免疫学课件complement

Complement systemXiaojianWangInstituteofimmunology,ZJUhttp:/Complementn Introductionn ActivationoftheComplementSystemn Regulationofcomplementactivationn BiologicfunctionofcomplementsystemJules Bodet(1870-1961),Discoverer of complementNobel prize in 1919complementIntroductioncomplementComplement(C)-补 体(complement，C)是 存 在 于 正 常 人 和 动 物 血 清与 组 织 液 中 的 一 组 经 活 化 后 具 有 酶 活 性 的 蛋 白 质。是 一 种 不 耐 热 的 成 分，可 辅 助 和 补 充 特 异 性 抗 体，介导免疫溶菌、溶血作用，故称为补体。ComplementSystem-补 体 是 由30 余 种 补 体 固 有 成 分、补 体 受 体 和 细 胞 膜补 体 调 节 蛋 白 的 多 分 子 系 统，故 称 为 补 体 系 统（complement system）。IntroductionComponentsofCsystem 1.InnateCcomponents2.RegulatoryProteins3.Complementreceptor complementIntroductionComponentsofCsystem 1.innatecomponentsclassicalpathway:C1q,C1r,C1s,C4,C3,C2Alternativepathway:B,D,P,C3MBLpathway:MBL,MASPterminalpathway:C5,C6,C7,C8,C9 complementIntroduction2.regulatoryproteinsC1-INH,C4-BP,Ifactor,HfactorSprotein,Sp40/40,decay-acceleratingfactor(DAF)plementreceptorCR1CR5,C3aR,C4aR,C5aRcomplementIntroduction nomenclature:C-complementC1,C2,C3,C5B,D,H,I,PfactorC4B,DAFa-smallfragmentC2a,C3ab-largefragmentC2b,C3b,C5b-activated(enzyme)C1i-inactivatediC3bcomplementThepropertiesofComplementglycoprotein:globulinLabiletoheat:TheactivityofCisdestroyed(inactivated)byheatingserumat56 for30minutes.Cproducedcells:HepatocytesandMacrophagesBelongsacutephaseproteinzymogentoprotease:numberofcomplementproteinsarezymogensthatcanbeactivatedbyproteolyticcleavagecomplementActivationoftheCSystemPathwaysofcomplementactivation:triggered-enzymecascade 1.Classicalpathway2.Alternativepathway3.MBLpathwayMBL:mannose-bindinglectincomplementClassicalpathway1.C1activationbyAg-Abcomplex2.C4andC2activationgenerationC3convertase3.C3activation(generationofC5convertase)4.GenerationofC5convertasemarkstheendoftheclassicalpathwaycomplementThreesteps：Classicalpathway1.Recognition(C1activation)involved：C1q,C1r,C1sAg+AbICbind C1qC1rC1sC12.Activationinvolved：C4,C2andC3(1)C4andC2activation,generationofC3convertase(2)C3activation(generationofC5convertase)3.Attack(terminalpathway)involved：C5,C6,C7,C8,C9themembraneattackcomplex(MAC):C5b6789theMACcauseslysisofcellsActivator:Ag-Abcomplex/ICCombindingCH2ofIgGorCH3ofIgMOneofIgMmoleculeortwomoleculesofIgGareneeded.IgMIgG3IgG1IgG2Solubleantibodycantactivatecomplement complementRecognition(C1activation)classical pathway complementC1 moleculeActivationThecomponentsinvolved:C4,C2andC3(1)C4andC2C3convertase(2)C4,C2,C3C5convertaseCa+C1rC1sC1qC4C4abClassicalPathwayGenerationofC3-convertaseC4bMg+C4aCa+C1rC1sC1qC2C2bbC2aC4b2aisC3convertaseClassicalPathwayGenerationofC3-convertaseC4bMg+C4aCa+C1rC1sC1qC2bC2aC3C3abC4b2a3bisC5convertase;itleadsintotheMembraneAttackPathwayClassicalPathwayGenerationofC3-convertasecomplementcomplementAttack(terminalpathway)involved：C5,C6,C7,C8,C9themembraneattackcomplex(MAC):C5b6789theMACcauseslysisofcellscomplement Terminalpathway(MAC)Terminal pathwaycomplementAlternativepathwayActivators：LPS(endotoxin),certaincomplexpolysaccharides,IgAandIgG4 AlternativepathwayItisratherdifferentfromtheMBLandclassicalpathway.1.noC1,C4andC2involvedfactorBandfactorDinvolved2.thepresenceofsuitableactivatorsurfaces,suchasbacterialandfungalcellwalls.3.C3b:fromtheclassicalpathway;spontaneousproducedC3b complement Charactersofalternativepathway1.itcanrecognize“self”and“non-self”2.theamplificationloopMannan-bindinglectinpathwayActivators：MBL(similartoC1q,hexamer)MBLrecognizescertaincarbohydratesexpressedonthesurfaceofmicroorganismsMBLactivatetwoMBL-associatedserineproteases-MASP-1andMASP-2cleavesC3cleavesC4,C2togenerateactivatethealternativetheC3convertase(C4b2a)pathwaydirectlyRegulationofcomplementactivation1.Self-regulationC4b2bC3bBbC4bC3bC5b2.ControlproteinsClassicalpathway:C1INHC4bpIMCPDAF(C3b 和Bb)Alternativepathway:HICR1DAFMCPProperdinFormationofMAC:C8bpCD59(MIRL)complementRegulation of complement activationcomplementRegulation of complement activationcomplementRegulation of complement activationcomplementARegulationofcomplementactivationcomplementBiologicfunctionofcomplementsystem1.mediatesanti-infectionimmunity(1)Lysisofcellormicroorganisms(2)opsonization(3)inflammation complementcomplementmediatedthelysisofcellscomplementopsonization opsonin:C3b,C4b,iC3bcell:phagocytereceptor:CR1,CR3,CR4function:enhancephagocytosiscomplement(3)inflammatoryresponse symptoms:redness,swelling,heatandpaininflammationmediators:C5a,C3a,C4a(anaphylatoxins)C5a(chemotaxis)complementBiologicfunctionofcomplementsystem complement2.Complementmaintainshomeostasis1)clearanceofICC3b2)eliminationofapoptosiscellsC1q,C3b,iC3b3.Complementmediatesadaptiveimmunity1)Inductionofimmuneresponse2)Proliferationanddifferentiationofimmunecellsc3d3)Effectivestageofimmuneresponse4)Immunememory4.InteractionwithotherenzymesystemSummaryReview the differences between the three pathways of complement in terms of how they are activated.Why the complement do not attack autologous cells?Thanks!