第3章-补体系统课件

第3章补体系统

(complement,C)第1节概述概念：补体系统—是存在与人和脊椎动物血清、组织液中和细胞表面的一组经活化后具有酶活性的糖蛋白。

分类补体的固有成份：C1～C9、B、D、MBL…补体调节成分：C1抑制物、I因子、H因子…补体受体：CR1~5、C3aR、C5aR…补体的基本特性1）连锁反应性:2）放大性： C1q、C3转化酶3）不稳定性: 56C30min4）作用的双重性：生理、病理5）反应的局限性：易失活、抗体、抑制成分理化性质对热不稳定，56°C30分钟即被灭活体液中C3含量最高多数补体属球蛋白补体代谢来源：主要由肝细胞和巨噬细胞产生合成的调节：组织特异性；多因素调节分解代谢：快于其他血浆蛋白第2节补体的激活经典途径(classicalpathway)替代途径(alternativepathway)凝集素途径(lectinpathway)经典途径激活物：免疫复合物（IC）条件：①C1仅与IgM的CH3或IgG1-3的CH2结合②每一个C1与两个以上Ig补体结合位点结合

Ab必需与Ag结合激活过程：1、识别阶段—C1S（C1酯酶）形成2、活化阶段—C5转化酶形成3、膜攻击阶段—MAC形成识别阶段参与成分：C1q、C1r、C1s过程：Ag与Ab结合补体结合位点（IgG的CH2；IgM的CH3）暴露C1q激活C1r活化C1s脂酶形成。IgM（未与Ag结合）IgM（已与Ag结合）活化阶段参与成分：C4、C2、C3目的：形成C5转化酶过程：C4C4b+C4aC2C2b+C2aC4b2bC3C3b+C3aC4b2b3bC1SC1S活化阶段膜攻击阶段参与成分：C5、C6、C7、C8、C9目的：形成MAC膜攻击复合物membraneattackcomplex,MAC组成：C5b678(9)n

，其中C9分子可有12-15个大小：10-11nm内径的小孔效应：胞内渗透压降低，细胞溶解 致死量钙离子被动向胞内弥散，细胞死亡MBL途径激活物：MBLMBL产生：感染巨噬细胞、中性粒细胞活化产生TNF、IL-1、IL-6等因子肝细胞激活合成分泌期急性蛋白（包括MBL、C反应蛋白等）MBL特点：Ca离子依赖蛋白，可与甘露糖残基结合，结构与C1q类似，具有活化C1q同样的生物学功能。旁路途径激活物质：Gˉ菌内毒素，聚合IgA、IgG4等参与成分：D、B、P因子，C3、C5~C9特点感染早期发生有效防御形成放大机制可识别自己和异己第3节补体活化的调控

自身衰变调控C3转化酶（C4b2b和C3bBb）C4b、C3b、C5b仅在与固相结合时状态才较稳定

调节因子调控负调节因子：C1INH、

C4结合蛋白、I因子、H因子、MAC、DAF等正调节因子：P因子、C3肾炎因子（抗C3转化酶Ab、稳定C3bBb）C1INH的作用C4BP的作用DAF因子的作用H因子的作用DAF因子的作用S蛋白的作用同源限制因子的作用第4节补体受体CR1（C3b/C4bR):抑制补体激活；调理作用；清除免疫复合物；免疫调节CR2(C3dR,CD21)：免疫调节；是EB病毒受体CR3(iC3bR,CD18)/CR4(iC3bR/C3dg,CD18)：参与吞噬细胞生物学作用；凝集素活性；参与黏附作用第5节补体的生物学活性MAC介导细胞溶解活性片段的生物学效应

调理作用引起炎症反应清除免疫复合物清除凋亡细胞免疫调节作用等一、参与宿主早期抗感染免疫

1、溶解细胞、细菌和病毒补体活化形成的MAC可导致靶细胞溶解，是机体抵抗微生物感染的重要防御机制。

2、调理作用C3b/C4b为中间桥梁，通过其N端与细菌等颗粒性抗原或免疫复合物结合后，再通过其C端与具有补体受体（CRI）的吞噬细胞结合，由此增强吞噬细胞的吞噬作用称为补体的调理作用；细菌或免疫复合物激活补体，结合C3b/C4b后，若与具有补体受体（CRI）的RBC和血小板结合，则可形成较大的聚合物，这种效应称为免疫黏附作用。调理作用3、炎症介质作用过敏毒素样作用：可使表面具有相应补体受体的肥大细胞和嗜碱性粒细胞等脱颗粒，释放组胺等血管活性物质，引起血管扩张、通透性增强、平滑肌收缩和支器官痉挛等的作用，称过敏毒素样作用。C3a、C4a、C5a有此作用。

趋化作用：C3a和C5a等能吸引具有相应受体的中性粒细胞和单核吞噬细胞向补体激活的炎症区域游走和聚集，增强炎症反应。二、维护机体内环境稳定清除免疫复合物（IC）：补体抑制新的IC形成；可溶解已沉积的IC；IC活化补体，借助C3b与血细胞结合，而被肝细胞清除。清除凋亡细胞：C1q、C3b、iC3b可识别和结合凋亡细胞，并通过与吞噬细胞受体相互作用而清除这些细胞。清除免疫复合物三、连接天然免疫与获得性免疫的桥梁参与免疫应答的诱导：C3b参与捕捉、固定抗原，是抗原易被APC处理与提呈。参与免疫细胞的增殖、分化：补体多种成分与多种免疫细胞相互作用，调节细胞的增殖分化。参与免疫应答的效应：如细胞毒性、调理作用及清除IC。参与免疫记忆四、补体与其他酶系统的相互作用补体与凝血、纤溶、激肽系统间存在着十分密切的相互影响及相互调节关系。补体遗传缺陷可导致的疾病缺陷蛋白影响功能相关疾病C1、C2、C4免疫复合物清除缺陷SLE、化脓性感染补体传统激活途径活化缺陷C3免疫复合物清除及补体活化无能SLE、化脓性感染、肾小球肾炎C1INH炎性介质产生失控遗传性血管水肿DAF、CD59补体对宿主细胞毒作用阵发性夜间血红蛋白尿CR3外周血单核细胞黏附缺陷感染（绿脓杆菌、假单胞菌等）H因子替代激活途径活化失控致低C3血症SLE、化脓性感染、肾小球肾炎complementcomplementclassicalname:heat-labilecomponentofplasmawhich‘complements’antibodyopsonisationandkillingofbacteriaplasmaproteinsmostofwhichcirculateasinactivezymogensandareactivatedatsitesofinflammationinitiatinganenzymecascadecontributionofthecomplementsystemtodiseaseinwhichcomplementisinappropriatelyactivated,inhibitedordeficientnomenclatureC1,C2,C3………C9B,D,P(factor)I,Hfactorforregulationa,b(peptidefragment)C4bC2a,C3bBb(thecomplexthathaveenzymaticactivity)Activationpathwaytheclassicalpathwaythealternativepathwaythelectinpathwayclassicalpathwayinitiatedbyantigen—antibodycomplexeslectinpathwaymannanbindinglectin(MBL)pathwaymannanbindinglectin(MBL)isaacuteprotein,amemberofthecollectingroupofproteinsthatrecognizerepeatingsugarpatterns，asmightoccuronthecarbohydratecapsuleofbacteria．PAMP(pathogenassociatedmolecularpattern)alternativepathwayphylogeneticallyitprobablyistheolderactivationpathwayItdoesnotabsolutelyrequireantibodyforactivation．threepathwaysproceedidenticallythroughbindingoftheterminalcomponentstoformamembraneattackcomplex，whichultimatelycausescelllysisSimpleviewEffectorC3a,C4a,C5a inflammatorycellchemotaxis,mast-celldegranC3b opsoninviaC3bR,solubilisationofi-cC5b-C8,C9 membraneattackcomplex-celllysisRegulatoryproteinscontroltheamplificationcascadeshortenzymehalflifeC3

centralmoleculeofthecomplementsystemConservedmolecule–inechinoderms(ancient700Myears),longbeforeIg.ThemostversatileandmultifunctionalmoleculedescribedtodateCaninteractspecificallywithatleast25differentmoleculesC3PromotesphagocytosisSupportslocalinflammatoryreactionsagainstpathogensInstructstheadaptiveimmuneresponseUnregulatedactivationcausestissuedamageUsedbypathogensforimmuneevasionTheFabofIgGorIgMbindtoepitopesonanantigen.C1q,C1r,andC1sthenassemblesontheFcportionoftheantibodiestoformC1,thefirstenzymeoftheclassicalcomplementpathway.TheenzymeC1isabletocleaveC4intoC4aandC4b,aswellasC2intoC2aandC2b.initiationIgG2C3ConvertaseTheenzymeC1isabletocleaveC4intoC4aandC4b.TheC4bbindstoadjacentproteinsandcarbohydratesonthesurfaceoftheantigen.C2thenbindstotheC4bandC1cleavesC2intoC2aandC2b.TheC4b2afunctionsasaC3convertasethatcansubsequentlycleavehundredsofmoleculesofC3intoC3aandC3b.C5ConvertaseMuchoftheC3bbindstoadjacentproteinsandcarbohydratesontheantigentoparticipateinopsonizationwhileC3acanstimulateinflammatoryresponses.SomeoftheC3bbindstoC4b2atoformC4b2a3b,aC5convertasethatcancleaveC5intoC5aandC5b.TheMembraneAttackComplex(MAC)CausingCellLysisThisC5b6789n,ormembraneattackcomplex(MAC),putsporesintolipidbilayermembranesofhumancellstowhichantibodieshavebound.Thisresultsincelllysis.MACcanalsodamagetheenvelopeofenvelopedvirusesandputporesintheoutermembraneandcytoplasmicmembraneofgram-negativebacteriacausingtheirlysis.

TheelectronmicrographshowsholespunchedthroughthecellwallofthebacteriumShigelladysenteriaebytheterminalcomponentsofthecomplementsystem.SomeoftheholesarelargerthanexpectedforC9channelsandprobablywereenlargedlaterbytheactionoflysozymeAlternative(innate)pathwaysThereisaspontaneousconversionofC3toC3b.OrdinarilytheC3bisquicklyinactivated:theC3bbindstoinhibitoryproteinsandsialicacidpresentonthesurfaceofbody'sowncells,andtheprocessisaborted.However,bacteriaandotherforeignmaterialsthatmaygetintothebodylacktheseproteinsandhavelittleornosialicacid.SotheC3bbindsaproteincalledFactorBformingacomplexofC3b•Bb.C3b•BbisalsoaC3convertaseactingonmoreC3toform:C3b•Bb•C3b,whichisaC5convertaseandcanstarttheassemblyoftheMAC.moreC3b[apositivefeedbackloop],amplifyingwhatmighthavestartedasasmallreaction(theformationofC3bbyeitherorboththeclassicalandalternativepathways)intoamassiveproductionofC3b.ActivationoftheAlternativeComplementPathwayandFormationofC3ConvertaseActivationofthealternativecomplementpathwaybeginswhenC3b(orC3i)bindstothecellwallandothersurfacecomponentsofmicrobes.AlternativepathwayproteinFactorBthencombineswiththecell-boundC3btoformC3bB.FactorDthensplitstheboundFactorBintoBbandBa,formingC3bBb.AserumproteincalledproperdinthenbindstotheBbtoformC3bBbPthatfunctionsasaC3convertasecapableofenzymaticallysplittinghundredsofmoleculesofC3intoC3aandC3b.Mannan-bindinglectin(MBL)MBLrecognisesC3-andC4-hydroxylgroupsofmannose,glucose,fucoseandN-acetyglucosamine,andactivatestheclassicalcomplementpathwayviaMBL-associatedserineproteases1and2RecognitionofcarbohydratesonmicrobesbutnotonselfbecausethestructureiscommononmicrobesbutisabsentonselfbindingrequiresmultipleassociationsbetweentherecognitionlectindomainsandtherepetitivecarbohydratestructureonmicrobeswhicharenotonmammalianmembranesPathogen-associatedmolecularpatterns(PAMP).essentialsurfacemoleculeswhichservenon-redundantfunctions,andarethereforeconservedthesearethebasisofanevolvednon-specificrecognitionbyhostcells.Thesemolecularpatternsarerecognisedbypatternrecognitionreceptors(PRR)onhostcellsExamplesofPAMPsarelipopolysaccharides(LPSorendotoxin) Gram-negativebacterialipoteichoicacid Gram-positivebacteriaformyl-peptides bacteriamannans yeastglycolipids mycobacteriadouble-strandedRNA,polyIC virusesBenefitsofC5aandC3bMostC3bbindstoantigensonthemicrobialsurface.SomeC3bcombineswithC2aandC4btoformthethirdenzymeofthecomplementpathwaythatisabletosplitC5intoC5aandC5b.C5astimulatesmastcellstoreleasehistamineforinflammationanddiapedesis.Italsofunctionsasachemoattractantforphagocytes.ThephagocytesarethenabletobindtotheC3battachedtothesurfaceofthemicroorganismallowingforopso