免疫学ii 03球蛋白

医学免疫学第三章免疫球蛋白Lecture3Immunoglobulin1.Concepts2.Structureofimmunoglobulins3.Immunogenicityofimmunoglobulins(Isotypes,Allotypes,&Idiotypes)4.Antibodyclasses5.Thefunctionofantibodies6.ArtificialAntibodyOutlineofthelectureEmilvonBehring(1845-1917)antibody-In1890byvonBehringandKitasatodescribedanactivityinserumoftoxin-immunizedanimalsthatneutralizedtoxin.Transferofimmuneserumcouldprotectnaïveanimalsfromdiphtheriaortetanus.HistoryAntibodies(Ab)

areproductsobtainedbyantigenstimulatingBlymphocytes,thenBcellswillproliferateintoplasmacellstoproducespecificantibodieswhichcanreactspecificallywithcorrespondingantigens.Immunoglobulins(Ig)

areallthoseglobulinswhichhavethefunctionorstructureofantibody.Twokindsofimmunoglobulins:

>secretedimmunoglobulins(sIg):Antibody >membraneimmunoglobulins(mIg):BCRDay02468RestingBcellAntibodyformingcell(plasmacell)YYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYYY抗体

(antibody,Ab)：是B细胞接受抗原刺激后增殖分化为浆细胞所产生的糖蛋白。主要存在于血清等体液中，能与相应抗原特异性结合显示免疫功能。是介导体液免疫的重要效应分子。免疫球蛋白（Immunoglobulin，Ig）：具有抗体活性或化学结构与抗体类似的球蛋白。

---分泌型（secretedIg,sIg）:Ab---膜型（membraneIg,mIg）:BCR1.Concepts2.Structureofimmunoglobulins3.Immunogenicityofimmunoglobulins(Isotypes,Allotypes,&Idiotypes)4.Antibodyclasses5.Thefunctionofantibodies6.ArtificialAntibodyOutlineofthelectureStructureofimmunoglobulinsBasicstructureHeavychainandLightchain（重链和轻链）VariableregionandConstantregion（可变区和恒定区）OtherstructuresHingeregion（铰链）Joiningchain（J链）

Secretorycomponent(SC，分泌片)Domains（功能区）FragmentationofIgbyproteolyticcleavage1.BasicstructureHeavychainandLightchainVariableregionandConstantregionOtherstructuresThebasicstructureFour-polypeptidesstructureTwoidentical

heavychain

andtwoidentical

lightchain

(2H+2L)Lightchaincombinewithheavychainthroughinterchain

disulfidebonds;andtwoheavychainscombinewitheachotheralsothroughinterchain

disulfidebonds.Heavychain(H):

440-550aminoacids;canbedividedintofivepolypeptides,respectivelynamed

α,γ,δ,ε,μ

polypeptides.Correspondently, antibodycanbedivided

IgA,IgG,IgD,IgE,IgM.

Lightchain(L):

about220 aminoacids.canbedivided intotwopolypeptides,respectivelycalled

κ

chainand

λ

chain.

1)

Heavychain(H)&Lightchain(L)Accordingthedegreeofvariabilityinaminoacidsequence.

Vregion

aretheN-terminalquarteroftheH-chainandtheN-terminalhalfoftheL-chain.Cregion

aretheC-terminalthree-quartersoftheH-chainandtheC-terminalhalfoftheL-chain.2)Variableregion(Vregion)andconstantregion(Cregion)Vregions

(VL+VH)arethesitewhereantigensbindspecificallytoantibodies.Fab

(antigenbindingfragment)aretheN-terminalhalfoftheH-chainandalloftheL-chain.Fc

(crystallizedfragment)aretheC-terminalhalfoftheH-chainfragmentthatcrystallized).FabFcSequencevariabilityinVregionsisconcentratedinseveralregions,called

Hypervariableregions(HV).hypervariableregionsarealsocalled

complementary-determiningregions(CDRs).

Itiscomlementarytothestructureofepitope.Frameworkregions(FR):

theremainregionsinVregions.Hypervariableregions(HV,CDR)andframeworkregions(FR)HingeregionJoiningchainandsecretorycomponent(SC)

3)

OtherstructuresIgG,IgDandIgAcontainanextendedpeptidesequencebetweenCH1andCH2domains.Thisregion,calledhingeregion.Berichinprolinesandisflexible,givingIgG,IgDandIgAsegmentalflexibility.IgM,IgElackhingeregion,buttheyhaveCH2inthisregionandhaveextraCH4.(1)

Hingeregion

(exceptforIgE,IgM)FlexibilityofimmunoglobulinsJoiningchain

aidtocombinemonomersinto polymers.FivemoleculesofIgMusually polymerizeintoalargerpentamer. Secretory

IgA

isadimmer.Secretorycomponent(SC)

canpreventthe secretoryIgAdimmersfromdegradationof otherproteases.SecretoryIgAalways distributeonlumenalsurface.(2)

Joiningchainandsecretorycomponent(SC)SecretoryIgAisadimmerIgMpolymerizeintoapentamer2.

ThedomainsofIgBothH-andL-chainshaveintrachaindisulfidebridgesevery90aminoacidresidues,whichcreatepolypeptideloops,

domains,,of110aminoacids.---Hchain

Variableregion

isonedomain,referredtoasVH;constantregionhasthreeorfourdomains,referredtoasCH1,CH2,CH3,CH4.(IgG,IgA,IgD

hasthreedomains-CH1,CH2,CH3inCregion;whileIgM,IgEhasfourdomains-CH1,CH2,CH3,CH4inCregion).

---L-chain

Variableregionisonedomain,referredtoasVL;constantregionalsohasonlyonedomain,referredtoasCL.DomainsofIgG,IgA,IgD1)Hchain:>Vregion:VH;>Cregion:CH1,CH2,CH3.(IgE,IgMhasanotherCH4)2)Lchain:>Vregion:VL;>Cregion:CL;3.ImmunoglobulinfragmentsPapaindigestion:

>Fabfragmentantigenbinding>Fcfragment.crystallizablePepsindigestion:

F(ab’)2(composedoftwoFab-likefragments);TheFcfragmentisdegradedintomanysmallfragment.Twoimportantproteases1.Concepts2.Structureofimmunoglobulins3.Immunogenicityofimmunoglobulins(Isotypes,Allotypes,&Idiotypes)4.Antibodyclasses5.Thefunctionofantibodies6.ArtificialAntibodyOutlineofthelecture抗体的异质性不同抗原表位刺激所产生不同的抗体分子，其识别抗原的特异性不同（V区不同）同一抗原表位诱生的不同类型的抗体，其识别抗原的特异性相同（C区不同）免疫球蛋白有不同种类免疫球蛋白同时可作为抗原，其具有不同的抗原特异性免疫球蛋白具有异质性Ig的类型类（class）：根据CH抗原特异性的不同分为五大类

γμαδεIgGIgMIgAIgDIgE

亚类（subclass）：同一类免疫球蛋白根据重链的免疫原性和二硫键的数目，位置的不同，可分为：IgG1-G4；IgA1-A2；IgM1-M2。型（type）：根据CL免疫原性的不同分为两个型：κ型和λ型亚型（subtype）：同一型免疫球蛋白可根据CL的N端氨基酸排列的差异，又可分为亚型Ig的血清型同种型（isotype）指同一种属所有个体的Ig分子共有的抗原特异性标志，位于IgC区。同种异型（allotype）指同一种属不同个体间Ig分子所具有的不同的抗原特异性标志，位于IgC区。独特型（idiotype）指同一个体不同B细胞克隆产生的Ig分子所特有的抗原特异性标志，独特型由若干个抗原决定基组成，又称为独特位，主要存在于V区。

isotype:

antigenicfeaturesofaclassofimmunoglobulin。

allotype:

varyamongindividualswithinaspecies

idiotype:

uniqueV-regionaminoacidsequencesofthehomogeneousimmunoglobulinmoleculesproducedbyasingleB-cellclone.1.Concepts2.Structureofimmunoglobulins3.Immunogenicityofimmunoglobulins(Isotypes,Allotypes,&Idiotypes)4.Antibodyclasses5.Thefunctionofantibodies6.ArtificialAntibodyOutlineofthelecture

immunoglobulinclassesThesearemonomer

formsastheyappearwhenexpressedasaBcellantigenreceptor.Whensecreted,thestructurescanbequitedifferent.IgMisa

pentamer

inserum,andIgAcanbea

dimer.ImmunoglobulinIsotypesareDistributedtoDifferentPartsofTheBody

IgM–Blood

IgG–Tissues

IgA–Mucosa

IgE-SurfacesIgG:invascularandextravascularspaces,alsoinsecretions;themostabundantIg;theonlyantibodyclassestocrosstheplacenta.Itsmainfunctionistoprovidethemainimmunitytomostbloodborneinfectiousagents.IgGIgM:thefirstantibody

producedinanimmuneresponse;canbeexpressedonthesurfaceofBcellasanantigenreceptor.itsmainfunctionisdefendingearlyphasejnfections.IgMPentamericIgMIgA:serumIgAandsecretaryIgA.MostIgAissynthesizedinmammaryandsalivaryglands,andalongtherespiratory,gastrointestinalandgenitourinarytracts.SecretaryIgAisthemajorimmunoglobulinpresentinexternalsecretionssuchascolostrums,milk,andsaliva.IgADimericIgAIgD:lowquantitiesinthecirculation.ItsprimaryfunctionisactingasanantigenreceptoronBlymphocytes.mIgMmIgDMatureBActivatedBImmatureBIgDIgE:verylowquantitiesinserum.Itplayasignificantroleinactivatingmastcells,enhancingacuteinflammationandinallergicreactions.AbmediatedallergyispredominantlyassociatedwithIgE.IgEPropertiesandbiologicalactivitiesoffiveclassesofIgProperty/activityIgGIgMIgAIgEIgDHeavychainγμαεδActivatesclassicalcomplementphathway++___Crossplacenta+____PresentonmembraneofmatureBcells（BCR）_+__+BindstomacrophageFcreceptors++___Presentinsecretions__+__Inducesmastcelldegranulation（脱颗粒）___+_1.Concepts2.Structureofimmunoglobulins3.Immunogenicityofimmunoglobulins(Isotypes,Allotypes,&Idiotypes)4.Antibodyclasses5.ThefunctionofIg6.ArtificialAntibodyOutlineofthelectureThefunctionofIgV区的功能特异性结合抗原（neutralization，中和作用），例如病毒，细菌，毒素等，发挥免疫效应。抗体结合相应抗原分子，发挥中和作用。

BCR特异性识别并结合抗原分子，介导体液免疫应答。CombinationofHVandepitopeVH

hasthreehypervariableregions(HV,CDR);VL

alsohasthreehypervariableregions(HV,CDR).ThesixhypervariableregionsinVHandVLconsistofthesitebindingtoepitope.complementarity-determiningregions

peptidepeptideepitopebindingofHVandepitopeNeutralizationByAntitoxinAntibodiesNeutralizationByAntiviralAntibodiesBacterial‘Neutralization’ByAbC区的功能

激活补体

IgM、IgG1~3

激活补体经典途径凝聚的IgA或IgG4

激活补体旁路途径与细胞表面FcR结合

1）调理作用（opsonization)；

IgFc段与吞噬细胞表面FcR结合促吞噬；

2）抗体依赖的细胞介导的细胞毒作用（Ab-dependentcell-mediatedcytotoxicity,ADCC)3)介导I型超敏反应

穿过胎盘和粘膜

IgG通过胎盘，提供被动免疫保护；

sIgA穿过粘膜，参与黏膜局部的抗感染免疫。InCHdomainsof

IgMandIgG,

thereexistC1qreceptorsthatcanbindtoC1q(onesubunitofC1).Afterbindingtoantigen,formingimmunecomplex,IgGorIgMantibodiescanactivatethe

classicalpathway

ofcomplementleadingtolysisofthetargetcellsandattractionimmunocytestotheactivationsite.Complementactivation动画演示调理吞噬作用

IgG类抗体与靶细胞表面抗原特异性结合，效应细胞（NK细胞、巨噬细胞、中性粒细胞）借助所表达的IgGFcR与靶细胞表面IgG的Fc段结合，从而直接杀伤靶细胞动画演示ADCC作用---MastcellsandbasophilshavereceptorsforFcportionofIgE.BindingofantigenstoIgEalreadyboundtoFcreceptorsforIgEonmastcellsresultsindegranulationandinducingthetypeIhypersensitivity.IgEcaninducetheclassIhypersensitivity.免疫损伤

IgEAntibodyBindsToMastCells&BasophilsToArmThemForMediatorRelease1.Concepts2.Structureofimmunoglobulins3.Antibodyclasses4.Immunogenicityofimmunoglobulins(Isotypes,Allotypes,&Idiotypes)5.Thefunctionofantibodies6.ArtificialAntibodyOutlineofthelecture第一代抗体polyclonalantibody，PcAb(多克隆抗体)第二代抗体Monoclonalantibody，McAb(单克隆抗体)第三代抗体GeneticallyengineeringAb,GeAbRecombinantantibody

，Re