医学免疫学英文

医学免疫学英文第1页/共60页immunoglobulinIntroductionThestructureofimmunoglobulinsHeterogeneityofimmunoglobulinsFunctionsofimmunoglobulinsThestructuresandpropertiesofimmunoglobulinclassesProductionofantibodies第2页/共60页immunoglobulinAntibody(Ab)

GlobulinproducedbyplasmacellsinresponsetoantigenandbindsspecificallytoparticularAg.AbisgenerallydefinedintermsoftheirspecificbindingtotheimmunizingAg

Immunoglobulins(Ig)TheIgsareglobulinwhichfunctionasAbsorsimilartoAbsinchemicalstructure.第3页/共60页IntroductionNotallofIghavethefunctionsofAb,e.g.PatientswithmultiplemyelomahaveveryhighlevelsofIg,butnotAb(toirrelevantthings))SecretedIg(sIg)-mediatedhumoralimmunityMembraneIg(mIg):BCRimmunoglobulin第4页/共60页immunoglobulinElectrophoreticmobilityofserumproteins第5页/共60页StructuresofsecretedandmembraneIgs第6页/共60页1.HeavyChainandLightChainheavychain(Hchain)50-75Kd450-550aaHchains:,,,,Isotypes:IgM,IgG,IgA,IgE,IgDLightchain(Lchain)25Kd214aaTypesofLchains:,immunoglobulinI.Basicstructureoftheimmunoglobulin第7页/共60页InanygivenIg,alltheHchainsareidentical.Anantibodymoleculehaseithertwolightchainsortwolightchains,butneveroneofeach.Inhumans,about60%ofAbmoleculeshavelightchains,and40%havelightchains.MarketchangesinthisratiocanoccurinpatientswithmonoclonalBcelltumors.immunoglobulin第8页/共60页第9页/共60页

2.Variableregionandconstantregion1)Variableregion(Vregion)

LightChain-VL(110aa)HeavyChain-VH(110aa)

immunoglobulin第10页/共60页immunoglobulin

HVR(hypervariableregion):9-12aa,3HVRsCDR(complementarity-determiningregion):CDR1,CDR2,CDR3FR(frameworkregion):15-30aa第11页/共60页immunoglobulinCDRbindswithepitopeofantigenAntigenpeptideAntigenpeptide第12页/共60页第13页/共60页

2)Constantregion(Cregion)

Lightchain-CL(110aa)Heavychain-CH(330-440aa)CH1,CH2,CH3,(CH4)immunoglobulin第14页/共60页immunoglobulin3.HingeRegion-betweentheCH1andCH2region-richinprolineresiduesflexibility:allowthetwoFabarmstobindepitope;becleavedbyproteases.-IgMandIgEhavenohingeregion第15页/共60页第16页/共60页第17页/共60页Structureoftheimmunoglobulinsimmunoglobulin第18页/共60页3DimagesoftheIgmoleculeshowthatitisnotstraightasdepictedinFigure.Itisfoldedintoglobularregions,eachofwhichcontainsanintra-chaindisulfidebond.Theseregionsarecalleddomains.LightChainDomains-VLandCLHeavyChainDomains-VH,CH1,CH2,CH3IgA,IgD,IgG(CH4inIgEandIgM)4.Domainsofimmunoglobulinimmunoglobulin第19页/共60页第20页/共60页Downloadedfrom:StudentConsult(on1June200601:58PM)©2005ElsevierBindingofanantigenbyanantibody.第21页/共60页第22页/共60页immunoglobulinFunctionsofthedomainsonIgVH和VL:抗原结合部位CH1-3和CL:Ig遗传标志CH2(IgG)、CH3(IgM):补体结合部位CH2-CH3(IgG):结合并通过胎盘CH3(IgG)CH4(IgE)：FcR结合部位第23页/共60页II.OthercomponentsintheIg1.JoiningchainJchainisasmallacidicproteinthatissynthesizedbyallplasmacellsthatsecretepolymericIgs(i.e.IgMandsIgA).Jointhemomomertopolymerimmunoglobulin第24页/共60页2.Secretorypiece(SP)Secretorycomponent(SC)isasingleglycopeptidewithMWof70KD.Producedbymucosaepithelialcells

Functions:protectsIgA,resistproteolysisinextrasecretoryliquid.

immunoglobulinlumen第25页/共60页III.ImmunoglobulinfragmentsFab(fragmentofantigenbinding)Fc(fragmentcrystalizable)第26页/共60页immunoglobulinHeterogenecityofIgCharacteristofIgBindingtoantigenImmunogenicity第27页/共60页IsotypeIsotypesaretheantigenicfeaturesofaclassofIgH(e.g.chainisdifferentfrom).Isotypesofonespeciescaninduceimmuneresponseinanotherspecies.immunoglobulinHeterogenecityofIg第28页/共60页ClassesandsubclassesofIg

IgG-(gamma)IgA-(alpha)IgM-(Mu)IgD-(delta)IgE-(epsilon)subclassIgG1~IgG4,IgA1~IgA2,IgM1~Igm2

TypeandsubtypeType:κ(Kappa)λ(lambda)

subtype:λ1~λ4immunoglobulin第29页/共60页第30页/共60页AllotypeimmunoglobulinThisreferstogeneticvariationbetweenindividualswithinaspecies.CH和CL上的一个或数个氨基酸残基的差异---

遗传标志Gm1-30第31页/共60页Idiotype(Id)immunoglobulinVariationintheVdomain,particularlyinCDR,producesidiotype.第32页/共60页FunctionsofVregionsRecognitionandbindingtoantigen

-HVR(CDR)-neutralizationoftoxins(e.g.diphtheria,tetanus);-immobilizationofmicroorganisms;-neutralizationofviralactivityAntibody:monomer(IgG,IgE)---2价dimer(sIgA)---4价Pentamer(IgM)---5价immunoglobulin第33页/共60页NeutralizationBacterialtoxinsHostcellToxinreceptorsNeutralizationbyantibodyPhagocytosisofantibody-antigencomplexbymacrophageFcreceptorFormingphagosome第34页/共60页neutralizationofviralactivity

第35页/共60页FunctionofCregions(Fcportion)1.Activationofcomplement:IgM,IgGAb(IgM、IgG)+Ag---C1q----补体经典途径

IgG4、IgA和IgE的凝聚物----补体旁路途径2.BindingtoFcreceptorofcellsOpsonization:enhancementofAguptakebymacrophages(M)Antibody-dependentcell-mediatedcytotoxicity(ADCC):NKcells.ParticipationintypeIhypersensitivity:IgE3.Passagethroughtheplacenta(IgG,CH2)andmucosa(sIgA)immunoglobulin第36页/共60页immunoglobulinOpsonizationofantibody第37页/共60页immunoglobulinAntibody-dependentcell-mediatedcytotoxicity(ADCC)第38页/共60页passagethroughtheplacenta(IgG)andmucosal(SIgA)Passagethroughmucosal(SIgA)第39页/共60页Functionofimmunoglobulinsimmunoglobulin第40页/共60页CharacteristicandfunctionofDifferentclassofIg第41页/共60页

(1)单体分子；

(2)四个亚类；

(3)血清中含量最高(75%Ig)；

(4)半衰期最长(20～23天)；

(5)3～5岁达成人水平(8.0～17mg/ml)；

(6)可与SPA结合。IgGimmunoglobulin第42页/共60页IgGimmunoglobulinFixescomplement–IgG1andIgG3fixcomplementwell;IgG4doesnotfixcomplement.2.Opsonization:enhancementofAguptakebymacrophages(M)3.Antibody-dependentcell-mediatedcytotoxicity(ADCC):NKcells3.CrossestheplacentaIgGistheonlyclassofIgthatcancrossestheplacentaanditconfersahighdegreeofpassiveimmunitytothenewborn第43页/共60页IgMimmunoglobulin1.Pentamer900kdMacroglobulin2.IgMisthefirstIgsynthesizedinlife3.IgMisthefirstIgproducedinprimaryimmuneresponse.4.IgMisagoodcomplementfixingIg5.IgMisalsoagoodagglutinatingIg6.IgMismIgM(IgD)ofBcells:7.Halftime:5Days第44页/共60页第45页/共60页IgAimmunoglobulinIgA:monomerandsecretaryserumIgA(IgA1)monomersecretoryIgA(IgA2)dimer2.sIgAexistsinsecretionssuchastears,saliva,colostrum,mucusandhasimportantroleinlocal(mucosal)immunity.3.IgAcanbetransmittedfrommothertonewborn第46页/共60页IgDimmunoglobulinIgDisfoundatlowlevelsinserum;itsroleinserumremainsunclear.IgDisprimarilyfoundonnaiveBcellsurfaceswhereitfunctionsasareceptorforantigen.3.MembraneIgDdisappearinactivatedormemoryBcell第47页/共60页IgEimmunoglobulinIgEistheleastcommonserumIg.ItbindsverytightlytoFcreceptorsonbasophilsandmastcellsevenbeforeinteractingwithantigen.Involvedinallergicreactions.IgEalsohelpstoclearparasites(e.g.worms)byeosinophils.第48页/共60页FiveClasses/Isotypes第49页/共60页Productionofantibodiesimmunoglobulin1)Polyclonalantibody2)Monoclonalantibody3)Geneticengineeringantibody第50页/共60页bearingmorethanoneepitopesAgB

cellsClonalproliferationPolyclonalantibodyImmunizingmousepAb第51页/共60页GeoregesKohlerandCesarMilstein,1984,monoclonalantibodyimmunoglobulin第52页/共60页immunoglobulinMonoclonalantibodyproduction第53页/共60页HumanMonoclonals?Itwouldbeverynicetohaveavailablehumanmonoclonals-muchmoreusefultherapeuticallyProblemsHardtogetantigen-primedBcellsInvitroprimedSCIDmiceKnock-outmiceNogoodimmortalpartnersCansometimestransformantibody-secretingBcells(EBV)immunoglobulin第54页/共60页GeneticallyengineeredantibodyChimericAbMouseVgene

+humanCgene

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