免疫学课件MHC

Major Histocompatibility Complex(MHC)and its encoding moleculesXiaojian Wang0571-88206268科研楼B IMMUNOLOGYMHC1.Introduction2.Structure of MHC genes and products 3.Polymorphism of MHC4.Interactions of MHC molecules with antigenic peptides5.Biological function of MHC molecules6.MHC and clinical medicineIntroduction 1.Histocompatibility antigen The Ags primarily responsible for rejection of genetically different tissues are known as histocompatibility Ags.Histocompatibility The ability to accept grafts between individuals.2.Histocompatibility antigen system Major histocompatibility antigen Minor histocompatibility antigen MHC 3.Major histocompatibility complex,MHC A cluster of genes on chromosome 6 in humans,encoding major histocompatibility antigen which regulates immune response.4.Human:Human leukocyte antigens(HLA)mouse:H-2MHCMouse MHC=H-2Mouse MHC=H-2humanhuman MHC=HLAMHC=HLAMouse MHC=H-2Mouse MHC=H-2IrIr基因基因1996 Nobel Prize(MHC restriction)Organization and Structure of MHC Genes and Products 1.Organization of MHC genes2.Products of MHC class I and MHC class II genes-HLA molecules3.Immune function related genesMHC1.Organization of MHC genesMHC H-2 K AA EE C4 Bf C2 D LChromosome 17(mouse)IA IEISOrganization of MHC genesMHCHLA DP DQ DR C4 B C A B A B A B B A B A Bf C2Chromosome 6(human)6p21.31 Organization of MHC genes2.Products of MHC class I and class II genes-HLA moleculesMHCMHC 1)HLA class I molecules 1)HLA class I molecules Genes:A,B,C Distribution:every nucleated cell Structure:chain(45kD)2m(12kD)chromosome 15 peptide-binding cleft:1+2 CD8 binding:3 Function:recognize and present the endogenous Ags to CD8+T cellsMHCHLA class I moleculeStructure of HLA I moleculeMHCHLA I moleculeMHC2)HLA class II moleculesMHC2)HLA class II molecules Genes:DR,DQ,DP Distribution:APC(B,DC,M)thymic epithelial cell,activated T cell Structure:chain(35kD)chain(28kD)peptide-binding cleft:1+1 CD4 binding:2 Function:recognize and present the exogenous Ags to CD4+T cells Structure of HLA II moleculeMHCHLA class II moleculeStructure of HLA moleculeMHC组织组织MHC I类分子类分子MHC II类分子类分子T细胞细胞B细胞细胞巨噬细胞巨噬细胞树突状细胞树突状细胞胸腺上皮细胞胸腺上皮细胞肝细胞肝细胞肾脏细胞肾脏细胞脑细胞脑细胞红细胞红细胞滋养层细胞滋养层细胞+-+/-+-HLA-HLA-、类抗原的分布类抗原的分布类抗原的分布类抗原的分布3.Immune function related genesMHC1.Serum complement coded genes HLA class III C4B,C4A,Bf,C22.Antigen presenting function related genes HLA class II LMP(proteasome subunit beta type,psmb):LMP2/7 encoding proteosome beta subunit Function:process endogenous Ag TAP(transporter associated with Ag processing):TAP1,TAP2 Function:transport endogenous Ag peptides Tapasin(TAP associated protein)Function:participate in the endogenous pathways,help the assemble of the MHCI in ER MHC HLA-DM:DMA and DMB participate in the exogenous pathways,help the peptide binding to the MHCII HLA-DO:negative regulation to DM The function of HLA-DMHLA-DM catalyses the removal of CLIPMIIC compartmentHLA-DMReplaces CLIP with a peptide antigen using a catalytic mechanism(i.e.efficient at sub-stoichiometric levels)Discovered using mutant cell lines that failed to present antigenHLA-DO may also play a role in peptide exchangeSequence in cytoplasmic tail retains HLA-DM in endosomesHLA-DMHLA-DR3.Non-classic class I gene(HLA Ib)HLA-E,HLA-G:inhibit NK cell activityMHCHLA-E：结合结合NK细胞细胞和部分和部分CTL细胞表面的细胞表面的C型凝集素受体超家族型凝集素受体超家族CD94/NKG2家族家族.抑制抑制NK 细胞功能细胞功能 表达于各种组织细胞，在羊膜和滋养层细胞表面高表达。表达于各种组织细胞，在羊膜和滋养层细胞表面高表达。功能：功能：A.生理状态下生理状态下NK处于抑制状态。处于抑制状态。B.母胎耐受母胎耐受 HLA-G：由：由链和链和2m组成，有组成，有15种等位基因。种等位基因。分布：主要分布于母胎界面绒毛外滋养层细胞，分布：主要分布于母胎界面绒毛外滋养层细胞，受体：杀伤细胞免疫球蛋白样受体（受体：杀伤细胞免疫球蛋白样受体（KIR）家族和白细）家族和白细 胞免疫球蛋白样受体（胞免疫球蛋白样受体（LIR）家族的某些成员。）家族的某些成员。功能：在母胎耐受中发挥功能。功能：在母胎耐受中发挥功能。4.Inflammation related genes TNF gene family:TNF,LTA,LTB Transcript factor gene family:I-BL,ZNF173 MIC family:MIC A(高多高多态性性),激活NK 细胞性MIC B Heat shock protein gene family:HSP70MHCImmune function related genesAg processing-related genesComplement encoding genesInflammation-related genesNon-classical MHC I genesPolymorphism of MHCMHCConcept of polymorphism The phenomenon of having multiple allels at given genetic locus in the population1.Mutiple-alleleEMBL-EBI HLA Sequence Database(http:/www.ebi.ac.uk/imgt/hla/stats.html)HLA alleles:3,201(class I:2,215,class II:986)(last updated:07/2010)HLA-A 673 alleles HLA-DPA1 27HLA-B 1077 HLA-DPB1 128HLA-C 360 HLA-DQA1 34HLA-E 9 HLA-DQB1 93HLA-F 21 HLA-DRA 3HLA-G 36 HLA-DRB 669 HLA-DRB1 585 HLA-DRB3 45 HLA-DRB4 13 HLA-DRB5 18Naming of HLA alleles allele allele Locus group number HLA-A*02 01 HLA-DRB1*11022.Codominant expression:MHC genes are codominantly expressed in each individual(therefore each individual has 6 class I and 6 class II MHC molecules),which means the alleles inherited from both parents are expressed equally.This maximizes the number of MHC molecules available to bind peptides for presentation to T cells.Linkage disequilibrium and haplotypeLinkage disequilibrium:the phenomenon that certain MHC alleles at different loci are inherited together more frequently than would be predicted by random assortment.e.