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Complement-outlineoflectureComponentsofthecomplementsystemComplementactivationpathways[e-mail]雷达物位计ComponentsofthecomplementsystemComplementactivationpathwaysImmunobiologyofcomplementHistoryandnomenclatureHeat-labileprincipleinserumthat‘complemented’antibodyactivity30proteins,3g/liter,15%oftheserumglobulinfractionMainlysynthesizedintheliver,alsobyepithelialcellsandmonocytesetcActivationofcomplementisessentiallyaproteolyticchainreactionTherearethreeactivationpathways:classical,alternativeandMBLWalportFigure1HistoryandnomenclatureProteinsintheclassicalpathwayaregivennumericalnumbers,C1-C9Proteinsinthealternativepathwayarereferredtoas‘Factors’,e.gFactorB,FactorDetcActivationofcomplementdoesnotalwaysfollowthenumericalorderWhenaparticularcomponentiscleaved,thelargefragmentisusuallyreferredtoasthe‘b’fragmentandthesmallerfragmentthe‘a’fragment,e.g.C3bandC3a.TheonlyexceptioniswiththecleavageofC2.BasicfeaturesofcomplementproteinsandactivationSomeofthecomplementcomponentsarezymogens-inactiveserineproteasesthatareactivatedaftercleavageorconformationalchange(C1,C2,FactorB).FactorDisconstitutivelyactive.Othercomplementproteinsarestructuralproteinsthatmay(C4,C3andC5)ormaynot(C6,C7,C8,C9)requirecleavagetobeactivated.C4andC3areproteinsthatcontaininternalthioesterbondsthatcancross-linkcovalentlytohydroxylgroupsonthecellsurfacesafteractivation.BasicfeaturesofcomplementproteinsandactivationSomeofthecomplementcomponentsarezymogens-inactiveserineproteasesthatareactivatedaftercleavageorconformationalchange(C1,C2,FactorB).FactorDisconstitutivelyactive.Othercomplementproteinsarestructuralproteinsthatmay(C4,C3andC5)ormaynot(C6,C7,C8,C9)requirecleavagetobeactivated.C4andC3areproteinsthatcontaininternalthioesterbondsthatcancross-linkcovalentlytohydroxylgroupsonthecellsurfacesafteractivation.C1isaspecialcomponentinthatitisnotasingleproteinbutratheracomplexofproteinscomposedofoneC1q,twoeachofC1randC1smolecules.C1qinturniscomposedof18polypeptidesorganizedinto6triplehelicesmadeupofA,B,Cchains.C1isacomplexofmultipleproteinsComplement-outlineoflectureComponentsofthecomplementsystemComplementactivationpathwaysImmunobiologyofcomplementWalportFigure1Alternativepathway:lowlevel‘tickover’InitialdiscoverywascontroversialTheinternalthioesterbondinC3canbehydrolyzedspontaneouslytogenerateanactivatedformofC3:C3(H2O).C3(H2O)canbindFactorBtoformC3(H2O)BwhichaftercleavagebyFactorD,formsaninitiatingC3convertaseC3(H2O)Bb.C3(H2O)BbwillcleaveC3andgenerateC3bwhichcancross-linktocellsurfaces.ImmobilizedC3bwillbindmoreFactorBandthereforestarttheamplificationloopWalportFigure1MajorpointsofactivationpathwaysAllpathwaysconvergeattheC3cleavagestepC3activationinitiatesaself-amplificationloopClassicalPathwayalwaysactivatestheAlternativePathwayClassicalPathwayrequiresCa++AlternativePathwayrequiresMg++C4bC2aandC3bBbaretwoC3convertasesAlternativepathwayisinitiatedbyspontaneous‘tickover’C4bC2aC3bandC3bBbC3bareC5convertasesC2andFactorBareanalogoustoeachother.Whicharezymogens,constitutivelyactiveprotease(s)andstructuralproteins?Whichstructuralproteinsneedtobecleavedandwhichdonotneedtobecleaved?Complement-outlineoflectureComponentsofthecomplementsystemComplementactivationpathwaysImmunobiologyofcomplementImmunobiologyofcomplementHostdefenseagainstinfectionAnaphylatoxinproduction(C5aandC3a)OpsonizationDirectlysisInterfacebetweeninnateandadaptiveimmunityDisposalofwasteWalportFigure1OpsonizationPhagocytesC3b-RC3bbacteriabacteriaC3andC4ligandsandtheirreceptorsoCR1(CD35):C3biC3bC4boCR2(CD21):iC3b,C3dgoCR3(Mac-1,CD18/CD11b):iC3boCR4(CD18/CD11c):iC3bC3C3biC3bC3dgC3dC3aC3fC3cC3gC5b-9complex:directcelllysis+C5b,C6,C7,C8,C9bacteriabacteriaC5b-9C3bImmunobiologyofcomplementHostdefenseagainstinfectionInterfacebetweeninnateandadaptiveimmunityLoweringthethresholdofBcellactivationBcellsurvivalingerminalcentersTcellfunctionDisposalofwasteLoweringthethresholdofBcellactivationC3d-boundantigencouldbe10,000foldmorepotentthannativeantigeninstimulatingacertainlevelofantibodyresponse.BcellsurvivalingerminalcentersTcellfunctionImmunobiologyofcomplementHostdefenseagainstinfectionInterfacebetweeninnateandadaptiveimmunityDisposalofwasteImmunecomplexclearanceComplementandapoptoticcellclearanceParadoxicalrolesofcomplementPro-inflammatory(C3consumptionandlupusflare-ups)C1q,C1r/C1sandC4deficiencypredisposesindividualstoSLE(97%,57%and75%penetrance)C1q,IgM,SerumamyloidPandDNaseIKOmicealldevelopautoimmunityHypothesisI:InnateimmunityisimportantforperipheraltoleranceInnateimmunesystemincludingcomplement,IgM,SAP,DNaseIhelpsintheremovalofpotentialautoantigensderivedfromapoptoticcellsandtherefore:ComplementplaysaphysiologicalroleinmaintainingperipheraltoleranceHypothesisII:ComplementplaysaroleincentraltoleranceBecausecomplementisimportantforBcellcoreceptoractivationinmatureBcellsintheperiphery,itmayalsoplayasimilarroleinBcelldevelopmentinthebonemorrowwhereBce