MHC(主要组织相容性复合体).ppt

Majorhistocompatibilitycomplex MHC OutlineofLecture Discovery conceptsofMHCStructure propertiesofMHCGenesStructure propertiesofMHCMoleculesPeptide MHCInteractionFunctionsofMHCMoleculesHLA clinicmedicine Rejectionresponse 1930 1940GorerSnell Agswhichcaninducerejectionresponsesintransplantationinmicearecalledhistocompatibilityantigens H 2Ag ThegenesencodeH 2Agsarecalledhistocompatibilitygenes H 2gene 1950s JeanDausset JanvanRoodBloodtransfusion KidneytransplantationCirculatingAbsreactwithAgsontheWBCordonororgans AlloantiseraAlloantibodiesAlloantigensTheseAgsaretheproductsofpolymorphicgenesthatdistin gushforeigntissuesfromselfTissues humanleukocyteantigens HLAs HumanMHCantigen DiscoveryofHumanMHC HLA Dr JeanDausset Majorhistocompatibilityantigen MHCmolecules aremoleculeswhichcaninduceintensivelyandrapidlytransplantationrejectionbetweentwohomogeneousvariants Majorhistocompatibilitycomplex MHC isaseriesofgeneclusterstightlyinterlockedwhichencodethemajorhistocompatibilityantigens HLA humanleukocyteantigen human sMHCantigen thegeneofitislocatedonchromosome6 H 2system mouse sMHCantigen thegeneofitislocatedonchromosome17 Majorhistocompatibilityantigen MHCmolecules Majorhistocompatibilitycomplex MHC gene HLA humanleukocyteantigen HLAgene Concepts Otherdiscovery 1960 1970 BenacerrafandMcDevittfoundimmuneresponsegenes Ir existinginMHCThereisMHCrestrictioninCTLkillingvirus infectedtargetcells ThemainfunctionisantigenpresentationtoTcells initiatingimmuneresponse OutlineofLecture Discovery conceptsofMHCStructure propertiesofMHCGenesStructure propertiesofMHCMoleculesMHCpolymorphismPeptide MHCInteractionFunctionsofMHCMoleculesHLA clinicmedicine GenemapsofhumanandmouseMHC HLAgene 3600kb Shortarmofchromosome6 100locus Organizedintoregionsencodingthreeclassesofmolecules SimplifiedmapoftheHLAregion CLASSI 3typesHLA A HLA B HLA C sometimescalledclassIagenes CLASSII 3typesHLA DP HLA DQ HLA DR sometimescalledclassIIagenes Threegeneregion HLA I HLA II HLA IIIgeneregionsHLA I encodeHLA ImoleculesHLA II encodeHLA IImoleculesHLA III encodeHLA IIImolecules notimportantinantigenpresentingprocedure HLA Igeneregion A B CgenelociHLA IIgeneregion DP DQ DRgeneloci participateinantigenpresentation HumanMHC HLAgene ClassicalHLAclass Igenes Eachmajorlocuscodesforapolypeptide thealpha chain TheclassIgenecomplexcontainsthreemajorloci B CandAandotherundefinedminorloci andassociateswithbeta 2microglobulin andisexpressedonnucleatedcellsurface presentendogenousantigensTheclassIantigensarepolymorphic ClassicalHLAclass IIgenes TheDRlocusmaycontainmorethanone upto4 functionalbeta chaingenes TheclassIIgenecomplexcontainsatleastthreeloci DP DQandDR Eachoftheselocicodesforonealpha andonebeta chainpolypeptidewhichassociatetogethertoformtheclassIIantigens TheclassIIantigensarealsopolymorphic mainlyexpressedonprofessionalAPC presentexogenousantigens DMAandDMBgenelocicodeaachainandbchainrespectively whichplayanimportantroleintheassemblingofMHCII LMP 2andLMP 7codeapolypeptide whichisaportionoftheproteasome TAP 1andTAP 2codetransporterinantigenprocessing TAP nonclassicalHLAclass IIgenes HLAclass genes encodevarioussecretedproteinsthathaveimmunefunctions include componentsofthecomplementsystem C4 Bf C2 moleculesinvolvedininflammation TNF HSP70etc MHCPolymorphism MHCgenesarehighlypolymorphic meaningthattherearemanydifferentallelespresentamongthedifferentindividualsinthepopulationandtheMHCisoneofthemostpolymorphicgeneticsystemsknowninhighervertebrates DeterminednotonlybyMultiplegenes butthegeneticfeaturesofMHC SignificanceofMHCPolymorphism tobeabletopresentanymicrobialpeptideantigentoensuresurvivalofthepopulationasawhole Geneticcontrolofimmuneresponses Irgene Personalidentification GeneticfeaturesofMHC HaplotypeMultipleallelesCodominantexpressionLinkageDisequilibrium Haplotypeinheritance MHChaplotype ThesetofMHCallelespresentoneachchromosomeInheritanceofHLAhaplotypes humanMHClociarecloselylinkedandusuallyinheritedasahaplotype Significance difficulttofindorgandonor usefulforpersonalidentification InheritanceofMHChaplotypes Mother a b c d Children a a b b c c d d multiplealleles Allelesarealternativeformsofagene andtheyareresponsiblefordifferencesinphenotypicexpressionofagiventrait Ageneforwhichatleasttwoallelesexistissaidtobepolymorphic Instancesinwhichaparticulargenemayexistinthreeormoreallelicformsareknownasmultiplealleleconditions Itisimportanttonotethatwhilemultipleallelesoccurandaremaintainedwithinapopulation anyindividualpossessesonlytwosuchalleles atequivalentlocionhomologouschromosomes Theremaybeasmanyasonehundreddifferentallelesatasinglelocus IfonealsoconsidersthatanindividualpossessesfiveormoreHLAloci itbecomesclearwhydonor recipientmatchesfororgantransplantationsaresorare thefewerHLAantigensthedonorandrecipienthaveincommon thegreaterthechanceofrejection Eachlocushasmanyalleles Co dominantinheritance Inheritanceinwhichtwoallelesofagenepairinaheterozygotebothhavefullphenotypicexpression Increasethepolymorphismofphenotypeinthegroup ExpressionofMHCallelesisco dominant LinkageDisequilibrium Linkagedisequilibriumisthedifferencebetweenthefrequencyobservedforaparticularcombinationofallelesandthatexpectedfromthefrequenciesoftheindividualalleles Linkagedisequilibriumisassociatedwiththesusceptibilityofsomedisease HLA A1occursin16 inapopulation frequency0 16 HLA B8in9 ofthatgroup frequency0 09 Theoreticallyabout1 4 ofthegroupshouldhavebothallelesInfactHLA A1andHLA B8arefoundtogetherin8 8 OutlineofLecture Discovery conceptsofMHCStructure propertiesofMHCGenesStructure propertiesofMHCMoleculesPeptide MHCInteractionFunctionsofMHCMoleculesHLA clinicmedicine chainisdividedintothreeparts extracellularregion transmembraneregion intracellularregion chainhasthreefunctionaldomains 1 2and 3domain b2 mchainonlyexistinextracellularregion Ithasonlyonedomain Itbindsto 3chainbynoncovalentbonds 1and 2domainsconstituteantigenbindingsitesaltogether 3and chainconsistsofnonpolymorphicregion 1 MHCclassImolecule andb2 mpolypeptidechain HLA I structure 1 peptide bindingregion a1 a2 polymorphicregion bindtopeptide 2 Ig likeregion a3 nonpolymorphicregion bindtoCD8 3 transmembraneregion fixHLA Ionmembrane 4 intracellularregion conductsignal 5 2 mchain maintainthethestabilityofthespatialconfiguration chainhastwodomains named 1and 2domains chainhastwodomains named 1and 2domains 1and 1constituteantigenspecificallybindingsites 2and 2consistofnonpolymorphicregion 2 HLA IImolecules and chains structure 1 peptide bindingregion a1 1 polymorphicregion bindtopeptide 2 Ig likeregion 2 2 nonpolymorphicregion bindtoCD4 3 transmembraneregion fixHLA IIonmembrane 4 intracellularregion conductsignal HLA II Peptidebindingregion Ig likeregion Transmembraneregion intracellularregion Comparing DistributionofHLAHLAclassImoleculesareexpressedonallnucleatedcells includeredbloodcells HLAclassIImoleculesareexpressedonthosecellswhichareefficientantigen presentingcellsfortheactivationofTcells suchasmacrophages Bcells DC andthymusepithelialcells OutlineofLecture Discovery conceptsofMHCStructure propertiesofMHCGenesStructure propertiesofMHCMoleculesPeptide MHCInteractionFunctionsofMHCMoleculesHLA clinicmedicine ClassI ClassII MHC bindingpeptides Eachhumanusuallyexpresses 3typesofMHCclassI A B C and3typesofMHCclassII DR DP DQ ThenumberofdifferentTcellantigenreceptorsisestimatedtobe1 000 000 000 000 000EachofwhichmaypotentiallyrecognizeadifferentpeptideantigenwhichpresentedwithMHCbyAPC Howcan6invariantmoleculeshavethecapacitytobindto1 000 000 000 000 000differentpeptides PeptidescanbeelutedfromMHCmolecules ElutedpeptidesfromMHCmoleculeshavedifferentsequencesbutcontainmotifs PeptidesboundtoaparticulartypeofMHCmoleculehaveconservedpatternsofaminoacids DifferenttypesofMHCmoleculebindpeptideswithdifferentpatternsofconservedaminoacids AcommonsequenceinapeptideantigenthatbindstoanMHCmoleculeiscalledamotifYXXXXXV I L OneMHCmoleculecanpresentdifferentpeptidewhichhascommonmotif anchorresidueTheaminoacidresiduesatseveraldefinedpositionsalongthepeptideanchortheantigenicpeptideintothegrooveoftheMHCmolecule theyarecalledanchorresidues pocketInsideofantigenbindingcleftofMHCchains therearesomepolymorphicresidueswhichinteractwithanchorresiduesspecifically calledpocket MolecularBasis anchorresidues Complementaryanchorresidues pocketsprovidethebroadspecificityofaparticulartypeofMHCmoleculeforpeptides MHCmoleculescanbindpeptidesofdifferentlength Peptidesequencebetweenanchorscanvary Numbersofaminoacidsbetweenanchorscanvarytoo Archedpeptide Closedpeptide bindinggrooveofHLAI shortpeptide Openedpeptide bindinggrooveofHLAII longpeptide OutlineofLecture Discovery conceptsofMHCStructure propertiesofMHCGenesStructure propertiesofMHCMoleculesPeptide MHCInteractionFunctionsofMHCMoleculesHLA clinicmedicine 1 Antigenpresentation 2 MHCrestriction 3 Tcelldevelopmentinthymus 4 Inducehomograftrejection 5 Geneticcontroltheimmuneresponse FunctionsofMHCMolecules 1 AntigenpresentationPeptide MHCcomplex peptidesof8 10aminoacidsendogeneousantigens peptidesof 13aminoacidsexogenousantigens DifferencesinAgpresentation MHCclassI MHCclassII AntigenrecognitionbyTcellsrequirespeptideantigensandpresentingcellsthatexpressMHCmolecules Tcellresponse NoTcellresponse NoTcellresponse NoTcellresponse NoTcellresponse APC 2 MHCrestrictionIntheimmuneresponse onlytheimmunocytesthathavethesameMHCphenotypescanhaveinteractionwitheachother Tcellreceptors TCRs recognizepeptidesinthepeptide MHCcomplex andCD4orCD8molecules moleculesexpressedonthesurfaceofTcells mustrecognizeMHC IIorMHC Imolecules respectively So TcellrecognitionisrestrictedbyMHCmolecules PeterDohertyandRolfZingernagelNobelprizewinnersforphysiologyorMedicine 1996 FortheepochaldiscoveryofMHCrestrictionofT cellrecognitionandthesingleT cellreceptoraltered selfhypothesis ForthelandmarkdiscoveryofMHCrestrictionofT cellrecognition andthealtered selfhypothesis Theimportanceofthisresearchdefinedthattheimmunecellscapableofkillingvirusinfectedcellsmustrecognizeapartofthevirustogetherwithmoleculesofthehostcalledmajorhistocompatability MHC ant