醫(yī)學(xué)免疫學(xué)英文版課件：Leukocyte Differentiation Antigens Cell Adhesion Molecules

LeukocyteDifferentiationAntigens

CellAdhesionMoleculesContentsConceptofleukocytedifferentiationantigens

（白細(xì)胞分化抗原）Conceptofclusterofdifferentiation

（CD分子，分化群）CelladhesionmoleculesLeukocytedifferentiationantigensLeukocytedifferentiationantigens:Cellsurfacemoleculeswhichmayappearordisappearfromthecellmembraneofleukocytesinthedifferentstagesofdifferentiationandactivation.

（第6版p58）Leukocytedifferentiationantigensarealsofoundoncellsotherthanleukocytes,suchaserythrocytes,endothelialcells,epithelialcells.ImmunoglobulinsuperfamilyCytokinereceptorfamilyC-TypelectinsuperfamilyIntegrinfamilyTNFsuperfamilyTNFreceptorsuperfamilyClassificationofLDAClusterofdifferentiation(CD):Cellsurfacemoleculescanberecognizedbyparticularmonoclonalantibodies.Allofthemonoclonalantibodiesthatreactwithaparticularmembranemoleculearegroupedtogetherasaclusterofdifferentiation(CD).EachnewmAbthatrecognizesacellsurfacemoleculeisanalyzedforwhetheritfallsintoarecognizedCDdesignation;ifnot,itisgivenanewCDdesignationthatreflectsanewmembranemolecule.CD1~CD363,upto363mostrecently(asof2010)inhumanAClusterofmAbsrecognizeoneMolecule=1CDCD3BC3JXT32GV6UCHT1OKT3...RIV7SP35C1805CD4OKT4ClusterClusterClustersHumanCDGroupsCD（example）TcellCD2、CD3、CD4、CD5、CD8、CD28、CD152(CTLA4)、

CD154(CD40L)、CD272(BTLA)、CD278(ICOS)、CD294(CRTH2)BcellCD19、CD20、CD21、CD40、CD79a(Ig)、CD79b(Ig)、

CD80(B7-1)、CD86(B7-2)、CD267(TACI)、CD268(BAFFR)、

CD269(BCMA)、CD307(IRTA2)Myeloidcell

CD14、CD35(CR1)、CD64(FcRI)、CD256(APRIL)、

CD257(BAFF)、CD312(EMR2)

Platelet

CD36、CD41、CD42aCD42d、CD51、

CD61、CD62PNKcellCD16(FcRIII)、CD56(NCAM-1)、CD94、CD158(KIR)、

CD161(NKR-P1A)、CD314(NKG2D)、CD335(NKp46)、

CD336(NKp44)、CD337(NKp30)

Non-lineageCD30、CD32(FcRII)、CD45RA、CD45RO、CD46(MCP)、

CD55(DAF)、CD59、CD252(OX40L)、CD279(PD1)、

CD281CD284(TLR1-TLR4)、CD289(TLR9)、CD305(LAIR-1)、

CD306(LAIR-2)、CD319(CRACC)HumanCDGroups

CD（example）AdhesionmoleculesCD11a-CD11c、CD15、CD15s(sLx)、CD18、

CD29、CD49aCD49f、CD54(ICAM-1)、

CD62E、CD62L、CD324(E-cadherin)、

CD325(N-cadherin)、CD326(EpCAM)Cytokine/

CD25(IL-2R)、CD95(Fas)、CD116-CDw137、CD178(FasL)、ChemokinereceptorsCD183(CXCR3)、CD184(CXCR4)、CD195(CCR5)、

CD261CD264(TRAIL-R1TRAIL-R4)Endothelia

CD105(TGF-RIII)、CD106(VCAM-1)、CD140(PDGFR)、

CD144、CD299(DCSIGN-related)、

CD309(VEGFR2)、JAM1(CD321)、JAM2(CD322)CarbohydratestructuresCD15u、CD60aCD60c、CD75、CDw327CDw329DendriticcellsCD80,CD86,CD85Stemcells

CD133、CD243

Erythrocytes

CD233CD242

StromalcellsCD331-334（FGFR1-FGFR4）TheCDsystemiscommonlyusedascellmarkersCD8CD8cytotoxicCelltypesandsubtypesdefinedbyCDsBcellTcellCD4+TcellTregs(CD4+CD25+)Typeofcell

CDmarkers

stemcells

CD34+,CD31-allleukocytegroupsCD45+Granulocyte

CD45+,CD15+Monocyte

CD45+,CD14+Tlymphocyte

CD45+,CD3+Thelpercell

CD45+,CD3+,CD4+CytotoxicTcell

CD45+,CD3+,CD8+Blymphocyte

CD45+,CD19+orCD45+,CD20+Thrombocyte

CD45+,CD61+Naturalkillercell

CD16+,CD56+,CD3-RulesforassigningaCDnumberatleastoneWorkshop—characterizedantibodyandgoodmoleculardata.theantigenisexpressedonthesurfaceofcellsinvolvedinimmunereactions.theantibodiesreactwithprimarycells(notjusttransfectantorrecombinantprotein).theantibodyisavailable.CDactsasReceptorsorLigands.Initiatesasignalcascade,alteringthebehaviorofthecell,orhasotherfunctions,suchascelladhesion.FunctionsofCDsMediatecell-cellinteraction:Homing,activation,effecterfunctionsFunctionsofCDs2.Receptorsrecognizeexogenousorsolublesubstance:pathogens,antibodies,cytokinesCDsrelatedtoTcellactivationTCRsignalingCD4andCD8?function?transmembraneglycoprotein?co-receptorofTcell*CD4:firstandseconddomainsbindtononpolymorphicregionofMHCⅡmolecules*CD8:IgV-likedomainofchainbindstononpolymorphic3regionofMHCⅠmolecules

*forcelladhesion*InvolvedinTCR-CD3signaltransductionAPCT細(xì)胞StructureofCD4StructureofCD8CCR51.CD4isaprimaryreceptorusedbyHIV-1togainentryintohostTcells.2.HIV-1attachestoCD4withaproteininitsviralenvelopeknownasgp120.ThebindingtoCD4createsashiftintheconformationofgp120allowingHIV-1tobindtoothersurfacereceptorsonthehostcell,thechemokinereceptors

CCR5.Followingastructuralchangeinanotherviralprotein(gp41),HIVinsertsaintothehostcellthatallowstheoutermembraneofthevirustofusewiththecellmembrane.3.HIVinfectionleadstoaprogressivereductioninthenumberofTcellspossessingCD4receptors.Therefore,medicalprofessionalsrefertotheCD4counttodecidewhentobegintreatmentforHIV-infectedpatients.Normalbloodvaluesare500-1200x106/L.CD40andCD40L(CD154)BCRcomplexco-receptorCDsrelatedtoBcellactivationCD79/CD79HeterodimercytoplasmicdomainscontainITAM.Function:1.transfersthesignalsthatleadtoBcellactivation.2.transportstheIgBCRsignalingCD19/CD21/CD81CD19/CD21/CD81interactionswithcomplementassociatedwithantigenplayaroleinantigen-inducedB-cellactivation.CD21=CR2,C3dR,EBVRCDsconstitutingFcRfamilyDifferenttypesofhumanFcreceptorsRoleofFcRI(CD64)intheAb-mediatedopsonizationofmicrobesRoleofFcRIII(CD16)andFcRIinADCC(antibody-dependentcell-mediatedcytotoxicity)Celladhesionmolecules,CAMAgroupofproteinsinvolvedinadhesionbetweencellsorbetweencellsandextracellularmatrix(ECM)

CAMsandCDmoleculesarerespectivelydesignatedaccordingtothedifferentaspectsofthesemolecules.CAMsaregroupeddependingontheiradhesionfunctions.CDmoleculescontainthemajorityofCAMsthathaveobtainedCDdesignation.AminorityofCAMshavenotbeengivenCDdesignation.CategoriesofCAM1.IgSF(immunoglobulinsuperfamily)2.Integrinfamily3.Selectinfamily4.Cadherinfamily5.Others:CD44

IntegrinIntegrinfamilyissonamedbecausethemoleculesofthisfamilyprimarilymediatethecellularadherencetoextracellularmatrix,enablingcellsandextracellularmatrixtoformtheintegration.Structure:Heterodimericproteinsconsistingoftwonon-covalentlyboundpolypeptides(chain1outof18,andchain1outof8).Componentsofintegrinfamily1:VLA(verylateactivationantigen,12members),ligand:VCAM-1(vascularcelladhsionmolecule-1) Tcellactivation(co-stimulationandadhesion)2:LFA-1(CD11a,lymphocytefunctionassociatedantigen-1,4members);Mac-1(CD11b)ligand:ICAM-1(intercellularadhesionmolecule-1)Tcellactivation,circulation,inflammation

3:gpIIbligand:Fg(fibrinogen)PlateletaggregationDistributionBroaddistributiononthesurfaceofcells.SelectinfamilyincludesL-selectin,P-selectinandE-selectin,whichplayimportantrolesinleukocyteadhesiontoendothelium,inflammationandlymphocytehoming.

Selectinfamily1.StructureTransmembraneglycoproteins,withanumberofextracellulardomainshomologoustothoseseenincomplementcontrolproteins(CCP).TheextracellularregionalsocontainsadomainrelatedtotheEGFreceptorandadistalCtypelectin-likedomain.2.Membersofselectinfamily

L-selectin:leukocytes(Cd62L)

P-selectin:plateletsandmegakaryocytes(Cd62P)

E-selectin:activatedendothelia(Cd62E)3.Ligand:carbohydrates,suchasCD15sFunctionsofCAM1.Servingasco-receptorsandprovidingco-stimulatorysignalsinimmunecellsrecognitionandactivationCD4/CD8-----MHCII/I(coreceptor)CD28-----B7(costimulation)2.Adhesionbetweenleukocytesandvascularendothelialcellsininflammation3.LymphocytehomingandrecirculationThesequenceofeventsinthemigrationofbloodleukocytestositesofinfection.Selectinsmediateweaktetheringandrollingofbloodneutrophilsontheendothelium;integrinsmediatefirmadhesionofneutrophilstotheendothelium,andchemokinesactivatetheneutrophilsandstimulatetheirmigrationthroughtheendotheliumtothesitesofinfection.RoleofCAMsinmigrationofna?veandeffectorTcells.Na?veTcellshometolymphnodeasaresultofL-selectinbindingtoitsligandonHEVs(high-endothelialvenules),whicharepresentonlyinlymphnodes.ActivatedTcellshometositesofinfectioninperipheraltissues,andthismigrationismediatedbyE-selectin,P-selectinandintegrins.LeucocytesadhesiontobloodvesselApplicationofCD,CAMandTheirmAb1.Elucidationofpathogenesis

CD4andAIDS,gp120bindstoCD42.Applicationindiagnosis

leukemia,AIDS(ratioofCD4+toCD8+Tcells)3.ProphylacticandTherapeuticapplicationGraftrejection:Anti-CD3,Anti-CD25non-Hodgkin’slymphoma:Anti-CD20NaturalKillercells3rdlineageoflymphocytesFunctionininnateimmunitytoprotectagainstviruses,bacteria,&tumorsProducecytokines&killabnormalcellsNKCells-Wheredotheylive?~5-20%peripheralbloodlymphocytes~5%lymphocytesinspleenAbundantinliverLowfrequencyinthymus,bonemarrow,uninfectedlymphnodesandlymphatics>90%oflymphocytesindecidualtissueNKCells-Whatdotheydo?Cellmediated-cytotoxicityAntibody-dependentcellularcytotoxicity(ADCC)Early

g-interferonproductionSecretionof

TNFa,LTa,GM-CSF,IL-5,M-CSF,IL-3,IL-10,IL-13,MIP-1a,

MIP-1b,RANTES,etc.NKcells-Howdotheykill?Predominantlyperforin/granzymesKagietalNature369:31,1994Secretedormembrane

TNFaDegliantonietalJExpMed162:15121985FasligandAraseetalJExpMed181:1235,1995TRAILZamaietalJExpMed188:2375,1998NKcells-whataretheygoodfor?Protectionfromviruses&tumorsImmunesurveillancefor

‘MissingSelf’NKcellspreferentiallykillcellsthathavelostMHCclassIProvidesprotectionagainstcellsescapingTcellrecognition（tumorandviral-infectedcellstendtoreducetheexpressionofMHCItoavoidtheattackfromTcells）PredictsexistenceofinhibitoryreceptorsforMHCclassIthatsparenormalcellsfromNKcellattack

Karreetal.Nature319:675,1986HumanChr19q13KillercellIg-likeReceptors(KIR)Activating&inhibitoryNKreceptorsKillerCellIg-likeReceptors(KIR)Igsuperfamily7-12functionalgenesonhumanchromosome19q13Extensiveallelicpolymorphism(norearrangement)Mono-allelicexpressionpossibleInhibitoryKIRrecognizepolymorphicHLA-A,-B,and–CActivatingreceptorshavenointrinsicsignalingcapacity..associatewithDAP12ITAM-adapterproteinExpressedbysubsetsofNKcellsandmemoryTc