36补体CKAMCD

1DepartmentofmicrobiologyandimmunologyShantouUniversityMedicalCollegeChapter5,6,72IComplementsystem（补体系统）IICytokine（细胞因子）IIICD&AM（分化群与粘附分子）31）.补体的发现（Bordet，1894）JulesBordet(1870-1961)IComplementsystemNobelprize,1919辅助抗菌抗体介导溶菌作用-----补体52).补体定义Complementsystem-Agroupofproteinsincludingmorethan30solubleproteinsandcellmembranereceptors,normallycirculateasinactivezymogens(proenzymes，酶前体);-Whenstimulatedbysometriggers,someofwhichactinanenzymaticcascade（酶促反应）,producingeffectormoleculesinvolvedininflammation,phagocytosis,andcelllysis.63).理化特性*热不稳定*多数以酶原形式存在*大约占血清总蛋白的10%，多数为球蛋白*各成分含量不等，C3成分量最高*主要由肝细胞和巨噬细胞合成74).补体成分Ⅰ、固有成分:1.Classicalpathway—C1、C2、C3、C42.MBLpathway—MBL、MASP3.Alternativepathway—Bfactor、Dfactor…4.Terminalpathway—C5~C9Ⅱ、调节蛋白properdin、factorH、factorI…III、补体受体：CR1~CR5、C2aR、C4aR…85).补体系统的命名固有成分:C1(q、r、s)~C9其余成分：factorB、factorD、factorP、factorH…调节蛋白：namedbyitsfunction：C1inhibitor,C4bindingprotein补体裂解片段：C3a、C3b具有酶活性的补体成分：C3bBb灭活片段：iC3b92.Activationofthecomplementsystem（补体活化）根据起始环节不同，分为*Classicalpathway（经典途径）*Mannan-bindinglectinpathway（甘露聚糖结合凝集素途径）*Alternativepathway（旁路途径）--共同末端通路：膜攻击阶段10*ClassicalPathway激活物:ThepathwayisactivatedprincipallybythebindingofC1qtotheFcportionsofAbthathaveboundAg.Itservesasaneffectormechanismofspecifichumoralimmunity.Triggerstimuli----Ab-Agcomplex（immunecomplex)11*ClassicalPathway（经典途径）激活条件:1.激活物:免疫复合物2.IgMCH3区或IgGCH2区结合,C1后才可激活3.1个C1分子须结合两个或两个以上Ig的Fc段才可通过经典途径激活12FcCH1CH2IgMCH3,IgGCH2(IgG1~IgG3)----补体结合位点(Ag)C1qbindingsiteunexposedC1qbindingsite»ClassicalPathwayI.识别阶段细胞膜IgGAgC1s活化ICcleavingcleavingC1qC1r2C1s2C1qC1rC1sMicrobiologyandimmunologyonline,Universityofsouthcarolinaschoolofmedicine裂解C4Microbiologyandimmunologyonline,UniversityofsouthcarolinaschoolofmedicineⅡ.活化阶段：C3和C5转化酶形成16C4bC4b2b=C3convertase2.C3转化酶形成Microbiologyandimmunologyonline,Universityofsouthcarolinaschoolofmedicine转化酶形成C4b2b3b=C5-convertaseMicrobiologyandimmunologyonline,Universityofsouthcarolinaschoolofmedicine膜攻击阶段C4b2b3b膜攻击复合物(MembraneAttackComplex，MAC)形成MAC溶解细胞20C3bC4bbC5转化酶裂解C5。Microbiologyandimmunologyonline,Universityofsouthcarolinaschoolofmedicine依次与C6,C7,C8,C9结合，形成膜攻击复合物。Microbiologyandimmunologyonline,Universityofsouthcarolinaschoolofmedicine:Kubyimmunology22IVBiologicaleffects:1.参与适应性免疫应答2.在抗感染的中晚期或再次免疫应答的发挥效应23C1C4aC2C4bC4C2aC4b2bC3aC3bC3C4b2b3bC5aC5bC5C5b6789C9C8C7C6ImmunecomplexC1ClassicalPathwayC3convertaseC5convertase24由免疫复合物（IC）激活激活顺序:C1qrs-C4-C2-C3-C5-C6-C7-C8-C9产生3个转化酶产生3个过敏毒素：C3a,C4a,C5a主要特点25MBL(mannan-bindinglectin）pathway（甘露聚糖结合凝集素途径）•由甘露聚糖结合凝集素激活•MBLC4C4a+C4b+病原体MASP2C4b2b甘露糖残基C2C2a+C2bMASP:MBL-associatedserineprotease(MASP1,MASP2)C4b2b:C3convertaseC3convertase26MBLMBL&C1qMBL为急性期蛋白，与C1q结构相似。C1qFrom:Kubyimmunology:参与固有免疫应答在抗感染免疫早期发挥效应28C3C3b+BfactorC3bBbC3bBb3bC3aBa正反馈放大activatePfactorAlternativePathway（旁路途径）•激活物：细菌、脂多糖、多糖、葡聚糖、凝聚IgA等细菌、脂多糖、多糖等(C3bnBb)自发裂解factorD29C3bbC3bBb=C3convertaseC3blevelsarenormallytightlycontrolled.Microbiologyandimmunologyonline,Universityofsouthcarolinaschoolofmedicine转化酶形成（C3bBb）30C3bStablealternativepathwayactivationoccursonthemicrobialsurfacebC3bMicrobiologyandimmunologyonline,Universityofsouthcarolinaschoolofmedicine稳定C3转化酶形成(C3bBbP)31C3bLackofregulatoryproteinsallowsforthestablecomplementactivationC3bbbMicrobiologyandimmunologyonline,Universityofsouthcarolinaschoolofmedicine转化酶形成(C3bBb3b)32特点识别“自己”与“非己”正反馈放大机制33Biologicaleffects:•参与固有免疫应答•在抗感染免疫早期发挥效应343条激活途径的异同相同:酶促反应补体成分裂解共同末端通路共用某些调节蛋白35不同点:classicalalternativeMBL激活物Ag-AbcomplexLPS,etalMBLbindtomannoseresidues起始环节C1C3MBL,MASP参与成分C1-C9C3,C5-C9,fB,fD,fPMASP1,2,C2-C9C3转化酶C4b2bC3bBbC4b2b,C3bBbC5转化酶C4b2b3bC3bnBbC4b2b3b参与效应SpecificimmunityInnateimmunityInnateimmunity36373.补体活化的调节自身调节：活化产物不稳定，易衰变补体调节因子增强或抑制活化e.g.C1INH,C4bP,CRI,MCP,FactorI,FactorH,factorI,DAF,HRF,MIRL38C1inhibitor(C1INH)bindsC1r2s2,causingdissociation分离fromC1q.C1INHFrom:Kubyimmunology39AssociationofC4bandC2aisblockedbybindingC4b-bindingprotein(C4bBP),complementreceptortypeI,ormembranecofactorprotein(MCP).Inhibitor-boundC4biscleavedbyFactorI.C4bBP,CRI,MCP,FactorIFrom:Kubyimmunology40Inalternativepathway,F