医学免疫学英文版课件：Complement system补体系统

Complementsystem补体系统IMMUNOLOGYComplementContents1.Introduction2.ActivationoftheComplementSystem

3.Regulationofcomplementactivation4.BiologicalfunctionofcomplementsystemJulesBodet(1870-1961),比利时科学家DiscovererofComplement1894Bordet发现绵羊抗霍乱血清能够溶解霍乱弧菌，加热56℃30min阻止其活性；加入新鲜非免疫血清可恢复其活性。百日咳杆菌1919NobelPrizeComplement补体（Complement）：新鲜血液中存在一种不耐热的成分，可辅助特异性抗体介导的溶菌作用。IntroductionComplement(C)

补体Agroupofserumproteinsinvolvedinthecontrolofinflammation,theactivationofphagocytesandthelyticattackoncellmembranes.Thisactivityisdestroyed(inactivated)byheatingserumat56Cfor30minutes.ComplementSystem

consistsofalargenumberofproteinswhichbecomeenzymesafterbeingactivated.ComplementActivationproteins2.Regulatoryproteins3.ComplementreceptorComplementProteinsoftheComplementSystemActivationProteinsClassicalpathway:C1q,C1r,C1s,C4,C2MBLpathway:MBL,MASPAlternativepathway:factorB,DTerminalpathway:C3,C5,C6,C7,C8,C9ComplementRegulatoryProteinsC1INH,C4bp,factorI,factorHSprotein,membranecofactorproteindecay-acceleratingfactor(DAF)…ComplementreceptorCR1~CR5,C3aR,C2aR,C4aR…ComplementII.

Complementcatabolism

Complementproducingcells

LiverhepatocytesMonocytes/MacrophagesEpithelialcellsRegulationofbiosynthesiscatabolismComplement＊固有成分按发现的先后分别命名为C1(q、r、s)、C2、…C9；＊其他成分以英文大写字母表示，如B因子、D因子、P因子；＊补体调节蛋白多以其功能命名，如C1抑制物、C4结合蛋白、促衰变因子等；＊补体受体多以其结合对象命名，如C3aR。＊补体活化后的裂解片段以该成分的符号后面附加小写英文字母表示。如C3a、C3b等；小片段用a，大片段用b。（人卫出版社第5版）C2特殊，C2a为大片段，C2b为小片段。＊具有酶活性的成分在其符号上划¯横线表示。＊被灭活后的成分其符号前加i。

NotationActivationofthecomplementsystemClassicalpathwayMBLpathway

MBL:mannan-bindinglectin3.AlternativepathwayComplementClassicalpathwayAsuitableAbboundtoAg,Ag-AbcomplexIgM>IgG3>IgG1>IgG2C1,C4,C2andC3,Ca++andMg++cations1.C1activation2.C4andC2activation(generationofC3convertase)3.C3activation(generationofC5convertase)4.GenerationofC5convertasemarkstheendoftheclassicalpathwayComplementDownloadedfrom:StudentConsult(on1June200604:16PM)©2005ElsevierActivatorsActivationofthispathwaymayoccurviaAg-Abcomplex(immunecomplex,IC)orbyaggregatedIg.IgG(IgG1,IgG3)andIgMaremostefficientinreactingwithcomplement.OnlyonemoleculeofIgMisrequired,whereasatleasttwomoleculesofIgGareneeded.Solubleantibodycan’tactivatecomplement

ComplementThreesteps1.

Recognition(C1activation)Thecomponentsinvolved：C1q,C1r,C1sAg+Ab→IC→bindC1q→C1r→C1s

→C12.ActivationThecomponentsinvolved:C4,C2andC3(1)C4andC2activation,generationofC3convertase(2)generationofC5convertase3.Attack(terminalpathway)Thecomponentsinvolved:C5,C6,C7,C8,C9themembraneattackcomplex(MAC):C5b6789Classicalpathway

ComplementC1moleculeCa++Downloadedfrom:StudentConsult(on1June200604:16PM)©2005ElsevierComplementClassicalpathwayAg-AbcomplexC3convertaseC4b2aC5convertaseC4b2a3bC4b2a3bC2bDownloadedfrom:StudentConsult(on1June200604:16PM)©2005ElsevierAlternativepathwayActivators：bacteriallipopolysaccharides(endotoxin),certaincomplexpolysaccharidesnormal:CirculatingplasmaC3undergoesspontaneoushydrolysisofitsthioesterbondtoformaconformationallyalteredspeciescalledC3(H2O).Oncethethioestergrouphasopened,C3(H2O)actslikeC3b.

C3→C3a↓D

C3b+B→C3bB→C3bBb(C3convertase)→bedissociated

↑-↑-

II/Habnormal:nofactorIandHonthesurfaceofbacterialC5convertase:C3bBb3borC3bnBbAlternativepathway

1.ItisratherdifferentfromtheMBLandclassicalpathway.2.noC1,C4andC2involvedfactorBandfactorDinvolved3.thepresenceofsuitableactivatorsurfaces,suchasbacterialandfungalcellwalls.4.C3b:fromtheclassicalpathway;spontaneousproducedC3b

ComplementAlternativepathway

ComplementAlternativepathway

1.Itcanrecognize“self”and“non-self”2.Theamplificationloop

MBLpathwayActivators：MBL(likeC1q)MBLrecognizescertaincarbohydratesexpressedonthesurfaceofmicroorganisms.

↓

MBLactivatetwoMBL-associatedserineproteases-------MASP-1andMASP-2.

↓↓cleavesC3cleavesC4andC2toactivatethealternativegeneratetheC3convertase(C4b2a)pathwaydirectlyActivationoftheComplementSystemMBLpathway

WhenMBLbindstoterminalmannosegroupsonbacterialcarbohydrates,itactivatesMASP-1andMASP-2,plementMBLpathway

ComplementbaDownloadedfrom:StudentConsult(on1June200604:16PM)©2005ElsevierTheComplementPathwaysLectinPathwayClassicalPathwayAlternativePathwayC1qC4C2C3C5toC9LysisMBLC3(H2O),C3bFactorsD,B,ProperdinMASP1,2,3C1r,C1sActivationoftheComplementSystemTerminalpathway:MAC(membraneattackcomplex)complementActivationoftheComplementSystemcomplement

TerminalpathwayDownloadedfrom:StudentConsult(on1June200602:08PM)©2005Elsevier不同途径补体系统激活的比较经典途径MBL途径旁路途径免疫复合物病原体甘露糖残基C1、C4、C2MASP、C4、C2病原体表面

C3、B、DC3转化酶C5转化酶攻膜复合体Regulationofcomplementactivation1.Self-regulation

C4b2bC3bBbC4bC3bC5b2.Controlproteins

classicalpathway:C1INHC4bpIMCPDAFalternativepathway:HICR1DAFPformationofMAC:C8bpCD59complementDownloadedfrom:StudentConsult(on1June200604:16PM)©2005ElsevierRegulationofcomplementactivationcomplementC1IHN缺陷引起血管神经性水肿RegulationofcomplementactivationcomplementRegulationofcomplementactivationcomplementRegulationofcomplementactivationcomplementRegulationofcomplementactivationcomplementBiologicalfunctionofcomplementsystem1.

complementmediatesanti-infectionimmunity

(1)Lysisofcellormicroorganisms(2)opsonization(3)inflammation

complementDownloadedfrom:StudentConsult(on1June200604:16PM)©2005Elsevier(1)complementmediatedlysisofcells溶菌溶细胞补体的溶细胞作用(2)opsonizationopsonin:C3b,C4b,iC3bcell:phagocytereceptor:CR1,CR3,CR4function:enhancephagocytosiscomplement细菌C3b受体吞噬细胞补体的调理作用(3)

inflammatoryresponse

symptoms:redness,swelling,heatandpaininflammationmediatorsanaphylatoxins:C5a,C3a,C4achemoattractant:C5acomplement肥大细胞过敏介质C5aC3a补体的过敏毒素作用C567C5aC3a补体的趋化作用中性粒细胞单核-巨噬细胞血管组织C1q——识别免疫复合物、识别病毒膜蛋白C4a——过敏毒素C4b——组成C3、C5转化酶、参与免疫粘附C2b——组成C3、C5转化酶C3a——过敏毒素、趋化因子C3b——组成C3、C5转化酶、参与免疫粘附、调理作用C5a——过敏毒素、趋化因子C5b、C6、C7——趋化因子、组成攻膜复合体C8、C9——组成攻膜复合体Ba——参与免疫调节Bb——组成C3、C5转化酶补体系统各成分的生物学作用2.ComplementmaintainshomeostasisclearanceofIC(immunecomplex):C3beliminationofapoptoticcells:C1q,C3b,iC3b清除免疫复合物3.Complementmediatesadaptiveimmunity(1)Participatesintheinductionofimmuneresponse(CD19/CD21/CD81onBcells)(2)Participatesintheproliferationanddiffere