05主要组织相容性抗原及其基因复合体(English version)

6主要组织相容性抗原及其基因复合体MajorHistocompatibilityAntigensandTheirGeneComplexHistocompatibility(transplantation)antigens:AntigensontissuesandcellsthatdeterminetheirrejectionwhengraftedbetweentwogeneticallydifferentindividualsDEFINITIONS:MHCcomplex:GroupofgenesonasinglechromosomeencodingtheMHCantigensHLA(humanleukocyteantigens):MHCantigensofman(firstdetectedonleukocytes)H-2antigens:MHCantigensofmouse2.Instudiesonresponsestoantigens,MHCgeneproductswerefoundtocontrolimmuneresponses,calledtheimmuneresponse(Ir)genes6-1ThebasicstructureandcellulardistributionofMHCmoleculesThebasicstructureofMHCmoleculesMHC-IMHC-IIa2a3a1b1b2b2ma1a2Peptide-bindingregionTransmembraneregionimmunoglobulin-likeregion1.ClassIMHC:a.ClassIMHCmoleculescontaintwoseparatepolypeptidechains(1)MHC-encodedalpha(orheavy)chain;43kDa(2)non-MHC-encodedbetachain(beta2microglobulin)12kDa(15#)Figures1showsthestructureofclassIMHC.IThebasicstructureofMHCmoleculea.containstwonon-covalentlyassociatedpolypeptidechains,bothMHC-encodedandpolymorphic2.ClassIIMHCFigure3showsthestructureofclassIIMHC.(1)alphachain;34kDa(2)betachain;29kDab.fourseparateregions(1)peptide-bindingregiongroove:a1+b1thegreatestpolymorphicvariabilityintheaminoacidsisinthosefacingthegrooveMHC-IIMHC-IIb1b2a1a2Peptide-bindingregionTransmembraneregionimmunoglobulin-likeregionIIcellulardistributionofMHCmoleculeMHC-IMHC-IIPeptidechainab2mabMW（kDa）4411.531-3426-29MolecularFormulaa/b2m（a/b）2Extracellularregiona1、a2、a3b2ma1、a2b1、b2Peptidebindingregiona1/a2a1/b1CD4/CD8bidingsitea3b2HLAcodinggeneA、B、CDRA、DPA、DQADRB、DPB、DQBcellulardistributionNearlyallnucleatedcellsMacrophage,DC,thymicepithelialcell,BcellandactivatedcellTable6-1thecompositionandstructureofMHC-IandMHC-IIofhumanHLA-I：A，B，C，E，G（b2m）HLA-II：DR，DQDPDRa,DRb，DQa,DQb，DPa,DPbHLAmoleculesachainRINGDPDMLMP2LMP7DQDRB2A2B1A1ABTAP1TAP2B2A2B3B1A1B*AClassIIClassIIIClassIchromosome6ClassIIClassIIIClassIDPDQDRC4BC4AB1C2HSPTNFBCAEFMICGHGenomicmapofMHCgenesofhumanRegionIofHLAgenesClassIIClassIIIClassIDPDQDRC4BC4AB1C2HSPTNFBCAEFMICGHEachmajorlocuscodesforapolypeptide;thealpha-chainthatcontainsantigenicdeterminants,ispolymorphic(hasmanyalleles)TheclassIgenecomplexcontainsthreemajorloci,B,CandAandotherundefinedminorloci.andassociateswithbeta-2microglobulin(beta-chain)andisexpressedonthecellsurface.a2a3a1b2mRegionIIofHLAgenesClassIIRINGDPDMLMP2LMP7DQDRB2A2B1A1ABTAP1TAP2B2A2B3B1A1B*ATheDRlocusmaycontainmorethanone(upto4)functionalbeta-chaingenes.TheclassIIgenecomplexcontainsatleastthreeloci,DP,DQandDR;Eachoftheselocicodesforonealpha-andonebeta-chainpolypeptidewhichassociatetogethertoformtheclassIIantigensTheclassIIantigensarealsopolymorphic.b1b2a1a2ThehereditaryruleofHLAgenes1.Haplotype(单倍型)HLAcomplexisagroupofcloselylinkedgenes.agroupofHLAgenesonasinglechromosomeiscalledhaplotype.A1A2B8B35haplotype:A1、B8/A2、B35diploid（二倍体）A1A2B8B35A2A10B40B16FatherMother×abcdA2B35A2B40A1B8A10B16A1B8A2B35A2B40A10B16adbdcbca12342.polymorphism（多态性)：多态性现象（polymorphism)是指一随机婚配的群体中，染色体同一基因座有两种以上基因型，即可编码二种以上的产物。HLA复合体是迄今已知人体最复杂的基因复合体，有高度的多态性。原因：multiplealleles(复等位基因)位于一对同源染色体上对应位置的一对基因称为等位基因（allele）；由于群体中的突变，同一座的基因系列称为复等位基因。HLA复合体的每一座存在为数众多的复等位基因，由于各个座位基因是随机组合的，故人群中的基因型可达108之多。A2A10B40B16A1A2B8B35A（6#）B（6#）codominance一对等位基因同为显性称为共显性。HLA复合体中每一个等位基因均为共显性，从而大大增加了人群中的HLA表型的多样性，达到107数量级。因此除了同卵双生者外，无关个体间HLA型别完全相同的可能性极小。A2A10B40B16A1A2B8B35HLAmolecule：A1，A2，B8，B35AABBHLAmolecule：A2，A10，B40，B16(共显性表达)3.linkagedisequilibrium(连锁不平衡)HLA复合体各等位基因均有其各自的基因频率。基因频率（frequency）是指群体中携带某一复等位基因者的比率。如果不同基因座上的两个复等位基因同时出现于个体中的计算频率和实际分布不一致，则认为两者之间存在连锁不平衡（linkagedisequilibrium）。DRB1*0301B6B8ABDRB5B8B3DRB4CB2B11DRB7DRB1*0301DRB69%12%9%12%=0.0108=1%7%closelylinked(紧密连锁)familymultipleallelesofHLA-IIB2A2B1A1BADPDMB2A2B1A1DQDRB1B2B3B4B5ADPB1*01010201020203010401040205010601DRB1*0101-01040301-03080401-042307010801-0813090110011101-11271201-12041301-13121401-14251501-15051601-1605DQB1*0201-02030301-03060401-04020501-05040601-0611DRB3*01010201-02050301MultiplealleleslociDPA1*010301040201020203010401DQA1*0101-010502010301-03030401-0501-05030601-DRB4*0101-01030101101012NDRB5*0101-01050201-02030801-41014401-6501PolymorphismofHLAgenesBCEAGA*0101-01020201-02170301-03021101-110323012402-241025012601-26082901-29023101232013301-33033401-3402360143016601-66026801-6803690174018001E*0101-0104B*0702-07060801-08031301-13031401-14021501-15311801-18032701-27103501-35183701-37023801-38023901-39044001-40084101-41024201-42024402-44074501,460147014801-48024901,50015101-51075301,54015501-55035601-56025701-57045801-58025901,670173017801-78028101,8201Cw*0102-010302020302-03040401-0403050106020701-07050801-08031202-120313011402-14031502-15051601-16021701-1702G*0101-0104multipleallelesofHLA-IlociMultipleallelesThefunctionoftheMHCmolecules1、2、约束免疫细胞之间的相互作用—MHC限制性MHCmoleculeasthereceptorforantigenicpeptideTCRVbAntigenicpeptideMHC-IIaTcellAPC1.HLAanddiseases2.AbnormalexpressionofHLAanddiseases3.HLAandrejection4.HLAandlegalmedicineMedicalapplicationofHLATable3.ExamplesofsignificantHLAanddiseaseassociationsDiseaseAssociatedAllelesFrequencyinRelativeRis