醫(yī)學(xué)免疫學(xué)英文版課件：Complement system補體系統(tǒng)

Complementsystem補體系統(tǒng)IMMUNOLOGYComplementContents1.Introduction2.ActivationoftheComplementSystem

3.Regulationofcomplementactivation4.BiologicalfunctionofcomplementsystemJulesBodet(1870-1961),比利時科學(xué)家DiscovererofComplement1894Bordet發(fā)現(xiàn)綿羊抗霍亂血清能夠溶解霍亂弧菌，加熱56℃30min阻止其活性；加入新鮮非免疫血清可恢復(fù)其活性。百日咳桿菌1919NobelPrizeComplement補體（Complement）：新鮮血液中存在一種不耐熱的成分，可輔助特異性抗體介導(dǎo)的溶菌作用。IntroductionComplement(C)

補體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＊固有成分按發(fā)現(xiàn)的先后分別命名為C1(q、r、s)、C2、…C9；＊其他成分以英文大寫字母表示，如B因子、D因子、P因子；＊補體調(diào)節(jié)蛋白多以其功能命名，如C1抑制物、C4結(jié)合蛋白、促衰變因子等；＊補體受體多以其結(jié)合對象命名，如C3aR。＊補體活化后的裂解片段以該成分的符號后面附加小寫英文字母表示。如C3a、C3b等；小片段用a，大片段用b。（人衛(wèi)出版社第5版）C2特殊，C2a為大片段，C2b為小片段。＊具有酶活性的成分在其符號上劃ˉ橫線表示。＊被滅活后的成分其符號前加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不同途徑補體系統(tǒng)激活的比較經(jīng)典途徑MBL途徑旁路途徑免疫復(fù)合物病原體甘露糖殘基C1、C4、C2MASP、C4、C2病原體表面

C3、B、DC3轉(zhuǎn)化酶C5轉(zhuǎn)化酶攻膜復(fù)合體Regulationofcomplementactivation1.Self-regulation

C4b2bC3bBbC4bC3bC5b2.Controlproteins

classicalpathway:C1INHC4bpIMCPDAFalternativepathway:HICR1DAFPformationofMAC:C8bpCD59complementDownloadedfrom:StudentConsult(on1June200604:16PM)?2005ElsevierRegulationofcomplementactivationcomplementC1IHN缺陷引起血管神經(jīng)性水腫RegulationofcomplementactivationcomplementRegulationofcomplementactivationcomplementRegulationofcomplementactivationcomplementRegulationofcomplementactivationcomplementBiologicalfunctionofcomplementsystem1.

complementmediatesanti-infectionimmunity

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

complementDownloadedfrom:StudentConsult(on1June200604:16PM)?2005Elsevier(1)complementmediatedlysisofcells溶菌溶細胞補體的溶細胞作用(2)opsonizationopsonin:C3b,C4b,iC3bcell:phagocytereceptor:CR1,CR3,CR4function:enhancephagocytosiscomplement細菌C3b受體吞噬細胞補體的調(diào)理作用(3)

inflammatoryresponse

symptoms:redness,swelling,heatandpaininflammationmediatorsanaphylatoxins:C5a,C3a,C4achemoattractant:C5acomplement肥大細胞過敏介質(zhì)C5aC3a補體的過敏毒素作用C567C5aC3a補體的趨化作用中性粒細胞單核-巨噬細胞血管組織C1q——識別免疫復(fù)合物、識別病毒膜蛋白C4a——過敏毒素C4b——組成C3、C5轉(zhuǎn)化酶、參與免疫粘附C2b——組成C3、C5轉(zhuǎn)化酶C3a——過敏毒素、趨化因子C3b——組成C3、C5轉(zhuǎn)化酶、參與免疫粘附、調(diào)理作用C5a——過敏毒素、趨化因子C5b、C6、C7——趨化因子、組成攻膜復(fù)合體C8、C9——組成攻膜復(fù)合體Ba——參與免疫調(diào)節(jié)Bb——組成C3、C5轉(zhuǎn)化酶補體系統(tǒng)各成分的生物學(xué)作用2.ComplementmaintainshomeostasisclearanceofIC(immunecomplex):C3beliminationofapoptoticcells:C1q,C3b,iC3b清除免疫復(fù)合物3.Complementmediatesadaptiveimmunity(1)Participatesintheinductionofimmuneresponse(CD19/CD21/CD81onBcells)(2)Participatesintheproliferationanddiffere