complement regulators and inhibitory

7/27/2019 Complement Regulators and Inhibitory

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Complmnt i on of th firt lin of dfnc in innatimmnity and i important for clllar intgrity, ti- homotai and modifying th adapti immnrpon13. Th actiatd complmnt ytm rcog-niz and liminat inading microorganim andth i nficial for th hot4,5. In addition, compl-mnt facilitat th limination of dad or modifid lfcll, ch a apoptotic particl and clllar dri 6,7.Th altrnati pathway of complmnt form a pon-tanoly and contantly actiatd immn rillancytm8,9. Th indiidal complmnt raction dlopin a qntial mannr, allowing rglation that mod-lat th intnity of th rpon and adjt th ffctorfnction for th pcific immn rpon.

Complmnt wa idntifid mor than 100 yarago a a rlt of it complmntary actricidal acti-ity and it rol in phagocytoi of clllar dri 10,11.Th actiatd complmnt ytm dirct immnffctor fnction and modlat th intnity of thrpon in a lf-controlling mannr. Thi allowfor th appropriat innat immn rpon, whichi ndd for rcognition and rmoal of infctio

agnt or modifid lf cll6,12. Now, 110 yar aftrth initial rport, th cntral rol of thi ytm inimmn dfnc i mch ttr known: many of thiological ffct of complmnt action ar ndr-tood in molclar trm and a rol for complmntin ti homotai i mrging. Complmnt acti-

ation in trn act iat pro-inflammatory mdiator,gnrat anaphylactic pptid, cytolytic compondand antimicroial compond, rcrit ffctor cll andindc ffctor rpon13,14. Th rlt in a modr-at and controlld otcom of complmnt actiation,which i nficial for th hot t dtrimntal for thinading microorganim15,16.

Th nficial apct of a modratly actiatd com-plmnt ytm incld immn rillanc, rmoalof clllar dri, organ rgnration and nroprotc-tion. Th two anaphylatoxin complmnt componnt 3a(C3a) and C5a ha a rol dring organ rgnration17,in nroprotction18 inclding in migration of n-ron19 and ynap limination20 and in th rlaof prognitor hamatopoitic tm cll21. In addition,crotalk and cooprati ffct twn C3a rcptor(C3aR), C5aR, C5a rcptor-lik 2 (C5L2) and Toll-likrcptor ha n rportd22. Th additional phyi-ological fnction highlight th rol of complmntin phyiology and homotai and dmontrat thatappropriat rglation and alancd or targtd actia-tion ar crcial to kp th complmnt ytm in itpropr phyiological tat.

Thi Riw foc on th complmnt rglatorthat modify and control th complmnt ytm. Whighlight th mchanim of complmnt control on dif-frnt iological rfac, ch a intact lf cll, whichact a non-actiator rfac, and modifid lf cll andmicroial cll rfac, which act a actiator rfac.

The complement cascade

Complement activation, amplification, progression

and regulation.Complmnt actiation occr in aqntial mannr and can diidd into for maintp: initiation of complmnt actiation, C3 conr-ta actiation and amplification, C5 conrta actia-tion, and trminal pathway actiity or th amly ofth trminal complmnt complx (TCC; alo knowna MAC) (FIG. 1). Onc actiatd, th complmnt ca-cad gnrat ffctor compond that ar dlirdto any rfac in an indicriminat mannr. Howr,progrion of th cacad and th action of th ffctor

*Department of Infection

Biology, Leibniz Institute for

Natural Product Research

and Infection Biology,

Beutenbergstrasse, 11a,

07745 Jena, Germany.Friedrich Schiller University,

Frstengraben 1, 07743

Jena, Germany.

Correspondence to P.F.Z.

e-mail:

[email protected]

doi:10.1038/nri2620

Puishd onin

4 Sptmr 2009

Complement regulators and inhibitoryproteinsPeter F. Zipfel* and Christine Skerka*

Abstract | The complement system is important for cellular integrity and tissue homeostasis.

Complement activation mediates the removal of microorganisms and the clearance of

modified self cells, such as apoptotic cells. Complement regulators control the spontaneously

activated complement cascade and any disturbances in this delicate balance can result in

damage to tissues and in autoimmune disease. Therefore, insights into the mechanisms ofcomplement regulation are crucial for understanding disease pathology and for enabling the

development of diagnostic tools and therapies for complement-associated diseases.

R E V I E W S

NATuRe RevIeWs |Immunology vOLuMe 9 | OCTObeR 2009 |729

2009 Macmillan Publishers Limited. All rights reserved
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|

Alternative pathway

Inflammation

Opsonization

Terminal complement complex (lysis)

C3a Initiation

b C3 convertase

c C5 convertase

d Terminal pathway

C3C4 and C2

C3b

C3bBbC3b C4bC2bC3b

C5bC9

C3a

C5a

C3bBb C4bC2b

C1

MASP

Classical pathway Lectin pathway

C5b

C5

Zymogen

An inactiv pr-form of

a protas that y itsf acksprotoytic activity. Upon

procssing or protoytic

cavag th protin dispays

nzymatic activity. Using such

inactiv pr-forms aows

targting of protin activity to

th right pac at th right tim.

Most compmnt protins,

ut aso componnts of th

coaguation cascad and othr

protass, xist and circuat as

inactiv pr-forms and rquir

modification and protoytic

procssing to convrtd

into an activ form.

molcl ar trictly controlld at ach ll y mltiplcomplmnt rglator and inhiitor. Th rglator

dicriminat twn lf and non-lf rfac, ch acll inclding modifid lf cll ti and infc-tio agnt79,15. sch rglator and inhiitory circitoprat at ry ll of th cacad and ar thrforcntral to ndrtanding complmnt action.

Th complmnt ytm conit of a t of inacticomponnt that ar linkd and actiatd in a cacadingmannr. Whn thy ncontr a iological rfac, thinacti zymogns ar trctrally modifid, amlwith additional componnt and ar conrtd to ffctorcompond or acti nzym that actiat nw trat and o th cacad progr. Th firt nzymatic rac-tion, which actiat C3 conrta, ar tightly controlld

to nr that actiation and gnration of iologicallyacti ffctor compond occr only at th appropri-at tim and it. If th actiation cacad progr,th raction ar amplifid and can rlt in potnt andpowrfl ffctor fnction. Th complmnt ytm hamor than ixty componnt and actiation fragmnt,which compri th nin cntral componnt of th ca-cad (C1 to C9), mltipl actiation prodct with diriological actiiti (for xampl, C3a, C3, iC3, C3d andC3dg)12,23, rglator and inhiitor (ch a factor H, fac-tor H-lik protin 1 (FHL1), complmnt factor H-rlatdprotin 1 (CFHR1), CR1 (alo known a CD35), C4-inding protin (C4bP), C1q anditronctin), protaand nwly amld nzym (for xampl, factor b,factor D, C3b and C4C2) or rcptor for ffctormolcl (ch a C3aR, C5aR, C5L2 and complmntcomponnt C1q rcptor (C1qR)) (TAble 1). Th nmrof known componnt of th ntwork, particlarly thrglator and rcptor, i continoly incraing andnw fnction for th protin ar ing idntifid.

Initiation of complement activation. Complmnt i acti-atd y thr major pathway. Th altrnati pathway ipontanoly and contantly actiatd on iological r-fac in plama and in mot or all othr ody flid 24. Thipontano actiation radily initiat amplification8.Th claical pathway i triggrd y an antiody ondto th targt antign25, t thi pathway can alo acti-

atd in an antiody-indpndnt mannr y ir andGram-ngati actria. Th lctin pathway i initiatdy carohydrat on microial rfac26,27. Actiationof ach of th pathway rlt in amly of th firtnzym of th cacad, which i trmd C3 conrta(FIG. 1). Complmnt i alo actiatd y an additionalypa pathway that act indpndntly ofC3 or ypath C3 conrta and i mdiatd y thromin actingon th C5 conrta28.

C3 convertase and amplification. Th conrta for thaltrnati pathway (C3b) i formd y C3 and fac-tor b, whra th conrta for th claical and lctinpathway (C4C2) i compod ofC4 and C2. bothconrta cla C3 to C3a and C3. C3a aid in thrcritmnt and actiation of innat immn ffctorcll and alo ha antimicroial and antifngal actiity29.If actiation progr, C3 i dpoitd clo to th itof gnration and, on formation of rfac-ond con-

rta, amplifi th cacad13,30. Th C3 fragmnt alo

coat microial or apoptotic rfac and mark th par-ticl for phagocytoi. On th rfac mmran of intactlf cll, C3 dpoition i prntd y rglator andfrthr progrion i lockd; y contrat, on microialrfac or on modifid lf cll actiation can progr.Howr, pathognic microorganim and apoptoticcll acqir oll rglator, which lock progr-ion of th cacad yond th ll of C3 conrta.C3 opsonizs th iological rfac, which ar thnclard y phagocytoi in a non-inflammatory mannr.Intrtingly, imilar or rlatd mchanim ar d forth non-inflammatory rmoal of modifid lf particland for attack and rmoal of microorganim.

Figure 1 | Cpt: a ctra iriac t. Complement is acentral defence mechanism of innate immunity and is activated in a tightly regulated

manner.a | Complement is initiated by three major pathways. The alternative pathway is

spontaneously and continuously activated. The classical pathway is induced when

antibodies bind to their corresponding antigen. The lectin pathway is triggered by the

binding of mannan binding lectin (MBL; also nown as MBP-C) to mannose residues on the

surface of microorganisms. This activates the MBL-associated proteases mannan-binding

lectin serine protease 1 (MASP1) and MASP2, which then cleave C4 and C2. b | Complement

activation occurs in a sequential manner. The three pathways initiate the formation of

enzymes nown as complement component 3 (C3) convertases (C3bBb for the alternative

pathway and C4bC2b for the classical and lectin pathways). These enzymes cleave the

central complement component C3 and generate the anaphylactic and antimicrobial

peptide C3a and the opsonin C3b, which can be deposited onto any nearby surface. This

activation is followed by an amplification reaction that generates additional C3 convertases

and deposits more C3b at the local site. Subsequently, C3b is inactivated and sequentially

degraded and the various degradation products mediate important effector functions.For example, C3b deposition on a surface results in opsonization, which allows for the

interaction of C3b with specific host C3 receptors expressed on the surface of immune

effector cells. c | If activation progresses, a new enzyme, the C5 convertase (C3bBbC3b for

the alternative pathway and C4bC2bC3b for the classical and lectin pathways), is generated.

C5 convertase cleaves C5, releases the potent anaphylactic peptide C5a and generates C5b.

d | C5b can initiate the terminal pathway , which recruits the components C6, C7, C8 and

C9 to the surface of the target and inserts the C9 complex as a pore (termed the terminal

complement complex) into the membrane. The activated complement system generates

multiple effector compounds that drive and orchestrate further immune reactions.

R E V I E W S

730 | OCTObeR 2009 | vOLuMe 9 www.atr.c/riw/i

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Table 1 |Complement regulators and receptors for effector proteins

Ratr Atratia

Pit facti

liad C rfac bidi rxpri

Fcti Rf

Soluble regulators and effectors

Factor H None Alternativepathway

C3b and C3d Acquired to surface Cofactor for factor I and accelerationof alternative pathway C3convertase decay

53

FHL1 None Alternativepathway

C3b Acquired to surface Cofactor for factor I and accelerationof alternative pathway C3convertase decay

54

Properdin None Alternativepathway

C3 Binds to apoptotic surfaces Stabilization of alternative pathwayconvertases

55,66

Carboxy-peptidase N

Anaphylatoxininactivator

Classicalpathway andlectin pathway

C3a, C4a andC5a

NA Inactivation of anaphylatoxins C3aand C5a

56,57

C4BP None Classicalpathway andlectin pathway

C4 Acquired to surface Cofactor for factor I and accelerationof classical pathway C3 convertasedecay

59

C1q None Classicalpathway

IgG and IgMimmunecomplexes

Binds to apoptotic surfaces Activation of the classical pathway 60

C1INH None Classicalpathway andlectin pathway

C1r, C1s andMASP2

NA Blocs serine protease and is asuicide substrate for C1r, C1s,MASP2, coagulation factors and C3b

58

CFHR1 None Terminalpathway

C5 convertaseand TCC

Acquired to surface Inhibition of C5 convertase and TCCassembly

62

Clusterin SP-40,40 andapolipoprotein J

Terminalpathway

C7, C8, C9and TCC

NA Transport of cholesterol, HDL,APOA1 and lipids

61,64

Vitronectin S-protein Terminalpathway

C5b-7 and TCC NA Adhesion protein, fibronectin-mediated cell attachment andArg-Gly-Asp site coagulationin immune defence againstStreptococcusspp.

63

Surface bound regulators and effectors

CR1 CD35 andimmuneadherencereceptor

C3 C3b, iC3b, C4band C1q

Many nucleated cellsand erythrocytes, B cells,leuocytes, monocytes andfollicular dendritic cells

Clearance of immune complexes,enhancement of phagocytosis andregulation of C3 breadown

68

CR2 CD21 andEpsteinBarrvirus receptor

C3 C3dg, C3d andiC3b

B cells, T cells and folliculardendritic cells

Regulation of B cell function, B cellco-receptor and retention of C3dtagged immune complexes

69,70

CR3 MAC1,CD11bCD18and M2integrin

C3 iC3b and factorH

Monocytes, macrophages,neutrophils, natural iller cells,eosinophils, myeloid cells,follicular dendritic cells, CD4+T cells and CD8+ T cells

iC3b enhances the contact ofopsonized targets, resulting inphagocytosis and adhesion by CR3

76

CR4 CD11cCD18andX2 integrin

C3 iC3b Monocytes and macrophages iC3b-mediated phagocytosis 77

CRIg VSIG4 C3 C3b, iC3b andC3c Macrophages iC3b-mediated phagocytosis andinhibition of alternative pathwayactivation

74

CD46 MCP C3 C3b and C4b All cells except erythrocytes C3 degradation, cofactor for factor Iand factor H, and effector for T cellmaturation

67,72

CD55 DAF C3 C4b2b andC3bBb

GPI anchor expression bymost cell types, includingerythrocytes, epithelial cellsand endothelial cells

Acceleration of C3 convertase decay 67,72

CD59 Protectin TCC C8 and TCC GPI anchor expression byerythrocytes and mostnucleated cells, includingrenal cells

Inhibition of TCC assembly andformation

73

R E V I E W S




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Opsonization

Th dposition of activation

products, for xamp th C3

activation fragmnt C3, on

th surfac of a targt to

mark th targt and faciitat

and nhanc rcognition and

uptak y phagocytic cs.

Phagocytosis iminats th

partic from th circuation

and aids in its dstruction.

C5 convertase. If th actiation cacad i allowd toprocd yond th claing of C3 into C3a and C3,an additional C3 molcl ind to th C3 conrta.Thi gnrat C3bC3, th C5 conrta for thaltrnati pathway, or C4C2C3, th C5 conrtafor th claical and lctin pathway31. both nzymcla C5 to C5a and C5. C5a i a powrfl anaphy-lactic pptid and th C5 fragmnt can initiat thtrminal pathway32(FIG. 1). Th C5a-indcd inflamma-tion and th C5-initiatd trminal pathway m to paratly rglatd33.

The terminal pathway. Th C5 fragmnt ond toth acti conrta initiat th trminal pathway,which rlt in dirctd, non-nzymatic amly ofth trminal pathway componnt C5, C6, C7, C8 andC9, which form th TCC. Th amly and confor-mational chang of th oll, hydrophilic protingnrat lipophilic, mmran-inrting complx.ultimatly, formation of a TCC lad to por forma-tion and cll lyi3436. Additional fnction for TCCcomponnt ha alo n rportd. Th incldtimlating actiity in T hlpr cll polarization, a rolfor mmran-ond C7 a a ink for th lat compl-

mnt componnt to control xci oll TCC-indcd inflammation and a rol for th oll TCCin platlt-actiating actiity3739.

Complement: a double-edged sword

Complmnt i important for th claranc of infctioagnt, t pathogn a nmr of aion tratgito modify and lock complmnt actiity. Mot patho-gn xpr rfac protin that ind to hot compl-mnt rglator or rcrit complmnt inhiitor andth lock or intrfr with complmnt ffctor fnc-tion. sch rfac-ond hot rglator dlay or nlock protcti hot innat immn rpon that

wold othrwi liminat th infctio agnt and kpth hot organim intact. Howr, a priting pathogntriggr additional immn raction. Th, dring aninfction y a pathogn, complmnt i indcd locallyand thi local complmnt actiation alo attack hotytandr cll at th it of infction. In thi itation, anattackd hot cll rqir maximal protction and nmro aailal rglator to nr rial. so, thhman complmnt ytm maintain a dlicat al-anc twn actiation and inhiition to allow actia-tion on forign or modifid lf rfac and protction oflf. Thi xplain why th rglation of complmntactiation i crcial for homotai.

Protection of self cells. Th action of complmnt ffc-tor molcl i lockd on th rfac of intact hotcll and iommran40,41 y a comination of intgralmmran, rfac-attachd and flid-pha rglator.Th concrtd action of rglator and inhiitor nrcll and ti intgrity(FIG. 2).

Dyrglation of th complmnt cacad rlt inimmnopathology and atoimmn dia. Mtationin th gn ncoding indiidal rglator can rlt indfcti control and inappropriat dliry of compl-

mnt actiation prodct onto th rfac of hot cll.Thi rlt in complmnt attack at lf-cll rfac and,dpnding on th intnity of complmnt actiation, inpathology ( low and FIG. 2 and TAble 2).

Mtation of a ingl complmnt gn can rltithr in th anc of th protin in th circlation orin th dyfnction of th inhiitor. Chang in a inglcomponnt can ditr th whol rglatory ntwork.In a normal tting, whn complmnt actiationoccr at low ll, th anc or dyfnction of aingl componnt can tolratd or compnatd fory th prnc and concrtd action of mltipl addi-tional rglator. Howr, whn a local complmnt

Table 1 (cont.) |Complement regulators and receptors for effector proteins

Ratr Atratia

Pit f acti liad C rfac bidi rxpri

Fcti Rf

Receptors for complement effector proteins

C3aR None C3 C3a Neutrophils, monocytes,eosinophils, antigen-presentingcells, T cells, astrocytes, neurons

and glial cells

Immune cell recruitment andinflammation

78

C5aR CD88 C5 C5a Myeloid cells, monocytes,neutrophils, dendritic cells,antigen-presenting cells, T cells,endothelial cells and renaltubular cells

Immune cell recruitment andinflammation

19,32,79,82

C5L2 None C5 C5a Macrophages and neutrophils Immune cell recruitment andinflammation and possibly actsas a decoy receptor

19,32,80,82

C1qR CD93 Classical pathway C1q Monocytes and B cells Phagocytosis and cell adhesion 83,84

SIGNR1 CD209 Classical pathway C1q Dendritic cells and microglialcells

Signalling, inflammation andphagocytosis

85

APOA1, apolipoprotein A-1; C, complement component; C1INH, C1 inhibitor; C4BP, C4b-binding protein; C5L2, C5a receptor-lie 2; CFHR1, complement factorH-related protein 1; CR, complement receptor; CRIg, complement receptor of the immunoglobulin superfamily; DAF, complement decay-accelerating factor;

FHL1, factor H-lie protein 1; GPI, glycosylphosphatidylinositol; HDL, high-density lipoprotein; MASP2, mannan-binding lectin serine protease 2; MCP, membranecofactor protein; NA, not applicable; SIGNR1, a mouse homologue of DC-SIGN, SIGN-related 1; TCC, terminal complement complex.

R E V I E W S


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Protection ofhost cells

a Non-inflammatoryremoval of modifiedhost cells

b Complement activationand removal of infectiousmicroorganisms

c

Inappropriate action

of regulators leads tohost cell damage

d Inefficient removal

of modified host cellscan lead to pathology

e Pathogens acquire host

regulators and avoidcomplement attack

f

ComplementPhysiology

Pathology

RegulatorsRegulators No regulators

No or defectiveregulators

No or defectiveregulators

Acquiredregulators

rpon i initiatd and amplifid at th it of aninfction th concrtd action of mmran-ondand rcritd rglator i rqird for th protction

of ytandr hot cll from complmnt-mdiatdlyi. Th anc or th dfcti fnction of a inglcomponnt rlt in incomplt local protction. Thialo dmontrat how complmnt act a a powr-fl wapon againt a actrial or iral infction. Whncomplmnt actiation i not proprly controlld orinhiitd at th hot rfac it can progr and lad toinflammation, pathology and ltimatly atoimmndia (FIG. 2).

Role of complement in clearance of modified self cells.Complmnt r an additional fnction in thhman ody a complmnt actiation prodct tag

modifid lf cll ch a apoptotic particl andncrotic cll and allow non-inflammatory rmoal orclaranc of immn complx4245. Th mmranof an apoptotic cll ndrgo dramatic morphologi-cal chang, rlting in th rakdown of mmranintgrity and th flip-flop of th mmran, which iaccompanid y th lo of th mmran complmntrglator at th cll rfac. Conqntly, ch modi-fid lf trctr r a actiating rfac for com-plmnt. To aoid complmnt-mdiatd attack andadapti immn rpon to lf antign, modifidlf rfac acqir th oll ffctor C1q in comi-nation with th rglator factor H. Thi initiat arlytp of th claical pathway t lock th formationand amplification of th C5 conrta4648.

In thi itation th initiation of th complmntcacad y C1q allow C3 gnration and dpoi-tion, t progrion yond th C3 conrta tagi lockd y th complmnt rglator. Thi lti-matly rlt in th C3-mdiatd non-inflamma-tory rmoal of cll dri y phagocytoi48,49(FIG. 2).

Inappropriat tagging of modifid lf rfac andinfficint claranc rlt in th accmlation of clllardri, and lf antign can thn r a atoantignin atoimmn dia50(FIG. 2).

Complement activation on the surface of micro-

organisms. Mot infctio agnt ar fficintly limi-natd y a modratly actiatd complmnt ytm,n in th anc of inflammatory mdiator. Nwlyrlad C3a rcrit immn ffctor cll, and C3or C3 actiation fragmnt dpoitd on th forignrfac promot phagocytoi throgh oponization.In addition, th actiatd trminal pathway form thTCC, which damag th microorganim. Mot micro-organim ar liminatd at thi tag8,9,51. Howr,dring million of yar of oltion, pathognicmicroorganim ha dlopd way of aoiding com-plmnt rcognition, ading hot complmnt attackand riing in an immnocomptnt hot51. A rcnttdy dcrid th crytal trctr of staphylococcalcomplmnt inhiitor (sCIN) from Staphylococcusaureus ond to th altrnati pathway C3 conrtaC3b52. Thi proidd inight into th action of C3conrta a wll a information on th mchanimof inhiition y sCIN.

Distribution of complement regulators

Th importanc of complmnt rtriction i high-lightd y th larg nmr of rglator idntifidto dat, which xcd that of th componnt of thcomplmnt cacad (C1 to C9) (TAble 1).

Complmnt rglator oprat at all ll and arcatgorizd in thr major cla: f lid pha, attachdto th rfac of hot cll and mmran-intgralcomplmnt claranc rcptor. srpriingly, ralrglator ha additional actiiti yond compl-mnt, a thy mdiat cll adhion and xtraclllarmatrix intraction or link th complmnt cacadwith othr important phyiological ntwork ch ath coaglation cacad.

Figure 2 | Th bfit ad ri f cpt. Complement activation has

multiple effects in a physiological setting, which can either benefit the host (ac) or

be detrimental to the host and possibly lead to pathology (df). a |Owing to the

spontaneous nature of complement activation, intact host cells must protect their

surfaces from the action of effector compounds. This protection is mediated by

multiple regulators. b |Complement is activated in a controlled manner on the

surface of damaged or modified host cells, such as apoptotic particles and necrotic

cells. This allows complement activation to proceed until C3b surface deposition,

but further progression (generation of complement component 5 (C5) convertase

and terminal complement complex assembly) is bloced. This results in the

non-inflammatory removal of modified self cells. c | Complement is activated and

amplified on the surface of invading microorganisms. Activation results in

recognition and damage of the invading microorganisms and in the removal of the

cellular debris. d |Inappropriate action of complement regulators results in damage

to the surface of intact host cells. |Inappropriate tagging of modified self cells,

which can lead to inefficient removal and accumulation of apoptotic particles, can

result in secondary necrosis and pathology. This is thought to be a contributing factor

to the initiation of autoimmune diseases.f|Some pathogenic microorganisms can

evade recognition and actively bloc immune attac by the activated complement

system. In this way, pathogens cross the first layer of immune defence, leading to the

establishment of an infection.

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Fluid phase complement regulators. Flid pha com-plmnt rglator ar ditritd in hman plamaand in ody flid ch a th ynoial and itroflid. Th rglator ar gropd according to thirmajor actiity and incld thaltrnati pathwayrglator factor H53, FHL1 (ReF. 54) and th actiatorprotin proprdin55(FIG. 3a). Caroxypptida N, whichcla and partly inactiat th anaphylactic pptid

C3a and C5a, act in all thr major complmnt actia-tion pathway56,57(TAble 1). soll claical and lctinpathway rglator incld C1 inhiitor (C1INH)58 andC4bP59. C1q ha a crcial rol in hot dfnc and inclaranc of immn complx60. Th known ollinhiitor of th trminal pathway incld th rcntlyidntifid CFHR1, cltrin and itronctin6163, whichha additional iological fnction yond complmnt.Cltrin, for xampl, i aociatd with high-dnitylipoprotin particl and act a an adhion protin anda a potnt indcr of cll aggrgation. vitronctin indto th xtraclllar matrix, fnction in cll attachmntor cll prading and act a an adhion protin with

fironctin-lik actiity64. Proprdin can dirctly indto and initiat complmnt actiation on a microialrfac and triggr local amly and action of thaltrnati pathway C3 conrta65,66.

Membrane-bound complement regulators. Th mm-ran of hot cll i alo qippd with complmntrglator67, inclding CR1 (ReF. 68), CR2 (alo known

a CD21)69,70, CD55 (alo known aDAF)71, CD46 (aloknown a MCP)72, CD59 (alo known a protctin)73 andcomplmnt rcptor of th immnoglolin pr-family (CRIg; alo known a vsIG4)74. CRIg i xprdin a long and a hort form. Th long protin CRIg andCR1 act frthr away from th cll mmran thanth hort mmran protin CD46, CD55 and CD59.Mmran-ond rglator control th thr majorcomplmnt actiation pathway and inactiat othC3 and C4 (CR1 and CD46). by contrat, flid pharglator ar mor pcific and control ithr th altr-nati, th claical or th lctin pathway and act almotxclily on ithr C3 or C4 (FIG. 3a).

Table 2|Complement deficiencies and complement-mediated diseases

Dia majr dfct Ca g affctd Rf

Atypical haemolytic uraemicsyndrome (aHUS) and possiblysome cases of thromboticthrombocytopenic purpura (TTP)

Defective C3 convertase,stabilization of the convertase,defective regulation, and increasedstability and turnover

Mostly heterozygousmutations, genetic defects andautoantibodies

Deficiency of CFHR1,CFHR3, factor B, factor Hand factor I

9,91,92,99

Membranoproliferative

glomerulonephritis, typeII (MPGN II; also nown asdense-deposit disease)

Defective C3 convertase Mostly homozygous mutations,

genetic defects, autoantibodiesand C3 nephritic factor

Factor H and C3 93,99

Systemic lupus erythematosus(SLE)

Defective clearance of apoptoticcells and bodies

Hereditary homozygous deficiencyand genetic defects

C1q, C1r, C1s, C2, C3 andC4

49,96,110,111

Pyogenic infections Inappropriate complement attac Infections withNeisseriameningitidis and Streptococcuspneumoniae

C3, factor H, factor I,properdin and TCC

99

Deficiency of properdin Infections with Neisseria spp. Gene mutation 51

Deficiency of factor I Infections with N. meningitidisand S. pneumoniae and otherrespiratory tract infection

Gene mutation 5

Deficiency of factor H Infection with N. meningitidis Gene mutation affectingprotein secretion

53

Haemolysis and thrombosis Erythrocyte lysis and thrombusformation

Unnown CD59, factor H anddeficiency of CFHR1 andCFHR3

9

Partial lipid dystrophy Loss of adipose tissue C3 nephritic factor Unnown 9

Hereditary angioedema Recurrent spontaneous non-allergicoedema of the subcutaneoustissues and mucous membranes

Mostly heterozygous mutations C1 inhibitor 9

Paroxysmal nocturnalhaemoglobinuria (PNH)

Failure of CD55 and CD59expression

Genetic deficiency of PIG-A, andfailure to form GPI anchor

PIGA 9

Age-related maculardegeneration (AMD)

Drusen formation and chronicinflammation

Unnown Factor H, C3, C2, deficiencyof CFHR1 and/or CFHR3,factor B and factor I

94,99,107

Tumour cells Overexpression of membrane and

secreted regulators, and enhancedbinding of soluble regulators

Unnown Unnown 97

C, complement component; CFHR, complement factor H-related protein; GPI, glycosylphosphatidylinositol; PIGA, phosphatidylinositol glycan anchor biosynthesis,class A; TCC, terminal complement complex.

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CRIgCR1

Cell membrane

Membrane

zone regulators

FHL1

Fluid phase

regulators

Alternative pathway

a Complement regulators

b Cell surface receptors for complement components

Classical pathway Terminal phase

CD46CD55 CD59

Properdin Carboxypeptidase N Vitronectin CFHR1C4BP

Factor H

C1q

C1INH Clusterin

CR1

CR2

CR3 CR4

C3aR

CRIg

CRIgsC5aR C5L2 C1qR C1qRII

|

Receptors for complement effector molecules.Complmntactiation prodct and ffctor compond hapotnt iological actiity. Thy indc and modlatinflammation, control inflammatory rpon, dirctmltipl clllar rpon and indc ffctor fnction,ch a tagging of clllar rfac and indction ornhancmnt of phagocytoi46,48.

Thr ar many rcptor for complmnt ffc-tor molcl, which ind and rpond to ffctorcompond ch a C3a and C5a, C3-oponizd r-fac, modifid lf rfac and taggd microorgan-im, toxin or antign. Fi major mmran-ondffctor rcptor, CR1, CR2, CR3 (alo known aCD11CD18), CR4 (alo known a CD11cCD18)

Figure 3 | Cpt ratr ad rfac rcptr. a | Complement regulators can exist either in the fluid

phase or at the cell membrane. There are multiple fluid phase complement regulators, which control different steps of

the cascade and are distributed in different compartments. Alternative pathway regulators distributed in the plasma

and body fluids are factor H, factor H lie protein 1 (FHL1) and the activator protein properdin. Carboxypeptidase N has

regulatory activity in the alternative pathway, the classical pathway and the lectin pathway. The soluble classical and

lectin pathway regulators include complement component 1q (C1q), C1 inhibitor (C1INH) and C4b-binding protein(C4BP). The soluble inhibitors of the terminal pathway include clusterin, vitronectin and complement factor H-related

protein 1 (CFHR1). Membrane zone complement regulators include CR1 (also nown as CD35), CD46 (also nown as

MCP), CD55 (also nown as DAF), CD59 (also nown as protectin) and complement receptor of the immunoglobulin

superfamily (CRIg; also nown as VSIG4). The complement regulators act in various ways. For example, C1INH induces

the dissociation of the C1 components. CD35, CD55 and C4BP displace a component of the C3 convertase in the

classical pathway. CD59 prevents final assembly of the membrane attac complex. b | The membrane of host cells is

equipped with complement receptors, including CR1, which binds C3b, iC3b and C4b, and CR2 (also nown as CD21),

which binds C3d and C3dg, CD46, CD55, CD59 (not shown) and CRIg. However, the distribution and number of the

individual membrane-bound receptors varies between different cell types and on different surfaces. On the membrane

of B cells, both CR1 and CR2, which act as co-receptors for surface-bound immunoglobulin, regulate B cell

differentiation and maturation and instruct B cells to respond to C3d-coupled foreign antigens. So, C3b attached to

the antigen interacts with CR2 and acts as a molecular adjuvant74.CR3 (also nown as MAC1, M2 integrin andCD11bCD18) and CR4 (also nown as X2 integrin and CD11cCD18) are alsointegrin receptors. CR3 and CR4 bindiC3b, C3dg and C3d and mediate phagocytosis of C3b-opsonized cells or particles. In addition, these receptors bind

multiple other ligands including the matrix protein fibrinogen75,76(TAbleS 1,3). The recently identified receptor CRIg,and the shorter form CRIgs, has a major role in the clearance of C3d- and iC3b-tagged particles, including

microorganisms and autologous cells77. C5L2, C5a receptor-lie 2.

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and CRIg, ind C3 or C4 dpoitd on th rfacof th targt and dri ffctor fnction corrpond-ing to th pcific form of th C3 and C4 actiationcompond7577(FIG. 3;TAble 1).

Th action of th anaphylactic fragmnt C3a and C5ai mdiatd y mmr of th n tranmmranpanning rcptor family, inclding C3aR and th tworfac rcptor C5aR and C5L2. Th iological rolof th nwly dcrid C5L2 i till ndr dicion.At prnt it i nclar whthr C5L2 mdiat ffctorfnction in rpon to C5a or whthr th rcptoract a a dcoy and attnat C5a fnction12,32,7882. Inaddition, C1q i rcognizd on th cll rfac y tworcptor: C1qR and th dndritic cll-pcific ICAM3-graing non-intgrin (DC-sIGN) homolog sIGN-rlatd 1 (sIGNR1; alo known a CD209)8385.

An important apct of th rol of mmranrcptor in rglation and th rpon to ffctorcompond i thir xprion and ditrition onindiidal cll linag or cll typ. srfac-attachdcomplmnt and ffctor rcptor ar not niformly

xprd y nclatd hot cll, rythrocyt or plat-lt. Conqntly, th ditrition and nmr of indi-

idal rcptor and th complt rcptor rprtoiron a gin cll mmran ar important paramtrfor dfining th protcti rfac coat and th clllarrpon to complmnt.

Surface-attached complement regulators. It i nowclar that ral f lid pha complmnt rglatoralo attach to cll rfac and to iommran cha th glomrlar amnt mmran of th kidnyand th brch mmran of th rtina8688. In addi-tion, th rglator ind to modifid lf rfacch a apoptotic particl, ncrotic odi and thxtraclllar matrix48,59. Th, factor H, FHL1, C4bP,CFHR1, cltrin and itronctin, which controlcomplmnt in th flid pha, alo attach to lipidilayr or to iommran and maintain complmnt-rglatory actiity. Thi rfac attachmnt form anadditional protcti layr (known a th rfac zon)for intact hot cll that control complmnt and lim-it formation of complmnt actiation prodct andffctor compond at th cll rfac. Thi flxiland protcti hildcooprat with th mmranzon, an innr hild that i formd y mmran-anchord rglator. At prnt, th ligand on th cllrfac and th iommran that anchor th flid

pha complmnt rglator ha not n idnti-fid at th molclar ll t, a hparin modifiand inhiit thi intraction, it ha n propodthat glycoaminoglycan act a cll and iommranrfac rcptor.

Th imltano attachmnt of mltipl rgla-tor crat an additional protcti rfac zon. Thapproximat dimnion of th rfac zon dpnd onth lngth and th dnity of th attachd protin. Forxampl, th lngth of a flly xtndd complmnt fac-tor H protin wa calclatd to 73 nm and that ofmmran ond CD46 to 14 nm89. A ingl, xtnddfactor H molcl can control an ara corrponding to

a hmiphr with a radi of approximatly 70 nm. Inaddition, mmran-ond rglator ch a CD46and CD59 ar rlad or hd from th mmran andth contrit to th protcti hild90.

Complement regulators in disease

Dia cad y dfcti complmnt fnctionmirror th cntral rillanc rol of complmntin th hman ody. Dfcti complmnt rglationand dficincy of particlar componnt acting arlyin th cacad can rlt in oth hot cll damag andaccmlation of immnological dri. Th dfctar aociatd with th rnal diordr atypical hamo-lytic ramic yndrom (aHus)91,92. similarly, a dfc-ti rfac zon and accmlation of dri ha nrportd to a ca of dn-dpoit dia (DDD;alo trmd mmranoprolifrati glomrlonphriti,typ II (MPGN II))93, th rtinal dia ag-rlatdmaclar dgnration (AMD)94,95 and ytmic lprythmato (sLe)96. by contrat, tmor cll andpathognic microorganim attach hot complmnt

rglator and mimic a lf rfac zon to cap com-plmnt rillanc, rlting in nrtrictd growthand infction, rpctily4,5,53,97,98.

Th thr ditinct diordr aHus, DDD and AMDmanift in diffrnt organ and ha diffrnt pathol-ogy. In aHus, thromi form in th glomrl, whraDDD and AMD inol formation of dpoit at rnaland rtinal it, rpctily. Howr, th diordrar cad y mtation in th am gn, and tham t of gn i aociatd with ach of th thrdiordr. each dia i clarly aociatd with r-fac damag occrring at platlt, rnal ndothlialcll, th glomrlar amnt mmran of th kid-ny or th brch mmran in th rtina. Th affctdgn ncod C3 and factor b (th two componntof C3 conrta) or th rglator of C3 conrtafactor H, CD46 and factor I99101. Th anc of CFHR1and CFHR3 in plama a a rlt of a chromoomaldltion ha oppoit ffct on th progrion of thdiordr102105: in aHus, th dltion m to rpr-nt a rik factor and i aociatd with gnration ofatoantiodi to factor H92,102,103, whra in AMD iti dcrid a haing a protcti ffct104. Dltionof ingl componnt ca pathology and dri thalancd complmnt rglatory ntwork in oppoingdirction. Th crytal trctr of th firt for domainof factor H in complx with it targt, C3, wa rcntly

idntifid, proiding information on th mchanim ofaction of factor H and a trctral ai for th ffctof dia-aociatd mtation106.

Th fact that thi t of gn can indc diathat manift in diffrnt organ ggt that th qan-tity of protin at local it i rlant and that mtatdprotin attach to diffrnt rfac in ditinct organ.For xampl, factor H gn mtation can ithrhomozygo or htrozygo and th can rlt in

ario concntration of fnctional protin oth in thcirclation and at th cll rfac. In addition, mtationthat rlt in amino acid xchang occr within di-tinct it and affct diffrnt fnctional domain of thi

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mltifnctional factor H protin. so, ingl mtationa wll a polymorphic xchang tranlat into diffr-nt ffct, ca diffrnt condition and can dfinwhthr th dfct manift in rnal or rtinal it.

Atypical haemolytic uraemic syndrome.In aHus, motpatint ha on dfcti alll and on intact alllof factor H. Thi rlt, in gnral trm, in a ~50%rdction in complmnt actiity. Thi rdcd llof fnctional protin allow complmnt control inth flid pha. Howr, following an immnologicalinlt, amplifid local complmnt actiation rqirmaximal protction of ytandr cll from lyi. In thiitation, damag to hot trctr can occr. sch acnario may xplain th incomplt pntranc of ht-rozygo mtation and may xplain why th diafrqntly dlop aftr an piod of infction.

In aHus, mot of th htrozygo factor H gnmtation cltr in th caroxy-trminal rfac rc-ognition rgion and la th complmnt-rglatoryrgion, in th amino-trmin, intact. Rdcd rfac

inding of mtant factor H wakn th protcti r-fac zon. In DeAP (dficint for CFHR protin andfactor H atoantiody poiti)Hus th dficincyfor CFHR1 and CFHR3 i frqntly aociatd withth dlopmnt of atoantiodi, which ind to andlock th C-trminal rcognition rgion of factor H92.

Dense-deposit disease. In DDD, mtation in th gnncoding factor H occr motly in homozygo or com-pond htrozygo condition and rlt in dfctiprotin crtion and th anc of th protin in thplama93. Thi lad to nrtrictd complmnt actia-tion in th plama. An additional apct of DDD i thprnc of atoantiodi (trmd C3 nphritic factor)that ind to a no-pitop of th C3 conrta, tailizth nzym and nhanc C3 claing105. both prdipoi-tion rlt in C3 conmption in th flid pha and localC3 dpoit formation at rfac that lack ndognorglator, ch a th glomrlar amnt mmranof th kidny and th brch mmran of th rtina.

Age-related macular degeneration. Th brch mm-ran in th rtina, imilar to th glomrlar amntmmran of th kidny, rqir mmran-ond ol-l rglator for control. Th, th anc or dfc-ti rfac inding of factor H may lad to ncontrolldcomplmnt actiation at ch nprotctd it.

Th AMD-aociatd factor H gn polymorphim(H402Y) i locatd in th hparin- and CRP-indingdomain 7 and affct rfac attachmnt of factor H toth brch mmran and rtinal pithlial cll a wlla protin dpoit known a drn107.

Frthr idnc for a common dia mchanimfor DDD and AMD i ad on rcnt protomic analy- of glomrlar dn dpoit and rtinal drn108,109.Th dpoit formd in th two ditinct organ comprialmot th am protin, inclding complmnt acti-

ation prodct and inflammatory componnt (cha C3, C3d and iC3), trminal pathway componnt(C5, C6, C7, and C8) and trminal pathway rglator

(CFHR1, cltrin and itronctin, CFHR2 and CFHR5).Thi orlap highlight th imilarity of AMD and DDD,how that complmnt i aociatd with th pathologyof oth dia and ggt that dfcti complmntrglation rlt in chronic inflammation.

Autoimmune diseases. Dfcti claranc of lf anti-gn or apoptotic particl and accmlation of clllardri can occr in th anc of C1q or C4. Thi canlad to xpor of lf antign to lymphocyt andcan alo lad to inappropriat actiation of lf-ractib and T cll47. Thi i conidrd a major cptiil-ity factor for dlopmnt of atoimmn dia.Dfcti complmnt action can rlt in th accm-lation of clllar dri or th formation of pathologicaldpoit (FIG. 2). Mtation and homozygo dficincyof gn of th claical pathway of complmnt actia-tion and th prnc of atoantiodi ar aociatdwith th pathogni of th ytmic atoimmn di-a sLe110,111. Mot homozygo dficinci for gnncoding componnt of th arly claical pathway,

inclding C1q, C1r and C1 a wll a C2, C3 and C4,ar trongly aociatd with th dlopmnt of sLe. Thtrongt aociation i ord with C1q dficinciand or 90% of th ca dlop rhmatic dia.In addition, dficinci of C5, C8 and manno ind-ing lctin (MbL) ar aociatd with sLe or lp-likyndrom. similarly acqird factor, ch a ato-antiodi in particlar atoantiodi to C1q, C3 andCR1, t alo C3 nphritic factor and atoantiodi toC42a and C1INH ar rportd in ca of sLe. Thdfct or nwly acqird factor proaly rlt in thfailr to clar C3-oponizd apoptotic cll or particland lad to condary ncroi and pathology.

Tumour cells. Cancr cll ar anothr typ of modifidlf cll that actily cap complmnt and immnrillanc. Th xprion of mmran-ondcomplmnt inhiitor (CD46, CD55 and CD59) iprglatd in ario primary tmor and tmorlin112. similarly, lng, oarian, glial and colon cancrcll how nhancd xprion and rfac indingof oll rglator, inclding factor H, FHL1, C4bPand factor I. In addition, complmnt actiation prod-ct ch a C5a ppr th antitmor rponmdiatd y CD8+ T cll and inhiition of compl-mnt actiation ha n ggtd a an option fortratmnt of cancr113,114.

Th rcnt concpt of th rol of complmnt india ha alrady n tranlatd from th nch toth did, a dfcti complmnt rglator or thanc of rglator i fficintly orcom y plamatranfion. similarly, th hmanizd monoclonal anti-ody pcific for C5 (clizma), which ha n ffi-cintly d a a tratmnt for aHus, proid an xcllntrcnt xampl of promiing tranlational rarch115,116.

Infectious pathogens. Th protcti complmnt hildi alo rlant in infctio dia a pathognic micro-organim, y xploiting oll hot complmnt rg-lator, gnrat a protcti hild on thir rfac.

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1. Walport, M. J. Complement. First of two parts.

N. Engl. J. Med.344, 10581066 (2001).

2. Walport, M. J. Complement. Second of two parts.

N. Engl. J. Med.344, 11401144 (2001).

3. Volonakis, J. E. & Frank. M. M.The Human Complement

System in Health and Disease (Dekker, New York,

1998).

4. Zipfel, P. F., Wurzner, R. & Skerka, C. Complement

evasion of pathogens: common strategies are shared

by diverse organisms. Mol. Immunol. 44, 38503857

(2007).

5. Rooijakkers, S. H. & van Strijp, J. A. Bacterial

complement evasion. Mol. Immunol. 44, 2332

(2007).

6. Ogden, C. A. & Elkon, K. B. Role of complement and

other innate immune mechanisms in the removal of

apoptotic cells. Curr. Dir. Autoimmun.9, 120142

(2006).

7. Medzhitov, R. & Janeway, C. A. Jr. Decoding the

patterns of self and nonself by the innate immune

system. Science296, 298300 (2002).

Acqiition of oll hot rglator conrt th

forign, non-lf rfac of th pathogn to a lf-likrfac. sch a camoflagd pathogn rmain iniilto th hot innat immn ytm.Pathogn can alomimic fatr of hot cll y xpring ndognorglator that lock complmnt actiation. Th ailityof th conrd mchanim of complmnt to damagmany diffrnt mmran typ i illtratd y th factthat dir hman pathogn, inclding Gram-ngatiactria, Gram-poiti actria, fngi, ir, mlticl-llar parait and hlminth, imilar, and n idn-tical, tratgi to ad hot complmnt attack4,5,51,98

(TAble 3). A complmnt form on of th firt arri-r of innat immnity any pathognic microorganimha to cro thi important layr of immn dfnc inordr to talih an infction. Intrtingly, th innatimmn rpon ar contant and all hman patho-gn fac th am complmnt attack. Thi may xplainwhy diffrnt cla of pathogn imilar tratgito ad hman complmnt attack.

Many diffrnt mchanim of action for indiidalinhiitor ha n dfind; for xampl, Borrelia burg-dorferi xpr fi diffrnt complmnt rglator-acqiring rfac protin, trmd CRAsP1CRAsP5,for immn aion117. strctral data xplain th intr-action in molclar trm; for xampl, th S. aureusxtraclllar firinogn inding protin (ef) lock thconformational actiation of th C3 molcl118, and

th Neisseria meningitidis factor H-inding protingnom-drid nirial antign 1870 (GNA1870)mimic hot rfac y inding hot factor H119. Th c-c of microial complmnt rglator GNA1870 indingprotin a accin candidat dmontrat th clinicalrlanc of th typ of protin120122(TAble 3).

Concluding remarks and perspectives

Complmnt-mdiatd innat immn fnction not onlyrcogniz and liminat infctio agnt t alo con-trol homotatic proc ch a organ and nrondlopmnt, claranc of clllar dri and liminationof infctio particl. In th ftr nw fnction willproaly idntifid for othr claag prodct, cha ba, C2a and C4a.

bca of it cntral rol in mltipl phyiologicalproc, dyrglation or imalanc of th compl-mnt ytm can rlt in pathology and dia thatmanift in diffrnt organ. Intrtingly, ditrancof th altrnati pathway in particlar, a matr rg-lator of homotai, ar aociatd with ral ato-immn dia. so, th mchanitic charactrization ofcomplmnt-mdiatd claranc and th idntificationof aociatd gn and gn prodct rprnt a majorchallng for th ftr.

In addition, an important apct of ftr work i toprcily dfin th link twn th complmnt ytmand othr important immn and homotatic ffctorcircit, ch a th coaglation cacad, and th intgra-tion of complmnt rcptor ignalling with othr path-way, ch a th Toll-lik rcptor ignalling ntwork.Th intrplay twn complmnt and coaglation y-tm i xpctd to proid nw cl to th pathologicalmchanim of ario dia, for xampl th ariodiordr that ar aociatd with throm formation.

Additional nw mthod for targting complmntar now ing dlopd122. On of th grat challngof ftr complmnt rarch i to pcifically intrfrwith, and lock, th damaging inflammatory ractionthat lad to pathology, t at th am tim maintain thprotcti ffct that ar nfical for th hot.

Table 3 |Host and pathogen complement regulators

Pit f acti Ht ratr Path-cdd ratr ad htratr bidi prti

Rf

Fid pha ratr mbra bd ratr

C3 convertase Factor H, FHL1, C4BP,properdin and C1INH

CR1, CD55, CD46 and CRIg CBPA, CRASP1CRASP5, GPM, EFB, FBA, FHA,GNA1870, HIC, IDES, LOS, M protein, OMP100,PAAP, PAE, PLA, PLY, POR, PRA1, PREH, PRTH,PSPA, PSPC, RCA, RCk, REC, SAk, SBI, SCIN,

SPEB, STCE, SSCL, TUF and YADA

4,5,5255,58,59,68,

71,72,74,98

C5 convertase CFHR1 None CHIPS, SCPA/SCPB and SSL-7 4,5,52,61,98

Terminal pathway CFHR1, clusterin andvitronectin

CD59 CD59-lie, FHA, OMP A, SIC, TRAT, USPA1 andUSPA2

4,5,52,6163,73,98

C, complement component; C1INH, C1 inhibitor; C4BP, C4b-binding protein; C5L2, C5a receptor-lie 2; CFHR1, complement factor H-related protein 1; CHIPS,chemotaxis inhibitory protein; CRASP, complement regulator-acquiring surface proteins; CRIg, complement receptor of the immunoglobulin superfamily;EFB, extracellular fibrinogen binding protein; FBA, fibronectin binding protein; FHL1, factor H-lie protein 1; GMP, phosphogycerate mutase; GNA1870,genome-derived neisserial antigen 1870; HIC, factor H-binding inhibitor of complement, IDES, IgG-degrading enzyme ofStreptococcus pyogenes;LOS, Lipooligosaccharide; M protein, membrane protein; OMP, outer membrane lipoprotein; PAAP, Pseudomonas aeruginosa protease; PAE, P. aeruginosaelastase; PLY, streptococcal pneumolysin; POR, outer membrane porins; PRA1, pH regulated antigen ofCandida albicans; PRTH, Porphyromonas protease;PSPA/C, pneumococcal surface protein A/C; SAk, staphyloinase; SBI, Staphylococcus aureus IgG binding protein; SCIN, staphylococcal complement inhibitor;SIC,streptococcal inhibitor of complement; SPEB, streptococcal pyogenic exotoxin B; SSL7, staphylococcal superantigen lie protein 7; STCE, streptococcalE protease; TUF, translation elongation factor ofP.aeruginosa; USPA, universal stress protein A; YADA; Yersinia adhesion protein A.

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AcknowledgementsThe work of both the authors is supported by the Deutsche

Forschungsgemeinschaft, Germany. P.F.Z.s work is also sup-

ported by Kidneeds, Iowa, USA, the National Institutes of

Health, USA, and ProRetina, Germany .

DATABASESUniProtKB:http://www.uniprot.org

C1INH | C1qR|C3 | C3aR | C4a | C4b | C4BP | C5|C5aR| C6 |

C7|C8 | C9|CD46| CD59 | CFHR1 | CR2 | CR1 |CRIg|DAF |

factor B | factor D|factor H| factor I| FHL1|properdin |

SIGNR1 | vitronectin

FURTHER INFORMATIONPeter F. Zipfels homepage:

http://www.hi-jena.de/mib/himib.htm

All lInks ARe ACTIve In THe onlIne PDF

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complement regulators and inhibitory

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