HISTOCOMPATIBILITYCOMPLEX(主要组织相容性复合体)

CHAPTER11THEMAJORHISTOCOMPATIBILITYCOMPLEXI.Introduction•Majorhistocompatibilityantigensystem•Majorhistocompatibilitycomplex:–Alargegeneticlocusthatincludesthehighlypolymorphicgenesencodingthepeptide-bindingmoleculesrecognizedbyTlymphocytes.TheMHClocusalsoincludesgenesencodingcytokines,moleculesinvolvedinantigenprocessing,andcomplementproteins.•H-2complex:murineMHCs•HLA:humanMHCwhichisknownasthehumanleucocytesantigensystem.–ThreeclassesofMHCgenescloselylinkedonchromosome•ClassⅠgene•ClassⅡgene•ClassⅢgeneII.TheorganizationofmurineandhumanMHC1.MouseH-2complex:–ClassⅠgene:K,DLclassⅠmolecules(αchain）–ClassⅡgene:IclassⅡmolecules(αβchain)–ClassⅢgene:Scomplement,TNFSKID/LChr.17centromereH-22.HumanHLAcomplex:DPDNDODQDRBCEAGHLAcomplexcentromereChr.6classlociProteinsencodingHLAclassⅠClassicalB,C,AHLAclassⅠmoleculesNon-classicalE,F,GHLAclassⅡClassicalDP,DQ,DRHLAclassIⅠmoleculesNon-classicalDN,DOHLAclassⅢComplement,TNF,HSPV.GeneticsofMHC•Polygenic•Polymorphic•Haplotypeinherited•CodominantA.HLA-ⅠmoleculesIII.ThestructureandfunctionofMHCmolecules1.Structure–Twopolypeptidechain:H-chainandβ2-microglobulin(notcodedbytheMHC)–Heavychainhas3domains:α1,α2,α3.–Heavychainα1andα2domainsformthebindinggroove(thepolymorphicregion)–α3domainbindtoCD82.Cellulardistibution–ClassⅠmoleculesareexpressedonallnucleatedcells(allcellsexceptforRBC)•Existsintheformof–Membraneboundmolecules–Solublemolecules2.Functioni.Antigenprocessingandpresenting(endogeneouspathway)–peptidesgeneratedinthecytosol(eg.Virusantigen)becomeassociatedwithMHCclassⅠmoleculeswhichmovetothesurfaceandcanberecognizedbyCD8+Tcell(cytotoxicTlymphocytes).ii.Involveintransplantrejectioniii.TcelldevelopmentinthymusB.HLA-Ⅱmolecules1.Structure–Heterodimersofαandβglycoproteinchains.–Eachchainhas2domains(α1,α2andβ1,β2)–α1andβ1formthebindinggroove.(thepolymorphicregion)–CD4bindtoβ2domain2.Cellulardistribution–classⅡmoleculesareexpressedon•Bcells•Mφ•Dendriticcells•Vascularendothelialcells3.Functionsi.Antigenprocessingandpresenting(exogeneouspathway):–bothpathogensincellularvesiclesandthosecomefromoutsidethecellarepresentedonMHCclassⅡmoleculesofAPCsandaretransportedtothecellsurfacewheretheycanberecognizedbyCD4+Tcellii.Involveintransplantrejectioniii.Regulationofimmuneresponseiv.TcelldevelopmentinthethymusC.Non-classicalHLA–(HLA-Ⅰb)1.Differentiationoractivationstates2.Disease3.CytokinesIV.FactorsinfluencingtheexpressionofHLAmolecules（1）内源性抗原提呈：抗原靶细胞组成HLAⅠ类分子-抗原肽复合物表达于细胞膜表面CD8+T细胞识别。（2）外源性抗原提呈：抗原APCHLAⅡ类分子-抗原肽复合物表达于细胞膜表面CD4+T细胞识别。HLA与疾病的关系（一）R.R(relativerisk，相对危险率)R.R值越大相关性越强。（二）举例1.强直性脊柱炎与B272.胰岛素依赖性糖尿病（IDDM）与DR3、DR4病人（Ag+/Ag-）对照（Ag+/Ag-）＝VI.SignificanceofMHC1.Controlofimmuneresponse•MHCrestriction:–TheabilityofTlymphocytestorespondonlywhentheyarepresentedwiththeappropriateantigeninassociationwitheither“self”MHCclassⅠorclassⅡmolecules.•Irgene(immuneresponsegene)血清学细胞学分子生物学实验方法补体介导的微量细胞毒试验混合淋巴细胞培养法（MLC)分子生物学技术原理抗体(HLA分型)+淋巴细胞(受者)+补体淋巴细胞受损判定结果（细胞死亡百分率）单向法双向法比较供、受者编码HLA抗原基因的DNA序列，判定供、受者间的相似程度。主要应用检测HLA-A、B、C抗原检测DR抗原HLA分型法原理及应用2.Graftrejectionandtissuematching3.AutoimmunediseasesusceptibilitySummuryKeypoints•ThedefinitionsofMHCandHLA.•ThecompositionofHLAgenecomplex•Thestructure,distributionandfunctionsofMHCclassⅠandⅡmolecules.