basic and translational concepts of immune-mediated glomerular

BRIEF REVIEW www.jasn.org

Basic and Translational Concepts of Immune-MediatedGlomerular Diseases

William G. Couser

Division of Nephrology, Department of Medicine, University of Washington School of Medicine, Seattle, Washington

ABSTRACTGenetically modified immune responses to infections and self-antigens initiatemostforms of GN by generating pathogen- and danger-associated molecular patternsthat stimulate Toll-like receptors and complement. These innate immune responsesactivate circulating monocytes and resident glomerular cells to release inflamma-tory mediators and initiate adaptive, antigen-specific immune responses thatcollectively damage glomerular structures. CD4 T cells are needed for B cell–drivenantibody production that leads to immune complex formation in glomeruli, comple-ment activation, and injury induced by both circulating inflammatory and residentglomerular effector cells. Th17 cells can also induce glomerular injury directly. In thisreview, information derived from studies in vitro, well characterized experimentalmodels, and humans summarize and update likely pathogenic mechanisms involvedin human diseases presenting as nephritis (postinfectious GN, IgA nephropathy,antiglomerular basement membrane and antineutrophil cytoplasmic antibody–mediated crescentic GN, lupus nephritis, type I membranoproliferative GN), andnephrotic syndrome (minimal change/FSGS, membranous nephropathy, and C3glomerulopathies). Advances in understanding the immunopathogenesis of eachof these entities offer many opportunities for future therapeutic interventions.

J Am Soc Nephrol 23: ccc–ccc, 2012. doi: 10.1681/ASN.2011030304

Recent reviews of the immune mecha-nisms that lead to glomerular diseasehave been published elsewhere.1,2 Thisreview is organized by diseases ratherthan mechanisms to provide a transla-tional overviewof how immune responsesmediate the glomerular injury seen byclinicians and pathologists. The pro-cesses described derive from studiesdone in vitro and in an array of animalmodels of glomerular diseases as well asin humans. Cell cultures are not glomer-uli, and mice and rats are not humans,but experience has taught us that mech-anisms defined in these settings oftentranslate into better understanding ofsimilar processes seen in human disease.Schematic overviews of the major path-ogenic sequences currently believed to

be operative in human GN and their in-teractions are presented in Figures 1through 4.

OVERVIEW OF BASIC IMMUNEMECHANISMS

The Innate Immune ResponseToll-Like ReceptorsToll-like receptors (TLRs) are ancientand ubiquitous pattern recognition recep-tors present on all cell membranes andintracellularly between cytoplasm and en-dosomes (Figure 1).3–6 TLRs recognizeconserved immunostimulatorymolecularpatterns (antigens) like peptidoglycans,LPSs, and bacterial and viral nucleicacids (pathogen-associated molecular

patterns [PAMPs]) as well as endogenouscell-derived patterns (danger-associatedmolecular patterns [DAMPs]). Anotherrelated cytoplasmic group of receptorscalled Nod-like receptors (NLRs) has re-cently been described.6 TLR ligation iscentral to activating the non-antigen-specific innate immune system in im-mediate response to pathogens, butTLR activation is also required for adap-tive, antigen-specific immune responsesby facilitating conversion of dendriticcells to antigen-presenting cells.4–7

TLRs activate multiple signaling path-ways that lead to local release of a varietyof cytokines, chemokines, and other in-flammatory mediators by all cells, includ-ing glomerular cells.4,5 Thus, TLRs andNLRs connect initiating events with me-diation of tissue injury in GN associatedwith infections or autoimmunity or both.

ComplementThe complement system and its regula-tory proteins are also ancient compo-nents of the innate immune system withmultiple roles inhumanGN(Figure2).7–11

The innate immune response involvesimmediate complement activationthrough the mannose binding lectin(MBL) or alternative pathways.7,10 Acti-vation of the MBL pathway proceeds

Published online ahead of print. Publication dateavailable at www.jasn.org.

Correspondence: Dr. William G. Couser, 16050169th Avenue NE, Woodinville, WA 98072. Email:[email protected]

Copyright © 2012 by the American Society ofNephrology

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whenMBL binds tomannose residues onpathogens and activates the serine pro-teases, MASP-1 and MASP-2, leading toactivation of C4 and C2. The alternativepathway is activated spontaneously byhydrolysis of C3 and amplified by defectsin complement regulation. Non-Ig zymo-gens such as damaged cells and bacterialand viral proteins can also activate thealternative pathway beginning directlyat C3. The same initiating event may ac-tivate more than one pathway.

Complement activation products arethe principal mediators of antibody-induced GN (Figures 1 and 2). Usuallythis involves C1q binding to Ig that leadsto classic pathway activation through C4and C2; however, some Igs, dependingon their level of glycosylation, can also

bind MBL. IgG subclasses 1 and 3 andIgM are classic complement pathway ac-tivators, whereas IgG 2 and 4, IgA, IgD,and IgE activate complement poorly.1,12

All complement activation pathwaysproceed through cleavage of C3 and C5leading to release of chemotactic factorssuch as C5a that attract inflammatorycells (neutrophils, macrophages, andplatelets) when abutting the circulationas well as formation of the terminalmembrane attack complex (C5b-9)(Figure 2).7–9 Sublytic quantities ofC5b-9 can insert into lipid bilayers ofadjacent glomerular cell membranes, ini-tiate several signaling pathways, and con-vert these cells to effector cells, whichmay proliferate; release a variety of cy-tokines, growth factors, eicosanoids,

oxidants, proteases, and other acute in-flammatorymediators; as well as upregu-late production of matrix componentsthat contribute to chronic scarring andsclerosis (Figure 1).1,12,13 Complementactivation products like C5a can also ac-tivate TLRs.14

Complement activation in vivo istightly regulated by a number of circu-lating and cell-bound complement regu-latory proteins (CRPs), whose functions,mutations and deficiencies are also im-portant in the development of severalglomerular diseases.8,9 Abnormalitiesin serum complement profiles are some-times helpful in assessing the nature ofthe underlying disease and its activity,but significant complement-mediatedinjury may occur locally without alter-ations in circulating complement com-ponents (Table 1).

The Adaptive Immune ResponseIgCD4 T helper cells stimulate B cells andplasma cells to make antibodies specificfor particular antigens (Figure 3). On thebasis of older studies of serum sicknessin rabbits induced by single (acute) orrepeated (chronic) injections of BSA,glomerular immune deposits have longbeen attributed to the passive trapping ofcirculating, soluble antigen-IgG anti-body complexes (ICs).15,16 Other studiesdone in antiglomerular antibody models(nephrotoxic nephritis; NTN) demon-strate that antibody deposition activatescomplement through the classic comple-ment pathway generating chemotacticfactors that attract circulating inflamma-tory effector cells, which then cause tissueinjury (Figures 1 and 3).17 Typical granu-lar IC deposits can also form locally, or insitu, due to antibody binding to either ex-ogenous planted antigens or endogenousglomerular components (Figure 3).18–23

There are several variables that determinethe biopsy findings and clinical conse-quences in IC GN: (1) where the depositsform—ICs of the same composition in asubendothelial distribution lead to exu-dative inflammatory cell infiltrates, inthe mesangium to mesangial cell pro-liferation and matrix expansion, andin a subepithelial distribution to a

Figure 1. Schematic overview of both the innate and adaptive immune mechanisms thatmediate tissue injury in GN. Etiologic events expose immunostimulatory PAMPs or DAMPsthat activate both the innate (red) and the adaptive (antigen specific, blue) immune sys-tems, which also interact with each other. Activation of the innate immune system occursimmediately and involves TLRs orNLRsonboth circulating inflammatory cells and residentglomerular cells. TLR activation results in release of inflammatory mediators that causeglomerular injury. Some PAMPs and DAMPs can activate complement directly through theinnate immune system. TLRs are also required to activate the adaptive immune systemthrough antigen-presenting cells that promote differentiation of CD4 helper cells, B cellactivation, and antibody production. Antibodies lead to circulating complex trapping orin situ formation of immune complexes that can activate both the TLR and complementcomponents of the innate immune system. Complement activation generates the che-motactic factor C5a that attracts circulating inflammatory cells (including neutrophils,macrophages, basophils, and natural killer cells), which release mediators and damageglomeruli and C5b-9 that activates resident glomerular cells to do the same. CD4 Th1 andTh2 cells cause tissue injury primarily thorough macrophages and basophils, respectively,whereas Th17 cells can mediate glomerular damage directly. CD4 regulatory cells (Tregs)downregulate the adaptive immune response.

2 Journal of the American Society of Nephrology J Am Soc Nephrol 23: ccc–ccc, 2012


noninflammatory lesion with podocyteinjury, effacement, and heavy protein-uria23–25; (2) the biologic properties of theantibody (or antigen) itself—particularlycomplement activating capacity, Fc re-ceptor affinity, ability to form lattices, orcryoprecipitability1,12,26; (3) the mecha-nism of deposit formation—when ICsform in situ, the process usually induceslocal tissue injury, whereas passive trap-ping of ICs formed in the circulation hasnot beenwell shown to be nephritogenic(Figure 3)1,22,23; and (4) the quantity—the more deposits form, the more severethe disease.

T CellsIn addition toprovidinghelp forBcells,27

some antigen-specific CD4 T cells alone,

sensitized to either self or nonself anti-gens that are localized in glomeruli, caninduce antibody-independent tissue in-jury.28,29 Although all subsets of T cellsare now implicated in GN, includingdendritic antigen-presenting cells(DCs) and CD4 helper cells of the Th1,Th2, and T regulatory (Treg) lineages,IL17-producing Th17 cells likely ac-count for much of T cell–induced in-flammation (Figure 4).30–34 Th17 cellsare attracted by mechanisms involvingchemokines and their receptors, and re-lease cytokines such as IL9, IL17, IL21,IL22, and TNFa, which induce othercells to produce additional proinflam-matory chemokines that attract neutro-phils and monocytes and also activateresident glomerular cells.30–33,35 Th17

cells are found in renal biopsies in severalforms of human GN.36 The T cell com-ponent of the adaptive immune responseis regulated by Tregs.27

Diseases Usually Presenting as GNPostinfectious or Poststreptococcal GNThe acute, diffuse exudative and pro-liferative lesion of poststreptococcal GN(PSGN) was long regarded as the humanequivalent of the acute, one-shot serumsickness model in rabbits leading to aprolonged search for the nephritogenicstreptococcal antigen. Although manycandidate proteins have been proposed,most have failed to meet strict criteriafor causality.37–39 However, streptococ-cal pyogenic exotoxin B (SpeB) meetsmost of these criteria,37,38 although ithas not been implicated in all cases ofepidemic PSGN.40 SpeB is a small (28kD), cationic (pK 9.3) cysteine prote-ase with complement-activating andplasmin-binding properties and repre-sents 90% of the secreted extracellularprotein made in vivo by nephritogenicstrains of group A streptococci.37,38 An-tibody to SpeB correlates with disease ac-tivity in PSGN and co-localizes with IgGand C3 in subepithelial humps.37–39,41

However, the intense exudative glomer-ular inflammatory response is not wellexplained by a serum sickness analogyand humps because circulating ICsdo not form subepithelial IC depositsdirectly and subepithelial IC depositsdo not produce inflammation.22–25

Moreover, IgG is sometimes absent oris only a minor constituent of the de-posits, whereas C3 deposition oftenboth precedes and exceeds detectableIgG.42,43

Possible explanations for these appar-ent contradictions include observationsthat some subendothelial deposits arealso present in PSGN,42,43 perhaps be-cause antibody to SpeB also exhibits mo-lecular mimicry with endothelial cells.44

In addition, SpeB alone can activatecomplement directly through the MBLpathway independent of IgG.37,38 SpeBalso exhibits plasmin-binding propertiesthat facilitate complement activation andmight cause proteolysis of glomerularbasement membrane (GBM), facilitating

Figure 2. Schematic depiction of the three pathways of complement activation as theyrelate to GN. In the adaptive immune system, complement-fixing antibodies (IgG1, IgG3,IgM) in immune complexes and CRP initiate classic pathway activation through C1q, C4,and C2 to form C4b2a, the classic pathway C3 convertase. In the innate immune system,PAMPs and DAMPs activate complement through the MBL or alternative pathways. Someinfectious PAMPs and DAMPs bind MBL leading to activation of MBL-associated serineproteases (MASPs), which activate C3 via C4, C2 and the classic pathway C3 convertase. Inthe alternative pathway, direct activation of C3 occurs spontaneously (“C3 tickover”) andby foreign surfaces, damaged cells, and IgA. Cleavage of C3 produces C3b, which com-bines with factor B and properdin to form the alternative pathway C3 convertase that isregulated by factors H and I to prevent excess C3 activation. Both classic and alternativepathway C3 convertases cleave C3 leading to release of C3b, which allows C5 convertaseformation. Cleavage of C5 produces the chemotactic factor C5a and C5b, which combineswith C6, C7, C8, and multiple C9 molecules to form the lipophilic C5b-9 membrane attackcomplex that can activate resident glomerular cells to become effector cells. C5b-9 for-mation is regulated by cell-bound CRPs such as CD59.

J Am Soc Nephrol 23: ccc–ccc, 2012 Mediation of GN 3

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the transit of dissociated subendothelialICs to form subepithelial humps.37,45,46

Finally, PSGN often exhibits autoim-mune features including both IgM andIgG rheumatoid factors with cryoglobu-lin activity, antiendothelial antibodies,anti-DNA antibodies, and antineutrophilcytoplasmic antibodies (ANCA), al-though their respective roles in mediat-ing the disease, if any, remain unclear(Table 1).47–50 Other forms of postinfec-tious GN such as those associated withendocarditis, infected ventricular-atrialshunts, visceral abscesses, and Staphylo-coccus aureus infectionwith IgA depositsare clearly mediated immunologically;however, the mechanisms involvedhave been explored in much lessdetail.39,41,51,52

IgA NephropathyIgA nephropathy (IgAN) is the mostcommon form of GN worldwide and ischaracterized by focal mesangial prolif-eration and matrix expansion accompa-nying diffuse mesangial deposits of IgA,and often IgG, C3, and C5b-9, usuallyassociatedwith recurrent episodes of GNthat often immediately follow mucosalviral infections.53–57 Although assumedto be mediated by mesangial trapping ofcirculating ICs, no exogenous antigenshave been identified consistently.55,56

IgA in mesangial deposits, and in ICform in the circulation, is polymeric

(mucosal) IgA1 that exhibits deficientO-linked glycosylation at five sites inthe hinge region of the molecule.55,56,58,59

The failure to normally glycosylate IgA1can be inherited in IgA nephropathy andHenoch-Schönlein purpura,60,61 but thedefect also seems to occur epigeneti-cally.62 Underglycosylated pIgA1 is pro-duced by mucosal B cells and might alsoreach the circulation if abnormal traffick-ing of these cells to the bone marrow oc-curs.63,64 Underglycosylated IgA1 predictsprogression and exhibits altered biologicproperties compared with normal IgA1including increased tendencies to self-aggregate, unmasking of MBL bindingsites leading to complement activation,binding to other molecules like fibronec-tin, IgG, and collagen IV. In circulatingmacromolecular form, it evades removalfrom the circulation by asialoglycopro-tein and CD 89 receptors, thus facilitat-ing mesangial localization.55,56,63,65–67 Itis not yet known if lanthanic mesangialIgA deposits seen in 6%–16% of normaldonor kidneys without disease containunderglycosylated IgA.

Although IgG autoantibodies to me-sangial cell antigens have been describedin IgAN,68 Suzuki et al. were the first toreport IgG antibodies directed to crypticantigenic structures in the hinge regionof the aberrantly glycosylated IgA1 mol-ecule (antiglycan antibodies), which cor-relate with disease activity.69 Antiglycan

antibodies form ICs with underglycosy-lated IgA1 that can be passively trappedin the mesangium.56 Alternatively, whenIgG antibody binds in situ to antigenicmaterial (or IgA1) in the mesangium,70

or on the mesangial cell membrane (theantithymocyte serum model in rats71–74),the mesangial cell response to acute im-mune injury closely simulates the clinicaland histopathologic features of humanIgAN.75–77

In IgAN, mesangial cells become ac-tivated through interactions between theIgA1 deposits and IgA Fca (CD89) re-ceptors, TLRs, and transferrin receptors(TfR, CD71).78,79 TLR activation by IgAaggregates, perhaps containing or ac-companied by PAMPs, may account forthe recurrent episodes of acute injurywith hematuria, particularly those thatimmediately follow infections.55,56,80

However, most experimental and clini-cal studies suggest a role for complementas well.7,9,81,82 C5b-9 generated fromcomplement activation induced by in-teraction of IgA1 aggregates with MBL,or in situ formation of ICs by IgG anti-glycan antibodies, inducesmesangial celltransformation to a-smooth muscleactin–expressing myofibroblast-likecells, upregulates genes for collagen typeI, and increases production of cyto-kines and growth factors such as IL1,IL6, TNFa, PDGF, TGFb, EGF, FGF,CTGF, andHGF, all resulting inmesangial

Table 1. Most common complement profiles and autoimmune features in GN

Disease Serum C Profile Autoimmune Features References

Poststreptococcal GN AP or MBL normalC1q, low C3-C9

Anti-C1q, IgG AECA*, anti-DNA, ANCA, proteindisulfide Isomerase (PDI), cardiac myosin

38,44,47–50

IgAN Normal Antiglycan, endothelial cell, mesangial cell, IgG, C1q 54,56,59Anti-GBM nephritis Normal Anti-GBM, ANCA (20%), anti-C1q 87,90,94,96ANCA-positive GN Normal Anti-MPO, PR3, cPR3, NET, DNA, endothelial cell,

? LAMP2119–122,124,133,134

Lupus nephritis CP, low C1q-C9 Anti-dsDNA, annexin, MPO, PR3, nucleosome, IgG,C1q, C1s,C1-INH, C4, cardiolipin, MBL, NET,H-ficolin, C3Nef

17,171–173

MPGN I CP, low C1q-C9 Anti-C3 Nef, C4 Nef, C1q 199,282MCD/FSGS Normal None 216,246,217,215Membranous nephropathy Normal Anti-PLA2R, DNA, NEP, aldose reductase, SOD2, C1q 83,268,255,257,260,281DDD AP, normal C1q,

low C3-C9Anti-C3Nef, C4 Nef, CFH, factor B, C1q 7,198,283,284,290

C3 nephropathy AP, normal C1q,low C3-C9

C3Nef, CFH, factor B 7,286

CP, classic pathway; AP, alternastive pathway; MBL, mannose binding lectin pathway; LAMP2, lysosomal membrane protein 2.



cell proliferation and matrix expan-sion.13,14,72–74,76–79,83 The pattern ofglomerular complement deposition inIgAN includes MBL, C4d, and C5b-9(but not C1q) that co-localize with IgA1and suggests both MBL and AP ratherthan classic pathway activation.81,82,84–86

Complement deposits correlate withboth disease severity and prognosis.84–86

Rapidly Progressive, Crescentic GNAnti-GBM NephritisAnti-GBMnephritis is characterized ini-tially by an acute, focal necrotizing GNwith crescents and linear deposition ofIgG,usuallywithC3, along theGBM.87,88

When associated with pulmonary alveo-lar hemorrhage, it is called Goodpas-ture’s syndrome. The role of anti-GBMantibody deposition inducing comple-ment activation, chemotactic factor re-lease, and neutrophil-mediated injurywas defined in NTN models in the1960s,89 and the pathogenicity of humananti-GBM antibody was confirmed bythe classic primate transfer studies ofLerner et al. in 1967.90 Studies in C32/2

and C42/2 mice implicate primarily theclassical complement pathway90–92 acti-vated by IgG1 and IgG3 anti-GBM anti-body that correlates with disease activityand recurrence in transplants.87,93,94 An-tibodies with apparently similar reactiv-ity (but with lower titers, lower avidity,and primarily of the IgG2 and IgG4subclasses) can be present in healthyhumans.95

GBM antigens are also expressed inseveral extrarenal tissues where they aresequestered by an endothelial cell layerimpermeable to IgG.96 The unique fe-nestrated endothelium in glomeruli al-lows free access of IgG to GBM. TheGBM antigen itself consists of two nor-mally sequestered or cryptic epitopes,EA and EB, residing on the noncollage-nous domain of both the a3 and a5chains of the NC1 hexamer of type IVcollagen.96,97 Antibody deposition re-quires perturbation of the quaternarystructure of the a3, a4, a5NCI hexamer,possibly initiated by oxidant injury,which results in a conformational changein the a3NCI and a5NCI domains (anautoimmune conformeropathy).96,98 In

rodent models, the nephritogenic GBMantigen has been mapped to as few asthree amino acid sequences in a core res-idue,99 but both intermolecular and in-tramolecular epitope spreading occur,suggesting that immune reactivity mayextend beyond the initial inducing auto-antigen.100 Pulmonary toxins such asinfections, smoke, and volatile hydro-carbons may damage endothelium andexpose antigen in alveolar capillariesaccounting for the pulmonary manifes-tations in Goodpasture’s syndrome.87,96

Whether such extrarenal events haveany role in autoimmunization is notknown.

T cell reactivity to GBM antigens wasfirst demonstrated 40 years ago, and apathogenic role for GBM antigen-specificsensitized T cells was proposed101 butgiven little credence at the time.102 How-ever, many subsequent studies haveconfirmed these original observationswith newer technologies103 and docu-mented that nephritogenic GBM anti-gens can induce a T cell–mediated GNwith crescents, proteinuria, and decreasedrenal function in the absence of anti-GBMantibody.29,104–107 The IL23/Th17 axis iscentral to the mediation of injury in anti-GBM models.31–34,36,108 Another uniquefeature of the T cell response to GBM isthe appearance of long-lived Tregs andinversion of the T cell effector/regulatorycell ratio later in the disease that may ac-count for why recurrences of anti-GBMdisease are uncommon compared withother autoimmune glomerulonephritidesin which Treg activity is often im-paired.109,110

The anti-GBM immune response inhumans is strongly linked to HLA DRB1alleles 1501, 0701, and 0101 with 1501conferring a relative risk ratio .8,whereas 0701 and 0101 are protec-tive.109,110 Possible triggering eventsinclude preceding infections or environ-mental toxins that might expose antigenicdeterminants in extrarenal tissue. Mostpatients have anti-GBM antibodies inthe circulation that predate clinical dis-ease.111 The disease can also be inducedexperimentallywith a small nephritogenicT cell epitope, pCol28-40, from thea3NC1 domain, which exhibits molecular

mimicry with PAMPs in some Gram-negative bacteria, especially Clostridiabotulinum.112 Finally, recent studies in-dicate that glomerular-derived antigenicpeptides that enter the urine can betaken up and degraded by tubular cellsand then presented to interstitial den-dritic cells leading to induction of animmune response in regional lymphnodes.113–116 The occurrence of ANCAantibodies and signs of vasculitis inup to 20% of anti-GBM patients, andexamples of anti-GBM disease occur-ring with membranous nephropathy,suggest that some of the proposed etio-logic factors in these diseases are op-erative in anti-GBM disease as well(Table 1).111,117,118

ANCA-Associated GNNecrotizing crescentic GN without im-mune deposits, later called pauci-immuneGN, was described in 1979,119 and adecade later linked to ANCA directedagainst myeloperoxidase (MPO) andproteinase 3 (PR3).120 It is character-ized by a focal necrotizing and crescen-tic GN with large gaps in the capillarywall associated with a smoldering, ne-phritic clinical course, usually in olderindividuals whomay also exhibit extra-renal vasculitic disease.120–122 The ma-jor entities associated with ANCA andGN are granulomatosis with polyangiitis(formerly known as Wegener’s granu-lomatosis),123 Churg-Strauss syn-drome, and microscopic polyangiitis,which may be renal-limited.124 Explo-rations of how anti-MPO and PR3antibodies mediate GN without depos-iting in glomeruli have defined entirelynew paradigms of immune glomerularinjury.125–128

In vitro studies show that cytokines,released in response to infections, primeneutrophils and upregulate adhesionmolecules on neutrophils and endothe-lial cells (L and E selectins, respectively)to facilitate localization in glomerularcapillaries.129,130 Cytokine-primed neu-trophils redistribute cytoplasmic pri-mary granules containing MPO andPR3 to the cell surface where ANCAIgG binds directly or through Fc, Fab’2,or neutrophil-specific Mac-1 receptors



activating a respiratory burst with re-lease of cationic MPO and PR3 as wellas other proteases and oxidants.129–135

Neutrophil extracellular traps (NETs)are also formed containing entrappedMPO, PR3, andMPODNA in a chroma-tin web and these can mediate injury di-rectly through TLRs as well as modulatethe immune response.134,136 In ANCA-GN, NETs are present in the circulationand in glomeruli co-localized with neu-trophils and DCs, and anti-NET anti-bodies are present along with circulatingMPO-DNA complexes (nucleosomes).134

Activation of TLR2 and TLR9 exacer-bate experimental crescentic GN.136

MPO can also cause glomerular injurydirectly through oxidative mechanismsinvolving the MPO-H2O2-halide sys-tem resulting in halogenation of glo-merular structures and severe glomerularinjury.137

In 2002, Xaio et al. provided the firstcompelling in vivo evidence for ANCApathogenicity by transferring spleencells from an MPO null mouse immu-nized with murine MPO to an immuno-logically compromised host to induce aT cell–independent crescentic GN withproteinuria and reduced renal func-tion.138 Similar studies implicate animmune response to PR3 in pathogene-sis.139 Other models have utilizedtransfer of MPO+ bone marrow,140 ad-juvants that enhance the immune re-sponse and increase cytokine levels,141

and mice with subclinical GN immu-nized to humanMPO inwhich the cres-centic GN that follows is mediated bythe immune response to endogenousMPO.142 Studies of the Xaio modelconfirm neutrophil dependence and,despite the absence of antibody deposits,a requirement for alternative comple-ment pathway activation involving C5aand C5a receptors.7–10,143–147 Both al-ternative complement pathway proteinsand C5b-9 deposits are found in glomer-uli in human disease.147

Two other ANCA antigens have alsobeen studied. Lysosomalmembrane pro-tein 2 exhibits molecular mimicry withthe Fim H group of adhesins on someGram-negative bacteria and is expressedon endothelial cells and neutrophils.

Figure 3. Mechanisms of glomerular immune deposit formation. (A) Glomerular immunedeposit formation secondary topassive trappingof circulating immunecomplexes.Antigen(blue dots) antibody (green) complexes are forming in slight antigen excess. Soluble im-mune complexes formed in the circulation are thenpassively trapped in subendothelial andmesangial areasof theglomerulus,where they form lattices andenlarge tobecome immunedeposits detectable by immunofluorescence and electron microscopy. (B) Glomerularimmune deposit formation secondary to in situ formation of immune deposits. In the firstphase, cationic antigens (blue) localize independently of antibody in subendothelial ormesangial sites (larger antigens) or beneath podocytes in the subepithelial space (smallerantigens). In the second phase, free antibody binds to these planted antigens to formimmune complexes in situ. (C) Glomerular in situ immune deposit formation due toautoantibodies to normal glomerular constituents (triangles). Antigens depicted areGoodpasture’s GBM antigen (red), mesangial antigens such as annexin (green), endo-thelial antigens such as human lysosomal membrane protein 2 (brown), and podocyteantigens such as PLA2R and NEP (blue).



Lysosomal membrane protein 2 anti-bodies correlate with disease activityand induce a focal necrotizing and cres-centic GN without immune deposits inanimals.148 However, these intriguingobservations require further confirma-tion. An antibody directed against a 13amino acid sequence in complementaryPR3 (cPR3),149,150 encoded by the anti-sense strand of PR3 DNA, has been de-tected in a minority (20%) of ANCApatients.151,152 Anti-cPR3 IgG elicits ananti-idiotypic antibody response thatis reactive with native (sense) PR3, sug-gesting a role for autoantigen com-plementarity in initiating the disease.Because amino acid sequences in cPR3also have homologies with several bac-teria and viruses, this could representanother link to potentially etiologic in-fectious agents and the innate immunesystem.151 Anti-cPR3 antibodies are alsoreactive with plasminogen and delaydissolution of clots in vitro, potentially

contributing to the prominent fibrin de-position seen in ANCA GN.121

Other groups reason that the absenceof antibody deposits in ANCA-positiveGN, the limited correlation betweenANCA levels and disease activity, andthe absence of any detectable ANCA inapproximately 10%–20% of patientswith typical microscopic polyangiitis153

suggest a primary role for antibody-independent, T cell–mediated immunemechanisms.106,154–156 Consistent withthis hypothesis are persistent activationof T cells and elevation of soluble T cellproducts that correlate with disease ac-tivity,127,157,158 the prominence of tradi-tional Th1 delayed-type hypersensitivitymarkers like T cells, macrophages, fi-brin, and occasional granulomas inANCA-positive GN156 and T cell reactiv-ity to ANCA antigens in some pa-tients.159–162 T cells alone, includingTh17 cells, induce focal necrotizing andcrescentic GN when sensitized to a

planted glomerular antigen as might oc-cur with planted cationic MPO.28,161 Arecent study used combinations of miceselectively deficient in T cells, B cells, orMPO to demonstrate that active immu-nizationwith humanMPO (inmice withsubclinical glomerular injury) inducescrescentic GN without immune depositsthat requires the presence of endogenousMPO and T cell reactivity to MPO, butdoes not require B cells or anti-MPO an-tibody.142 Th17 cells and IL17a, as wellas TLRs 2 and 9, are also essential to thedevelopment of GN in a T cell–dependentmodel.136,161

Proposed etiologic agents in ANCAdisease include environmental toxinssuch as silica and infectious agents,including Gram-positive (S. aureus)and Gram-negative (Fim H adhesins)bacteria, viral infections, and severaldrugs.122,124–128 There also have been sig-nificant but low-level associations withpotential susceptibility genes and theirpolymorphisms, including ANCA anti-gens, HLA, immune response proteins,Fc receptors, cytokines and others, butno high-level associations have been de-scribed,163 other than DRB1*15 in AfricanAmericans.164 The relatively frequent ob-servation of ANCA antibodies in otherautoimmune glomerular diseases in-cluding anti-GBM disease, lupus, andmembranous nephropathy suggeststhat common etiologic or susceptibilityfactors may be present (Table 1).165–167

Lupus NephritisIn lupus nephritis, IgG, IgM, IgA (fullhouse), and C3 deposits are localizedprimarily in the mesangium in milddisease (mesangial lupus nephritis, classI and II), along the subendothelial aspectof the capillary wall with increasing pro-liferative/inflammatory lesions (focal ordiffuse proliferative lupus nephritis,class III and IV), or in the subepithelialspace with membranous lupus nephritis(class V).168,169 The autoimmune respon-ses that underlie lupus have been exten-sively studied in humans and in mousestrains that spontaneously develop thedisease and are beyond the scope ofthis review.170–173 The best-established

Figure 4. The T cell component of the adaptive immune system in GN. Antigen is pre-sented to naïve CD4 T cells by dendritic cells (signal 1). Depending on the predominatecytokine environment, T cells differentiate into CD4 T cell subsets that play different rolesin the pathogenesis of glomerular disease. In the presence of ΤGFb, Tregs develop thatmake TGFb, IL10, and CTLA4 that downregulate and control the immune response. IL12stimulates differentiation into Th1 cells that make IFNg and TNF and produce traditionalT cell/macrophage–mediated delayed-type hypersensitivity reactions. IL2, IL4, and IL13favor development of Th2 cells that make IL4, IL5, and IL13 and lead to allergic-type hy-persensitivity reactions involving IgE and eosinophils. The CD4 T cells most implicated inthe pathogenesis of GN are Th17 cells that differentiate in the presence of TGFb, IL6, andespecially IL17 and produce IL17a and IL21 that facilitate recruitment of other in-flammatory cells and can also cause tissue injury directly.



functional immune abnormalities inlupus are loss of tolerance to numerousself-antigens, B cell hyperactivity withoverproduction of autoantibodies, anddefective T cell regulation.170

The most prominent serologic fea-ture of lupus is the presence of IgGanti-double-stranded DNA antibodies(anti-DNA) in serum and in glomeru-lar deposits.170,174 The deposits are usu-ally attributed to DNA–anti-DNA ICstrapped from the circulation, althoughinfusing anti-DNA or DNA–anti-DNAICs has not achieved either significantglomerular capillary wall localization ordisease expression in vivo.22,170,175

Somemonoclonal anti-DNA antibodiesexhibit cross-reactivity with capillarywall antigens, especially laminin anda-actinin176,177 and may become inter-nalized by cells within caveola, achievenuclear localization, and directly altercell functions including apoptosis.178

Mesangial deposits have also been asso-ciated with antibody to mesangial cellannexin, which co-localizes with IgGand C3 and correlates with disease ac-tivity.179 However, most recent studiesconclude that deposited anti-DNA re-acts with extracellular DNA in theform of nucleosomes that consist ofan anionic segment of DNA woundaround a highly cationic histone core,giving the structure a net positive chargeand thereby a high affinity for glomerularanionic sites.171,172 Defective apoptosisin SLE, perhaps related to an acquireddefect in DNAse I, leads to necrosis andrelease of chromatin debris from apopto-tic blebs allowing access of nucleosomesto antigen-presenting DCs as well as en-try into the circulation.170–172,180 Cir-culating nucleosomes are abundant inpatients with lupus nephritis, antinucleo-some antibodies correlate with disease,and both are present in membrane-associated electron-dense deposits.170–172

Although this could represent an epiphe-nomenon, nucleosomes are required foranti-DNA antibody localization to occurin glomeruli.171,172 Whether they localizeinitially as free antigenic material to initi-ate in situ IC formation or are trapped aspreformed ICs is not known. Nucleo-somes exhibit several other relevant

biologic properties, including the abilityto activate dendritic cells through bind-ing to TLRs 2 and 9, and they likely di-rectly activate resident glomerular cellsthrough TLRs as well.181,182 In that ca-pacity, they may mimic infectious non-self structures to generate DAMPs thatcould lead to both loss of tolerance andlocal inflammation.182

Other non-nucleosome autoanti-bodies have also been implicated in dif-ferent aspects of the renal lesions in lupus,particularly lupus anticoagulant, anticar-diolipin, antiphospholipid, and anti-b2glycoprotein I antibodies in glomerularmicrothrombosis, as well as anti-C1qantibodies, mixed cryoglobulins con-taining rheumatoid factors, and others(Table 1).170,183,184 Recent studies inboth experimental and human lupus alsoimplicate the Th2 immune response withB cell differentiation, activation of baso-phils, and production of IgE anti-DNAan-tibodies that deposit in glomeruli.185 B cellactivating factor (BAFF or BLyS), a cyto-kine of the TNF ligand superfamily thatactivates B cells and modulates the im-mune response by inhibiting B cell ap-optosis, is increased in lupus, likelycontributes to autoantibody produc-tion, and has recently become a poten-tial therapeutic target.186

The subepithelial immune deposits inclassV (membranous) lupus nephritis169

could result from dissociation of suben-dothelial ICs with transit across GBM toreform in a subepithelial location45,46 orfrom deposition of other lupus autoanti-bodies with specificity for podocyteantigens as occurs in idiopathic mem-branous nephropathy (see below).

Complement activated by IC depositsis a major mediator of tissue injury inlupus nephritis through both intracap-illary generation of neutrophil and mac-rophage chemotactic factors (class II–IV)and formation of C5b-9 (class V).7,9,10,187

Disease severity is reduced in murinemodels that lack selected complementproteins and is increased with deficientregulatory proteins.184,187,188 Blockingstudies in murine models suggest thatthe AP of complement is more importantin mediating kidney damage than theclassic pathway.189 The observation

that deficiencies of classic pathway pro-teins C1.C4.C2 are associated withincreased risk for lupus suggests protec-tive roles for complement as well.9,10,187

For example, 90% of patients with in-herited Ciq deficiency develop lupus, andC1q is produced by dendritic cells and in-volved in tolerance induction and clear-ance of both apoptotic cells and ICs.9,10

T cells exhibit complex and abnormalphenotypes in lupus.170,171,173 ActivatedT cells are expanded, provide excess helpto B cells, localize in renal cell infiltrates,and produce IL17, which correlateswith disease activity, all implying CD4and Th17 cell involvement.170,171,190

Antigen-specific T cell reactivity to nu-clear antigens is well documented inlupus nephritis,190 and Th17 cells andIL17 are increased in human and mu-rine SLE and correlate with diseaseactivity.170,171,173,191 IL17-producing Tcells, either Th17 or CD42CD82 (doublenegative) T cells, are present in nephritickidneys, and decreasing IL17 productionimproves murine lupus nephritis.170,191

In addition to increased CD4 activityin SLE, most studies also suggest an ac-companying defect in T regulatory cellactivity.170,171,173,192

The epigenetic events that induceautoimmunity in lupus include environ-mental exposures such as ultraviolet lightand certain drugs and viral infections,especially Epstein–Barr virus.170–173

Some of these interact with the immunesystem through inhibition of DNAmethylation, which can lead to over-expression of some genes resulting inhypomethylated CD4 cells, overpro-duction of some cytokines and Mdm2,and overproduction of IgG by B cells.193

There also are sufficiently well estab-lished co-occurrences of lupus nephritiswith other GNs, includingANCA-positiveGN,166 IgA,194 membranous nephropa-thy,169 and even a minimal change-likepodocytopathy195 to suggest commonetiologic factors (Table 1).

Type I Membranoproliferative GNType I membranoproliferative GN(MPGN I) has many clinical and patho-logic similarities to a renal-limited lupus



nephritis, including frequent autoanti-bodies such as rheumatoid factors andantinuclear, anticardiolipin, anti-C1q,anti-C3 convertase (C3Nef), and anti-endothelial antibodies (Table 1).196–199Hy-pocomplementemiawith a classic pathwayprofile, and increased disease susceptibilityin the presence of C2 and C4 deficiency, isalso common to both entities.7,9,10,188,200

The histologic features of capillary wallthickening, cellular proliferation, and infil-trating inflammatory cells associated withprimarily mesangial and subendothelialdeposits of IgG, IgM, and C3 are similarto lupus nephritis and are also seen in avariety of chronic neoplasias (especiallymonoclonal gammopathies), infections,and other autoimmune processes.196–199,201

However, in contrast to lupus, MPGN Iin adults is seen almost exclusively(.90%) in association with hepatitis Cviral (HCV) infection, and the glomerulardeposits often have prominent ultrastruc-tural features of cryoglobulins.202–204

The principal nephritogenic HCVantigen seems to be non-envelopedHCV E2 core protein, which is demon-strable in circulating ICs and in glomer-ular deposits.205–207 IgG3 antibodybound to HCV E2 can interact with theglobular domain of C1q, engage B cellsthrough both B cell receptors and TLR7,and elicit production of monoclonalIgMk antibody to polyclonal anti-HCVIgG (rheumatoid factor).196–199,208 Thesesoluble, but cryoprecipitable, aggregatesof IgG, IgM, viral proteins/nucleic acids,and C1q constitute the mesangial andsubendothelial immune deposits foundin glomeruli and cause local inflammationthrough direct interaction with TLRs 3, 7,and 9 on both infiltrating inflammatorycells and/or resident glomerular cells aswell as by inducing more classic pathwayC activation.196–198,209–213 As in lupus, thesubepithelial deposits often seen inMPGNI (and sometimes referred to as type IIIMPGN) may represent subendothelialdeposits that dissociate and reform insitu or autoantibodies to as yet uniden-tified podocyte antigens.45,46

As in lupus, complement likely playsboth nephritogenic and protective rolesinMPGNI.C1q seems tobe important inmediating the initial interaction between

IgM, IgG, HCV complexes, B cells, andTLRs,196,197,212 and complement activa-tion by immune deposits through theclassic pathway likely aggravates tissueinjury,7,10 although overexpression of acomplement regulatory protein, Crry,in a well studied murine model did notsignificantly ameliorate the disease.214

The roles of CD4 effector cells and Tregsin MPGN I are not yet well defined ineither animal models or in humans.

Diseases That Usually Present withNephrotic SyndromeMinimal Change Disease/IdiopathicFSGS SpectrumThere aremany clinical and pathogeneticobservations in minimal change disease(MCD)andidiopathicFSGS,whichsuggestthat they may represent different points onthe same disease spectrum. Some patientswithMCDare steroid resistant anddevelopFSGS, whereas some patients with biopsy-documented FSGS are steroid responsiveand behave like MCD.215–217 Both can betriggered by multiple initiating events, in-cluding infections, drugs, malignancies,and others.215–217 Both are diseases of thepodocyte that have been associated withcirculating permeability factors,215,217–220

can recur immediately in transplants,221,222

and can resolve when affected kidneysare placed in normal environments.223

Thus, differences in disease phenotypeand clinical expression could reflect varia-tion in the quantity of a commonmediatoror group of mediators.

Alternatively, mutations or epigeneticdifferences in podocyte genes that alterresponse to, or recovery from, such cir-culating mediators might also accountfor differences between MCD and FSGS.Mutations in podocyte genes that regu-late the slit diaphragm, cell membrane,and cytoskeleton are increasingly recog-nized, not only in FSGS but in otherformsofGNaswell.224AfricanAmericanswith nondiabetic nephropathy express var-iants in the gene encoding APOL1.225–229

Both clinical and experimental studiesdocument the importance of severalother genes, especially ones that regu-late the podocyte actin cytoskeleton,in modulating the development of pro-teinuria, foot process effacement, and

sclerosis, including RhoA, urokinasereceptor, Pdlim2, and connective tissuegrowth factor.230–234 Experimentally,podocyte expression of angiopoietin-like-4 is upregulated in experimentalMCD and responds to steroids.235 Al-ternatively, the possibility that MCDand FGS could involve entirely differ-ent pathogenetic mechanisms actingon normal podocytes has not beenexcluded.

Some evidence suggests that bothMCD and idiopathic FSGS reflect theeffect on podocytes of circulating, per-haps T cell–derived, non-IgG perme-ability factors,215,217–220 as suggestedfirst by Shalhoub in 1974.218 Studies byMcCarthy et al. demonstrate a factor inthe serum of patients with recurrentFSGS that alters the albumin reflec-tion coefficient of normal glomeruli invitro.220 In MCD, Koyama et al. showedthat factors secreted by T cell hydridomasderived from patients with active MCDtransfer a MCD-like lesion to normalrats.219 Despite these in vitro and in vivoobservations, identification of the re-sponsible factor(s) has proven frustrat-ingly elusive.220 Many cytokines andother mediators—including hemopexin,soluble podocyte urokinase receptor,TNFa, IL13, angiopoietin-like 4, andcardiotrophin-like cytokine 1—are in-creased in patients with MCD or FSGSand several also increase glomerular al-bumin permeability in vitro.231,236–238

Soluble urokinase receptor has been im-plicated in activating podocyte b3 integ-rins leading to FSGS,231 and mountingevidence suggests that increased plasmalevels of soluble podocyte urokinase re-ceptor mediate proteinuria in both activeand recurrent FSGS (but not MCD)through a similar integrin-related mecha-nism.230 Neutralization of cardiotrophin-like cytokine 1 reduces permeability factoractivity in FSGS serum as does galactoseand normal serum and urine.215–217

Human studies document Th2 polar-ization and elevated levels of IL13, a Th2cytokine with podocyte receptors, inactive MCD.236,237 IL13 alters podocytefunction238,239 and overexpression ofIL13 induces albuminuria and foot pro-cess effacement.240 Transfer of CD34+



stem cells from patients with activeMCD also transfers proteinuria andcauses podocyte foot process efface-ment, although the responsible factoris unclear.241 CD80 (B7.1) is a T cellco-stimulatory molecule involved in an-tigen processing that is also expressed onpodocytes. Podocyte CD80 activationthrough TLR 3 and 4, independent ofT cells, causes proteinuria and foot pro-cess effacement.242,243 Recent studies byGarin et al. document increased levels ofCD80 in podocytes and in urine in activeMCD, but not FSGS,244 although mea-surement of urinary mRNA encodingCD80 demonstrates higher levels inFSGS than in MCD.245 CD80 also func-tions as an inhibitorymolecule in T cell–DC interaction and is downregulated byCTLA4, which is decreased in both se-rum and urine in active MCD.244 Thus,an initiating event, or first hit, such as aninfectious process, might lead to activa-tion of podocyte CD80 by IL13 or TLR 3or 4 ligands leading to actin rearrange-ment and albuminuria with CD80 shed-ding in the urine.245–247 The second hitwould involve defective CD80 regula-tion by either Tregs or podocyte-derivedCTLA4.246 Podocyte overexpression ofangiopoeitin-like-4, which, like CD80, isincreased in serum and podocytes inMCD patients, induces a steroid-sensitiveMCD-like glomerular lesion with heavyproteinuria, suggesting a role for thismol-ecule in the podocyte response.235 Finally,recent studies also suggest a role for pari-etal epithelial cells in formation of scle-rotic lesions.248,249

Membranous NephropathyIdiopathic membranous nephropathyis a noninflammatory glomerular lesionwith exclusively subepithelial deposits ofIgG and complement and heavy pro-teinuria.250,251 Heymann nephritis is arat model that closely mimics the humandisease.252 Studies in both active andpassive Heymann nephritis modelsshow that IgG antibodies form subepi-thelial immune deposits in situ by bind-ing to a podocyte protein complex nowcalled megalin,18,19,253 and that protein-uria is mediated by sublytic C5b-9 attack

on podocytes.1,2,83 Sublytic C5b-9 acti-vates several signaling pathways, altersthe actin cytoskeleton, and upregulatesexpression of TGFb and TGFb receptorsand matrix production leading to GBMthickening and spike formation. In-creased podocyte production of oxidantsand proteases damages underlying GBMleading to proteinuria.83 C5b-9 alsoleads to podocyte DNA damage and im-paired ability to complete the cell cycle,which may contribute to apoptosis, po-docytopenia, shedding of podocytes inthe urine, and development of glomeru-lar sclerosis.254

Proof of principle that membranousnephropathy in humans can also resultfrom an analogous autoimmune mecha-nism was first provided by Debiec et al.,who reported alloimmunization of an in-fant to neutral endopeptidase (NEP) ex-pressed on podocytes, resulting from amaternal NEP deficiency, which led totransplacental transfer of anti-NEP IgGand typical membranous nephropathy inthe newborn.255 However, the anti-NEPmechanism is not operative in most casesof adult idiopathic membranous ne-phropathy.256 Recently, Beck et al., usingmicrodissection and proteomic technol-ogy, identified another antipodocyte auto-antibody directed against the M-typephospholipase A2 receptor (PLA2R) in70%–80%of patients with primarymem-branous nephropathy and showed thatIgG anti-PLA2R was present in the glo-merular deposits and correlated withdisease activity, response to therapy, andrecurrence in transplants.257,258 Othershave confirmed these findings.259,260 An-tibodies reactive with aldose reductaseenolase and SOD as well as PLA2R havealso been eluted from membranous glo-meruli, but thesemay represent secondaryphenomena related to oxidant stress ratherthan primary pathogenic mediators.259

Whether the role of C5b-9 in medi-ating proteinuria as established in Hey-mann nephritis, and in the chronicserum sickness models of membranousnephropathy as well,261,262 mediates po-docyte injury and proteinuria in humanmembranous nephropathy is unclear.Complement-independent mechanismsof proteinuria are also well described

with IgG antipodocyte antibodies in sev-eral models,263–265 including Heymannnephritis,266,267 although these modelsdo not exhibit the prominent C3 andC5b-9 deposits seen in the complement-dependent Heymann models and inhumans.268,269 Despite the prominentcomplement deposition in membra-nous nephropathy, deposited anti-PLA2R antibody is predominately ofthe poorly complement-fixing IgG4 sub-class, although complement activationmight be induced by the lesser quantitiesof IgG1 and IgG3 usually present as occurswith anti-NEP IgG.256 However, in bothhuman membranous nephropathy andHeymann nephritis, classic complementpathway components are often absent inglomerulardeposits.269 Preliminary studieshave reported that IgG4 anti-PLA2Rbound to podocytes can activate C via theMBL pathway and induce sublytic podo-cyte injury analogous to the mechanismsdefined in the Heymannmodels in rats.270

Membranous nephropathy can spon-taneously remit,271 but once developed,the glomerular lesion heals very slowlyresulting in persistent proteinuria forweeks or months after the immune re-sponse has abated and subepithelialdeposits no longer are forming.272 Thislikely explains why only 70%–80%of pa-tients with proteinuria and membra-nous nephropathy on biopsy have activedisease as defined by elevated anti-PLAR2 levels.257,258 Glomerular deposi-tion of C3c and urinary excretion ofC5b-9 have both been established exper-imentally as valid biomarkers of ongoingimmune deposit formation in membra-nous nephropathy,272,273 but theseshould soon be supplanted by directmeasurements of anti-PLA2R antibodyin serum,274 which correlates with dis-ease activity and response to therapy.275

Although a role for cytotoxic T cells isproposed in complement-independentmodels of Heymann nephritis,276,277 Tcells do not have access to podocytes orthe subepithelial space and are rarely seenin most Heymann nephritis models orhuman membranous nephropathy.269,278

No systematic studies of the role of T cellsin human membranous nephropathyhave been reported.



Noetiologicagentshavebeen identifiedconsistently in idiopathic membranousnephropathy. However, a genome-wideassociation study reports very strongassociations with single nucleotide poly-morphisms in genes that encode forHLA-DQA1 and PLA2R.279 Whetherthese associations relate to renderingPLA2R antigenic or to altering its ex-pression by podocytes is unclear.

Anumberof potential etiologic agentshave been identified in secondary formsof membranous nephropathy, includinghepatitis B and C virus infection, severaldrugs, exposure to environmental toxinssuch as hydrocarbons, formaldehyde, cat-ionic BSA in cows’ milk (in infants),280

and solid organ tumors.269 Although30% of patients with tumor-associatedmembranous were found to be positivefor anti-PLA2R in one study,281 these sec-ondary forms of membranous nephropa-thy, including class V lupus membranousnephropathy, have generally not been as-sociatedwith anti-PLA2R, and their path-ogenesis remains unknown.

C3 GlomerulopathiesDense Deposit DiseaseDense deposit disease (DDD) has beenreferred to as type II MPGN because aminority of cases resemble MPGN I bylight microscopy and can have a similarnephritic/nephrotic clinical presenta-tion.199,282–284 However, DDD lacks Igdeposits and has little pathogenic over-lap with adult MPGN I, which is an im-mune complex disease. DDD is now bestviewed as a C3 glomerulopathy, a formof GN characterized by deposits of com-plement without Igs and usually associ-ated with abnormalities in complementregulation.285,286 DDD is a disorder ofalternative complement pathway regula-tion characterized by linear depositionof alternative pathway and terminalcomplement proteins including C5b-9,without IgG, along the contours ofribbon-like intramembranous electron-dense deposits within GBM and in themesangium (mesangial rings).282–284,287

The complement profile in serum and inglomerular deposits reflects alternative, orMBL, pathway activation.7–10,198,199,282–284

Normally, low-level spontaneous

hydrolysis of C3 to produce C3b leadsto formation of the alternative pathwayC3 convertase, C3bBb,which then cata-lyzes more C3 activation (C3 tickover).C3bBb is tightly regulated by circulatingcomplement factor H (CFH), whichbinds the active Bb site on the convertaseto impair degradation of the enzymeand prolong its half-life, leading to hy-percatabolism of C3.7–10,198,282–284,288

Over 80% of DDD patients have an IgGautoantibody to the Bb active site of thealternative pathway C3 convertase (C3nephritic factor, C3Nef) exposed afterinteraction of factor B with C3b thatprevents normal CFH binding.282–284

However, DDD can also be associatedwith other loss of CFH function condi-tions independent of C3Nef, includingcongenital absence or single nucleotidepolymorphisms of CFH, neutralizationby an anti-CFH antibody288–290 or anti-body to factor B,291 and, less commonly,with gain in function mutations in C3that lead to C3 convertases resistant toCFH regulation.284 In mice, CFH defi-ciency induces massive complement ac-tivation and a DDD phenotype that isameliorated by administration of CFHor properdin.292,293 Chronic unregu-lated C3 activation generates a varietyof alternative pathway complement acti-vation products that accumulate, per-haps by charge interactions, along theinner GBM to form the classic densedeposits seen by electron micro-scopy.284,287,290 In turn, this accumula-tion of proteinsmodifies filtration barrierstructure and integrity, leading to pro-teinuria and nephrotic syndrome. DDDis associated with other similar disordersof complement regulation such as par-tial lipodystrophy, but no specific etio-logic factors have been identified.

C3 NephropathyGlomerular deposits of C3 without Igalso characterize another C3 glomeru-lopathy variant, sometimes termed C3nephropathy or C3 deposition glomeru-lopathy; however, the electron-dense de-posits are primarily at mesangial andsubendothelial sites rather than withinGBM.7,285,286 These lesions also may beassociated with a spectrum of histologic

abnormalities including MPGN I–likefindings.285,286 The disorder seems toaffect younger patients who often havehematuria and proteinuria but less com-monly exhibit hypocomplementemia,nephrotic syndrome, or progression com-pared with DDD.288 Evidence of disor-dered complement regulation in theform of either mutated CRPs (H402 alleleof factor H, factor I), anti-CFH or anti-factor B antibodies, or C3Nef is also pres-ent in most of these patients.285,286,288–291

A familial form of the disease in peopleof Cypriot origin due to mutations inCFHR (CFHR5nephropathy)has recentlybeen described.294 The composition of thedeposits and the reason for their differentdistribution compared with DDD are notknown, although studies in murine mod-els of MPGN suggest that abnormalitiesin complement factor I may play a role.295

OVERVIEW OF IMMUNEMECHANISMS

Recent advances in understanding thepathogenesis of immune glomerulardiseases now link infectious processes,especially chronic viral ones, with auto-immunity andGN.Although once viewedprimarily as human equivalents of theantibody-mediated serumsickness (IC)orNTN (anti-GBM) models of GN in ani-mals, most human glomerulonephritidesare now believed to be primarily autoim-mune diseases. They involve both innateand adaptive immune mechanisms, withdistinction between the two becomingincreasingly blurred, andT cell aswell asantibody-driven adaptive immune re-sponses (Figures 1 through 4). Links toetiologic infectious agents more likelyproceed through recognition of PAMPsby TLRs and triggering of autoimmuneprocesses than through direct effects ofICs containing exogenous antigens trappedfrom the circulation.However, progress intranslating these scientific advances tobetter therapies has been slow, and clini-cians currently still rely almost entirely oncorticosteroids and toxic, nonselectiveimmunosuppressive agents for treatment.

As the relevant sciences have evolved,three things have remained constant—the



patients, the utility of well character-ized animal models of their diseases, andthe contributions of physician-scientistswho have accounted for most of the ad-vances described above. The patients andthe animal models will remain and thetechnology to study them will advancedramatically in the years ahead. However,the future supply of qualified physician-scientists is threatened. In closing, it isworth noting that continued progress inthis area will require the continuous avail-ability anddedication of investigators whofully understand both the tools of basicscience and the clinical and pathologicmanifestations of human renal diseases,for knowledge of both will be requiredto generate and test new hypotheses thatcan lead to improvements in therapy. Per-haps this review can serve as an encourage-ment to some whomight follow that path.

ACKNOWLEDGMENTS

The author thanks Michael Carey, whose

willingness to undergo untested therapies for

his Goodpasture’s syndrome in 1966 ignited

my initial interest in immunologic glomer-

ular diseases; Edmund Lewis, who nurtured

and expanded that interest; and several for-

mer fellows and colleagues who have pro-

vided continuous intellectual and scientific

stimulation to understand more—particularly

David Salant, Kline Bolton, Rick Johnson, and

Masaomi Nangaku.

DISCLOSURESNone.

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