComparativeBiochemistry and Physiology B vol 154 no 3 pp 282ndash289 2009

[132] A E Oslashstergaard S A M Martin T Wang R J M Stet andC J Secombes ldquoRainbow trout (Oncorhynchus mykiss) pos-sessmultiple novel immunoglobulin-like transcripts containingeither an ITAM or ITIMsrdquo Developmental and ComparativeImmunology vol 33 no 4 pp 525ndash532 2009

[133] H Eiffert E Quentin and J Decker ldquoThe primary structureof the human free secretory component and the arrangementof disulfide bondsrdquo Hoppe-Seylerrsquos Zeitschrift fur PhysiologischeChemie vol 365 no 12 pp 1489ndash1495 1984

[134] E Fallgreen-Gebauer W Gebauer A Bastian et al ldquoThe cova-lent linkage of secretory component to IgA Structure of sIgArdquoBiological Chemistry Hoppe-Seyler vol 374 no 11 pp 1023ndash1028 1993

[135] J MWoof ldquoThe structure of IgArdquo inMucosal Immune DefenseImmunoglobulin A C S Kaetzel Ed chapter 1 pp 1ndash24Springer New York NY USA 2007

[136] A Bonner A Almogren P B Furtado M A Kerr and S JPerkins ldquoLocation of secretory component on the Fc edge ofdimeric IgA1 reveals insight into the role of secretory IgA1 inmucosal immunityrdquoMucosal Immunology vol 2 no 1 pp 74ndash84 2009

[137] A Bonner A Almogren P B Furtado M A Kerr and S JPerkins ldquoThe nonplanar secretory IgA2 and near planar secre-tory IgA1 solution structures rationalize their different mucosalimmune responsesrdquo The Journal of Biological Chemistry vol284 no 8 pp 5077ndash5087 2009

[138] J Johansen B Braathen and P Brandtzaeg ldquoRole of J chain insecretory immunoglobulin formationrdquo Scandinavian Journal ofImmunology vol 52 no 3 pp 240ndash248 2000

[139] B A Hendrickson D A Conner D J Ladd et al ldquoAlteredhepatic transport of immunoglobulin A in mice lacking the Jchainrdquo Journal of Experimental Medicine vol 182 no 6 pp1905ndash1911 1995

[140] B A Hendrickson L Rindisbacher B Corthesy et al ldquoLackof association of secretory component with IgA in J chain-deficient micerdquo The Journal of Immunology vol 157 no 2 pp750ndash754 1996

[141] N Lycke L Erlandsson L Ekman K Schon and T Lean-derson ldquoLack of J chain inhibits the transport of gut IgA andabrogates the development of intestinal antitoxic protectionrdquoThe Journal of Immunology vol 163 no 2 pp 913ndash919 1999

[142] F-E Johansen R Braathen and P Brandtzaeg ldquoThe J chainis essential for polymeric Ig receptor-mediated epithelial trans-port of IgArdquoThe Journal of Immunology vol 167 no 9 pp 5185ndash5192 2001

[143] R E Ley D A Peterson and J I Gordon ldquoEcological andevolutionary forces shaping microbial diversity in the humanintestinerdquo Cell vol 124 no 4 pp 837ndash848 2006

[144] M McFall-Ngai ldquoAdaptive immunity care for the communityrdquoNature vol 445 no 7124 p 153 2007

[145] A J Macpherson K D McCoy F-E Johansen and PBrandtzaeg ldquoThe immune geography of IgA induction andfunctionrdquoMucosal Immunology vol 1 no 1 pp 11ndash22 2008

[146] D Kvale and P Brandtzaeg ldquoConstitutive and cytokine inducedexpression of HLA molecules secretory component and inter-cellular adhesion molecule-1 is modulated by butyrate in thecolonic epithelial cell line HT-29rdquo Gut vol 36 no 5 pp 737ndash742 1995

[147] L VHooperMHWong AThelin L Hansson P G Falk andJ I Gordon ldquoMolecular analysis of commensal host-microbialrelationships in the intestinerdquo Science vol 291 no 5505 pp 881ndash884 2001

[148] S Hapfelmeier M A E Lawson E Slack et al ldquoReversiblemicrobial colonization of germ-free mice reveals the dynamicsof IgA immune responsesrdquo Science vol 328 no 5986 pp 1705ndash1709 2010

[149] DH ReikvamMDerrien R Islam et al ldquoEpithelial-microbialcross-talk in polymeric Ig receptor deficient micerdquo EuropeanJournal of Immunology vol 42 no 11 pp 2959ndash2970 2012

[150] EW Rogier A L Frantz M E C Bruno et al ldquoSecretory anti-bodies in breast milk promote long-term intestinal homeostasisby regulating the gut microbiota and host gene expressionrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 111 no 8 pp 3074ndash3079 2014

[151] G M Barton and R Medzhitov ldquoToll-like receptor signalingpathwaysrdquo Science vol 300 no 5625 pp 1524ndash1525 2003

[152] K Takeda and S Akira ldquoToll receptors and pathogen resis-tancerdquo Cellular Microbiology vol 5 no 3 pp 143ndash153 2003

[153] E Cario andD K Podolsky ldquoDifferential alteration in intestinalepithelial cell expression of Toll-like receptor 3 (TLR3) andTLR4 in inflammatory bowel diseaserdquo Infection and Immunityvol 68 no 12 pp 7010ndash7017 2000

[154] M Hausmann S Kiessling S Mestermann et al ldquoToll-likereceptors 2 and 4 are up-regulated during intestinal inflamma-tionrdquo Gastroenterology vol 122 no 7 pp 1987ndash2000 2002

[155] M T Abreu L S Thomas S Y Tesfay et al ldquoRegulation ofTLR4 and MD-2 in the intestinal epithelium evidence for dys-regulated LPS signaling in human inflammatory bowel diseaserdquoin Proceedings of the 90th Annual Meeting of the AmericanAssociation for Immunologists Abstract 3634 Denver ColoUSA 2003

[156] T A Schneeman M E C Bruno H Schjerven F-E JohansenL Chady and C S Kaetzel ldquoRegulation of the polymeric Igreceptor by signaling through TLRs 3 and 4 linking innate andadaptive immune responsesrdquo The Journal of Immunology vol175 no 1 pp 376ndash384 2005

[157] M E C Bruno A L Frantz E W Rogier F-E Johansen andC S Kaetzel ldquoRegulation of the polymeric immunoglobulinreceptor by the classical and alternative NF-120581B pathways inintestinal epithelial cellsrdquoMucosal Immunology vol 4 no 4 pp468ndash478 2011

[158] M E C Bruno E W Rogier A L Frantz A T Stefka SN Thompson and C S Kaetzel ldquoRegulation of the poly-meric immunoglobulin receptor in intestinal epithelial cellsby Enterobacteriaceae implications for mucosal homeostasisrdquoImmunological Investigations vol 39 no 4-5 pp 356ndash382 2010

[159] A L Frantz E W Rogier C R Weber et al ldquoTargeted deletionof MyD88 in intestinal epithelial cells results in compromisedantibacterial immunity associatedwith downregulation of poly-meric immunoglobulin receptor mucin-2 and antibacterialpeptidesrdquoMucosal Immunology vol 5 no 5 pp 501ndash512 2012

[160] E W Rogier A L Frantz M E C Bruno and C S KaetzelldquoSecretory IgA is concentrated in the outer layer of intestinalmucus along with gut bacteriardquo Pathogens In press

[161] M B Geuking K D McCoy and A J Macpherson ldquoThe func-tion of secretory IgA in the context of the intestinal continuumof adaptive immune responses in host-microbial mutualismrdquoSeminars in Immunology vol 24 no 1 pp 36ndash42 2012

20 ISRN Immunology

[162] L VHooper D R Littman andA JMacpherson ldquoInteractionsbetween the microbiota and the immune systemrdquo Science vol336 no 6086 pp 1268ndash1273 2012

[163] A J Macpherson M B Geuking E Slack S Hapfelmeierand K D McCoy ldquoThe habitat double life citizenship andforgetfulness of IgArdquo Immunological Reviews vol 245 no 1 pp132ndash146 2012

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

18 ISRN Immunology

[101] H Rabbani Q Pan N Kondo C I E Smith and L Ham-marstrom ldquoDuplications and deletions of the human IGHClocus evolutionary implicationsrdquo Immunogenetics vol 45 no2 pp 136ndash141 1996

[102] P F Weinheimer J Mestecky and R T Acton ldquoSpecies distri-bution of J chainrdquoThe Journal of Immunology vol 107 no 4 pp1211ndash1212 1971

[103] F P Inman and J Mestecky ldquoThe J chain of polymeric immu-noglobulinsrdquo inContemporary Topics inMolecular Immunologyvol 3 pp 111ndash141 Springer New York NY USA 1974

[104] P Brandtzaeg ldquoPresence of J chain in human immunocytescontaining various immunoglobulin classesrdquo Nature vol 252no 5482 pp 418ndash420 1974

[105] L Tacchi E Larragoite and I Salinas ldquoDiscovery of J chain inAfrican lungfish (Protopterus dolloi Sarcopterygii) using highthroughput transcriptome sequencing implications in mucosalimmunityrdquo PLoS ONE vol 8 no 8 Article ID e70650 2013

[106] I K Zarkadis D Mastellos and J D Lambris ldquoPhylogeneticaspects of the complement systemrdquo Developmental and Com-parative Immunology vol 25 no 8-9 pp 745ndash762 2001

[107] A P West Jr A B Herr and P J Bjorkman ldquoThe chickenyolk sac IgY receptor a functional equivalent of themammalianMHC-related Fc receptor is a phospholipase A

2receptor

homologrdquo Immunity vol 20 no 5 pp 601ndash610 2004[108] D B Tesar E J Cheung and P J Bjorkman ldquoThe chicken

yolk sac IgY receptor a mammalian mannose receptor familymember transcytoses IgY across polarized epithelial cellsrdquoMolecular Biology of the Cell vol 19 no 4 pp 1587ndash1593 2008

[109] A I Taylor R L Beavil B J Sutton and R A Calvert ldquoAmonomeric chicken IgY receptor binds IgY with 21 stoichiom-etryrdquo The Journal of Biological Chemistry vol 284 no 36 pp24168ndash24175 2009

[110] K Baker S-W Qiao T Kuo et al ldquoImmune and non-immunefunctions of the (not so) neonatal Fc receptor FcRnrdquo Seminarsin Immunopathology vol 31 no 2 pp 223ndash236 2009

[111] K Baker R S Blumberg and C S Kaetzel ldquoImmunoglob-ulin transport and immunoglobulin receptorsrdquo in MucosalImmunology J Mestecky W Strober H Cheroutre B KelsallB N Lambrecht andMW Russell Eds chapter 20 AcademicPressElsevier Waltham Mass USA 2014

[112] C S Kaetzel ldquoThepolymeric immunoglobulin receptorrdquo in eLSJohn Wiley amp Sons Chichester UK 2013

[113] N J Mantis N Rol and B Corthesy ldquoSecretory IgArsquos complexroles in immunity andmucosal homeostasis in the gutrdquoMucosalImmunology vol 4 no 6 pp 603ndash611 2011

[114] J V Peppard M E Rose and P Hesketh ldquoA functional homo-logue of mammalian secretory component exists in chickensrdquoEuropean Journal of Immunology vol 13 no 7 pp 566ndash5701983

[115] K E Mostov M Friedlander and G Blobel ldquoThe receptorfor transepithelial transport of IgA and IgM contains multipleimmunoglobulin-like domainsrdquo Nature vol 308 no 5954 pp37ndash43 1984

[116] P Krajci R Solberg M Sandberg O Oyen T Jahnsen and PBrandtzaeg ldquoMolecular cloning of the human transmembranesecretory component (poly-Ig receptor) and its mRNA expres-sion in human tissuesrdquo Biochemical and Biophysical ResearchCommunications vol 158 no 3 pp 783ndash789 1989

[117] P Krajci D Kvale K Tasken and P Brandtzaeg ldquoMolecularcloning and exon-intron mapping of the gene encoding humantransmembrane secretory component (the poly-Ig receptor)rdquo

European Journal of Immunology vol 22 no 9 pp 2309ndash23151992

[118] J F Piskurich J A France C M Tamer C A Willmer CS Kaetzel and D M Kaetzel ldquoInterferon-120574 induces polymericimmunoglobulin receptormRNA in human intestinal epithelialcells by a protein synthesis dependent mechanismrdquo MolecularImmunology vol 30 no 4 pp 413ndash421 1993

[119] J F Piskurich M H Blanchard K R Youngman J A Franceand C S Kaetzel ldquoMolecular cloning of the mouse polymericIg receptor functional regions of the molecule are conservedamong five mammalian speciesrdquo The Journal of Immunologyvol 154 no 4 pp 1735ndash1747 1995

[120] M A Kulseth P Krajci O Myklebost and S RogneldquoCloning and characterization of two forms of bovine polymericimmunoglobulin receptor cDNArdquo DNA and Cell Biology vol14 no 3 pp 251ndash256 1995

[121] K S Koch A S Gleiberman T Aoki et al ldquoDiscordant expres-sion and variable numbers of neighboring GGA- and GAA-richtriplet repeats in the 31015840 untranslated regions of two groups ofmessenger RNAs encoded by the rat polymeric immunoglob-ulin receptor generdquo Nucleic Acids Research vol 23 no 7 pp1098ndash1112 1995

[122] F M Adamski and J Demmer ldquoTwo stages of increased IgAtransfer during lactation in themarsupialTrichosurus vulpecula(brushtail possum)rdquoThe Journal of Immunology vol 162 no 10pp 6009ndash6015 1999

[123] H Kumura T Sone K-I Shimazaki and E KobayashildquoSequence analysis of porcine polymeric immunoglobulinreceptor from mammary epithelial cells present in colostrumrdquoThe Journal of Dairy Research vol 67 no 4 pp 631ndash636 2000

[124] C L Taylor G A Harrison C M Watson and E M DeaneldquocDNA cloning of the polymeric immunoglobulin receptor ofthe marsupial Macropus eugenii (tammar wallaby)rdquo EuropeanJournal of Immunogenetics vol 29 no 2 pp 87ndash93 2002

[125] R Braathen V S Hohman P Brandtzaeg and F-E JohansenldquoSecretory antibody formation conserved binding interactionsbetween J chain and polymeric Ig receptor from humans andamphibiansrdquo The Journal of Immunology vol 178 no 3 pp1589ndash1597 2007

[126] M J Lewis BWagner R M Irvine and J MWoof ldquoIgA in thehorse cloning of equine polymeric Ig receptor and J chain andcharacterization of recombinant forms of equine IgArdquoMucosalImmunology vol 3 no 6 pp 610ndash621 2010

[127] A J Leon D Banner L Xu et al ldquoSequencing annotation andcharacterization of the influenza ferret infectomerdquo Journal ofVirology vol 87 no 4 pp 1957ndash1966 2013

[128] W H Wieland D Orzaez A Lammers H K ParmentierM W A Verstegen and A Schots ldquoA functional polymericimmunoglobulin receptor in chicken (Gallus gallus) indicatesancient role of secretory IgA inmucosal immunityrdquoBiochemicalJournal vol 380 no 3 pp 669ndash676 2004

[129] K Hamuro H Suetake N R Saha K Kikuchi and YSuzuki ldquoA teleost polymeric Ig receptor exhibiting two Ig-likedomains transports tetrameric IgM into the skinrdquo The Journalof Immunology vol 178 no 9 pp 5682ndash5689 2007

[130] J H W M Rombout S J L van der Tuin G Yang et alldquoExpression of the polymeric immunoglobulin receptor (pIgR)in mucosal tissues of common carp (Cyprinus carpio L)rdquo Fishand Shellfish Immunology vol 24 no 5 pp 620ndash628 2008

[131] L-N Feng D-Q Lu J-X Bei et al ldquoMolecular cloning andfunctional analysis of polymeric immunoglobulin receptor gene

ISRN Immunology 19

in orange-spotted grouper (Epinephelus coioides)rdquo ComparativeBiochemistry and Physiology B vol 154 no 3 pp 282ndash289 2009

[132] A E Oslashstergaard S A M Martin T Wang R J M Stet andC J Secombes ldquoRainbow trout (Oncorhynchus mykiss) pos-sessmultiple novel immunoglobulin-like transcripts containingeither an ITAM or ITIMsrdquo Developmental and ComparativeImmunology vol 33 no 4 pp 525ndash532 2009

[133] H Eiffert E Quentin and J Decker ldquoThe primary structureof the human free secretory component and the arrangementof disulfide bondsrdquo Hoppe-Seylerrsquos Zeitschrift fur PhysiologischeChemie vol 365 no 12 pp 1489ndash1495 1984

[134] E Fallgreen-Gebauer W Gebauer A Bastian et al ldquoThe cova-lent linkage of secretory component to IgA Structure of sIgArdquoBiological Chemistry Hoppe-Seyler vol 374 no 11 pp 1023ndash1028 1993

[135] J MWoof ldquoThe structure of IgArdquo inMucosal Immune DefenseImmunoglobulin A C S Kaetzel Ed chapter 1 pp 1ndash24Springer New York NY USA 2007

[136] A Bonner A Almogren P B Furtado M A Kerr and S JPerkins ldquoLocation of secretory component on the Fc edge ofdimeric IgA1 reveals insight into the role of secretory IgA1 inmucosal immunityrdquoMucosal Immunology vol 2 no 1 pp 74ndash84 2009

[137] A Bonner A Almogren P B Furtado M A Kerr and S JPerkins ldquoThe nonplanar secretory IgA2 and near planar secre-tory IgA1 solution structures rationalize their different mucosalimmune responsesrdquo The Journal of Biological Chemistry vol284 no 8 pp 5077ndash5087 2009

[138] J Johansen B Braathen and P Brandtzaeg ldquoRole of J chain insecretory immunoglobulin formationrdquo Scandinavian Journal ofImmunology vol 52 no 3 pp 240ndash248 2000

[139] B A Hendrickson D A Conner D J Ladd et al ldquoAlteredhepatic transport of immunoglobulin A in mice lacking the Jchainrdquo Journal of Experimental Medicine vol 182 no 6 pp1905ndash1911 1995

[140] B A Hendrickson L Rindisbacher B Corthesy et al ldquoLackof association of secretory component with IgA in J chain-deficient micerdquo The Journal of Immunology vol 157 no 2 pp750ndash754 1996

[141] N Lycke L Erlandsson L Ekman K Schon and T Lean-derson ldquoLack of J chain inhibits the transport of gut IgA andabrogates the development of intestinal antitoxic protectionrdquoThe Journal of Immunology vol 163 no 2 pp 913ndash919 1999

[142] F-E Johansen R Braathen and P Brandtzaeg ldquoThe J chainis essential for polymeric Ig receptor-mediated epithelial trans-port of IgArdquoThe Journal of Immunology vol 167 no 9 pp 5185ndash5192 2001

[143] R E Ley D A Peterson and J I Gordon ldquoEcological andevolutionary forces shaping microbial diversity in the humanintestinerdquo Cell vol 124 no 4 pp 837ndash848 2006

[144] M McFall-Ngai ldquoAdaptive immunity care for the communityrdquoNature vol 445 no 7124 p 153 2007

[145] A J Macpherson K D McCoy F-E Johansen and PBrandtzaeg ldquoThe immune geography of IgA induction andfunctionrdquoMucosal Immunology vol 1 no 1 pp 11ndash22 2008

[146] D Kvale and P Brandtzaeg ldquoConstitutive and cytokine inducedexpression of HLA molecules secretory component and inter-cellular adhesion molecule-1 is modulated by butyrate in thecolonic epithelial cell line HT-29rdquo Gut vol 36 no 5 pp 737ndash742 1995

[147] L VHooperMHWong AThelin L Hansson P G Falk andJ I Gordon ldquoMolecular analysis of commensal host-microbialrelationships in the intestinerdquo Science vol 291 no 5505 pp 881ndash884 2001

[148] S Hapfelmeier M A E Lawson E Slack et al ldquoReversiblemicrobial colonization of germ-free mice reveals the dynamicsof IgA immune responsesrdquo Science vol 328 no 5986 pp 1705ndash1709 2010

[149] DH ReikvamMDerrien R Islam et al ldquoEpithelial-microbialcross-talk in polymeric Ig receptor deficient micerdquo EuropeanJournal of Immunology vol 42 no 11 pp 2959ndash2970 2012

[150] EW Rogier A L Frantz M E C Bruno et al ldquoSecretory anti-bodies in breast milk promote long-term intestinal homeostasisby regulating the gut microbiota and host gene expressionrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 111 no 8 pp 3074ndash3079 2014

[151] G M Barton and R Medzhitov ldquoToll-like receptor signalingpathwaysrdquo Science vol 300 no 5625 pp 1524ndash1525 2003

[152] K Takeda and S Akira ldquoToll receptors and pathogen resis-tancerdquo Cellular Microbiology vol 5 no 3 pp 143ndash153 2003

[153] E Cario andD K Podolsky ldquoDifferential alteration in intestinalepithelial cell expression of Toll-like receptor 3 (TLR3) andTLR4 in inflammatory bowel diseaserdquo Infection and Immunityvol 68 no 12 pp 7010ndash7017 2000

[154] M Hausmann S Kiessling S Mestermann et al ldquoToll-likereceptors 2 and 4 are up-regulated during intestinal inflamma-tionrdquo Gastroenterology vol 122 no 7 pp 1987ndash2000 2002

[155] M T Abreu L S Thomas S Y Tesfay et al ldquoRegulation ofTLR4 and MD-2 in the intestinal epithelium evidence for dys-regulated LPS signaling in human inflammatory bowel diseaserdquoin Proceedings of the 90th Annual Meeting of the AmericanAssociation for Immunologists Abstract 3634 Denver ColoUSA 2003

[156] T A Schneeman M E C Bruno H Schjerven F-E JohansenL Chady and C S Kaetzel ldquoRegulation of the polymeric Igreceptor by signaling through TLRs 3 and 4 linking innate andadaptive immune responsesrdquo The Journal of Immunology vol175 no 1 pp 376ndash384 2005

[157] M E C Bruno A L Frantz E W Rogier F-E Johansen andC S Kaetzel ldquoRegulation of the polymeric immunoglobulinreceptor by the classical and alternative NF-120581B pathways inintestinal epithelial cellsrdquoMucosal Immunology vol 4 no 4 pp468ndash478 2011

[158] M E C Bruno E W Rogier A L Frantz A T Stefka SN Thompson and C S Kaetzel ldquoRegulation of the poly-meric immunoglobulin receptor in intestinal epithelial cellsby Enterobacteriaceae implications for mucosal homeostasisrdquoImmunological Investigations vol 39 no 4-5 pp 356ndash382 2010

[159] A L Frantz E W Rogier C R Weber et al ldquoTargeted deletionof MyD88 in intestinal epithelial cells results in compromisedantibacterial immunity associatedwith downregulation of poly-meric immunoglobulin receptor mucin-2 and antibacterialpeptidesrdquoMucosal Immunology vol 5 no 5 pp 501ndash512 2012

[160] E W Rogier A L Frantz M E C Bruno and C S KaetzelldquoSecretory IgA is concentrated in the outer layer of intestinalmucus along with gut bacteriardquo Pathogens In press

[161] M B Geuking K D McCoy and A J Macpherson ldquoThe func-tion of secretory IgA in the context of the intestinal continuumof adaptive immune responses in host-microbial mutualismrdquoSeminars in Immunology vol 24 no 1 pp 36ndash42 2012

20 ISRN Immunology

[162] L VHooper D R Littman andA JMacpherson ldquoInteractionsbetween the microbiota and the immune systemrdquo Science vol336 no 6086 pp 1268ndash1273 2012

[163] A J Macpherson M B Geuking E Slack S Hapfelmeierand K D McCoy ldquoThe habitat double life citizenship andforgetfulness of IgArdquo Immunological Reviews vol 245 no 1 pp132ndash146 2012

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

ISRN Immunology 19

in orange-spotted grouper (Epinephelus coioides)rdquo ComparativeBiochemistry and Physiology B vol 154 no 3 pp 282ndash289 2009

[132] A E Oslashstergaard S A M Martin T Wang R J M Stet andC J Secombes ldquoRainbow trout (Oncorhynchus mykiss) pos-sessmultiple novel immunoglobulin-like transcripts containingeither an ITAM or ITIMsrdquo Developmental and ComparativeImmunology vol 33 no 4 pp 525ndash532 2009

[133] H Eiffert E Quentin and J Decker ldquoThe primary structureof the human free secretory component and the arrangementof disulfide bondsrdquo Hoppe-Seylerrsquos Zeitschrift fur PhysiologischeChemie vol 365 no 12 pp 1489ndash1495 1984

[134] E Fallgreen-Gebauer W Gebauer A Bastian et al ldquoThe cova-lent linkage of secretory component to IgA Structure of sIgArdquoBiological Chemistry Hoppe-Seyler vol 374 no 11 pp 1023ndash1028 1993

[135] J MWoof ldquoThe structure of IgArdquo inMucosal Immune DefenseImmunoglobulin A C S Kaetzel Ed chapter 1 pp 1ndash24Springer New York NY USA 2007

[136] A Bonner A Almogren P B Furtado M A Kerr and S JPerkins ldquoLocation of secretory component on the Fc edge ofdimeric IgA1 reveals insight into the role of secretory IgA1 inmucosal immunityrdquoMucosal Immunology vol 2 no 1 pp 74ndash84 2009

[137] A Bonner A Almogren P B Furtado M A Kerr and S JPerkins ldquoThe nonplanar secretory IgA2 and near planar secre-tory IgA1 solution structures rationalize their different mucosalimmune responsesrdquo The Journal of Biological Chemistry vol284 no 8 pp 5077ndash5087 2009

[138] J Johansen B Braathen and P Brandtzaeg ldquoRole of J chain insecretory immunoglobulin formationrdquo Scandinavian Journal ofImmunology vol 52 no 3 pp 240ndash248 2000

[139] B A Hendrickson D A Conner D J Ladd et al ldquoAlteredhepatic transport of immunoglobulin A in mice lacking the Jchainrdquo Journal of Experimental Medicine vol 182 no 6 pp1905ndash1911 1995

[140] B A Hendrickson L Rindisbacher B Corthesy et al ldquoLackof association of secretory component with IgA in J chain-deficient micerdquo The Journal of Immunology vol 157 no 2 pp750ndash754 1996

[141] N Lycke L Erlandsson L Ekman K Schon and T Lean-derson ldquoLack of J chain inhibits the transport of gut IgA andabrogates the development of intestinal antitoxic protectionrdquoThe Journal of Immunology vol 163 no 2 pp 913ndash919 1999

[142] F-E Johansen R Braathen and P Brandtzaeg ldquoThe J chainis essential for polymeric Ig receptor-mediated epithelial trans-port of IgArdquoThe Journal of Immunology vol 167 no 9 pp 5185ndash5192 2001

[143] R E Ley D A Peterson and J I Gordon ldquoEcological andevolutionary forces shaping microbial diversity in the humanintestinerdquo Cell vol 124 no 4 pp 837ndash848 2006

[144] M McFall-Ngai ldquoAdaptive immunity care for the communityrdquoNature vol 445 no 7124 p 153 2007

[145] A J Macpherson K D McCoy F-E Johansen and PBrandtzaeg ldquoThe immune geography of IgA induction andfunctionrdquoMucosal Immunology vol 1 no 1 pp 11ndash22 2008

[146] D Kvale and P Brandtzaeg ldquoConstitutive and cytokine inducedexpression of HLA molecules secretory component and inter-cellular adhesion molecule-1 is modulated by butyrate in thecolonic epithelial cell line HT-29rdquo Gut vol 36 no 5 pp 737ndash742 1995

[147] L VHooperMHWong AThelin L Hansson P G Falk andJ I Gordon ldquoMolecular analysis of commensal host-microbialrelationships in the intestinerdquo Science vol 291 no 5505 pp 881ndash884 2001

[148] S Hapfelmeier M A E Lawson E Slack et al ldquoReversiblemicrobial colonization of germ-free mice reveals the dynamicsof IgA immune responsesrdquo Science vol 328 no 5986 pp 1705ndash1709 2010

[149] DH ReikvamMDerrien R Islam et al ldquoEpithelial-microbialcross-talk in polymeric Ig receptor deficient micerdquo EuropeanJournal of Immunology vol 42 no 11 pp 2959ndash2970 2012

[150] EW Rogier A L Frantz M E C Bruno et al ldquoSecretory anti-bodies in breast milk promote long-term intestinal homeostasisby regulating the gut microbiota and host gene expressionrdquoProceedings of the National Academy of Sciences of the UnitedStates of America vol 111 no 8 pp 3074ndash3079 2014

[151] G M Barton and R Medzhitov ldquoToll-like receptor signalingpathwaysrdquo Science vol 300 no 5625 pp 1524ndash1525 2003

[152] K Takeda and S Akira ldquoToll receptors and pathogen resis-tancerdquo Cellular Microbiology vol 5 no 3 pp 143ndash153 2003

[153] E Cario andD K Podolsky ldquoDifferential alteration in intestinalepithelial cell expression of Toll-like receptor 3 (TLR3) andTLR4 in inflammatory bowel diseaserdquo Infection and Immunityvol 68 no 12 pp 7010ndash7017 2000

[154] M Hausmann S Kiessling S Mestermann et al ldquoToll-likereceptors 2 and 4 are up-regulated during intestinal inflamma-tionrdquo Gastroenterology vol 122 no 7 pp 1987ndash2000 2002

[155] M T Abreu L S Thomas S Y Tesfay et al ldquoRegulation ofTLR4 and MD-2 in the intestinal epithelium evidence for dys-regulated LPS signaling in human inflammatory bowel diseaserdquoin Proceedings of the 90th Annual Meeting of the AmericanAssociation for Immunologists Abstract 3634 Denver ColoUSA 2003

[156] T A Schneeman M E C Bruno H Schjerven F-E JohansenL Chady and C S Kaetzel ldquoRegulation of the polymeric Igreceptor by signaling through TLRs 3 and 4 linking innate andadaptive immune responsesrdquo The Journal of Immunology vol175 no 1 pp 376ndash384 2005

[157] M E C Bruno A L Frantz E W Rogier F-E Johansen andC S Kaetzel ldquoRegulation of the polymeric immunoglobulinreceptor by the classical and alternative NF-120581B pathways inintestinal epithelial cellsrdquoMucosal Immunology vol 4 no 4 pp468ndash478 2011

[158] M E C Bruno E W Rogier A L Frantz A T Stefka SN Thompson and C S Kaetzel ldquoRegulation of the poly-meric immunoglobulin receptor in intestinal epithelial cellsby Enterobacteriaceae implications for mucosal homeostasisrdquoImmunological Investigations vol 39 no 4-5 pp 356ndash382 2010

[159] A L Frantz E W Rogier C R Weber et al ldquoTargeted deletionof MyD88 in intestinal epithelial cells results in compromisedantibacterial immunity associatedwith downregulation of poly-meric immunoglobulin receptor mucin-2 and antibacterialpeptidesrdquoMucosal Immunology vol 5 no 5 pp 501ndash512 2012

[160] E W Rogier A L Frantz M E C Bruno and C S KaetzelldquoSecretory IgA is concentrated in the outer layer of intestinalmucus along with gut bacteriardquo Pathogens In press

[161] M B Geuking K D McCoy and A J Macpherson ldquoThe func-tion of secretory IgA in the context of the intestinal continuumof adaptive immune responses in host-microbial mutualismrdquoSeminars in Immunology vol 24 no 1 pp 36ndash42 2012

20 ISRN Immunology

[162] L VHooper D R Littman andA JMacpherson ldquoInteractionsbetween the microbiota and the immune systemrdquo Science vol336 no 6086 pp 1268ndash1273 2012

[163] A J Macpherson M B Geuking E Slack S Hapfelmeierand K D McCoy ldquoThe habitat double life citizenship andforgetfulness of IgArdquo Immunological Reviews vol 245 no 1 pp132ndash146 2012

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

20 ISRN Immunology

[162] L VHooper D R Littman andA JMacpherson ldquoInteractionsbetween the microbiota and the immune systemrdquo Science vol336 no 6086 pp 1268ndash1273 2012

[163] A J Macpherson M B Geuking E Slack S Hapfelmeierand K D McCoy ldquoThe habitat double life citizenship andforgetfulness of IgArdquo Immunological Reviews vol 245 no 1 pp132ndash146 2012

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

MEDIATORSINFLAMMATION

of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Behavioural Neurology

EndocrinologyInternational Journal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Disease Markers

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

BioMed Research International

OncologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Oxidative Medicine and Cellular Longevity

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Computational and Mathematical Methods in Medicine

OphthalmologyJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Diabetes ResearchJournal of

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Research and TreatmentAIDS

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Gastroenterology Research and Practice

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom