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1、Major Histocompatibility Complex (MHC),Contents:,Introduction Genomic organization of the MHC The genetics of HLA HLA antigen system The functions of HLA(Assembly & presentation of peptide-MHC complexes) HLA and Clinic,Introduction,1. Histocompatibility The ability to accept grafts between individua
2、ls. 2. Histocompatibility antigen (i.e., transplantation Ag)The Ags primarily responsible for rejection of genetically different tissues are known as histocompatibility Ags. 3. Histocompatibility antigen system 4. Major histocompatibility antigen system (MHS)human- Human leukocyte antigens (HLA)mous
3、e - H-2,5. minor histocompatibility antigen system (mHS) 6. Major histocompatibility complex (MHC): A cluster of genes on one chromosome in vertebrate, encoding cell surface molecules that are polymorphic and that code for antigens which lead to rapid graft rejection between members of a single spec
4、ies which differ at these loci. Several classes of protein such as MHC class I and II proteins are encoded in this region. Human MHC molecules (Ag)=HLAHLA complex=human MHC,Discovery of the MHC,Discovery of the mouse MHCDiscovery of the Human MHC,Nobel Prize in Physiology or Medicine 1980,George D.
5、Snell (1/3), Jean Dausset (1/3) Discoveries concerning genetically determined structures on the cell surface that regulate immunological reactions H-genes (histocompatibility genes), H-2 gene Human transplantation antigens (HLA) -MHC,MHC的发现,The organization of MHC,K I S DA A E E D L,H-2 complex Chro
6、mosome 17(mouse),Inbred micecommon strains haplotype BALB/C H-2dDBA/2 H-2dC57BL/6 H-2bC3H/Hej H-2kRecombinant mice,HLA complex, HLA DP DQ DR C4 B C A Bf C2,LMP2 LMP7 Chromosome 6TAP1 TAP2 (human),The HLA genes1. class genes (1) Classical class I genes:three Classical loci：A、B、C (HLAa),(2) non- Class
7、ical class genes (HLAb) : HLA-E binds peptides derived from the signal sequences of the classical classmolecules, creating complexes that are recognized by KIR on NK cells. HLA-G forms a dimer with 2m that acts to control immune response at the fetal-maternal interface.M C (MHC class chain-related)F
8、unction: participate in the cytotoxicity.,2. class genes (1) Classical class II genes:three Classical loci：DP, DQ, DR, each with its A and B genesDP: DPA1,DPB1,DPA2,DPB2 (pseudogenes)DQ: DQA1,DQB1,DQA2,DQB2,DQB3 DR: DRA,DRB1,DRB3,DRB4,DRB5,DRB2,DRB6,DRB7,DRB8,DRB9,(2) non- Classical class II genes a
9、ntigen presenting function related genes：LMP (low molecular weight polypeptide or large multifunctional proteosome): LMP2、LMP7Function: process endogenous Ag TAP (transporter of antigen peptide): TAP1、TAP2 Function: transport endogenous Ag peptides,Immune function related genes,HLA-DM: DMA,DMBFuncti
10、on: participate in the exogenous pathwaysHLA-DO: DOA,DOBFunction: negative regulation to DMtapasin (TAP associated protein): Function: participate in the endogenous pathways,(1) serum complement coded genes: C2, C4A, C4B, Bf,3. class genes:,(2) inflammation related genes:TNF gene family: TNF,LTA,LTB
11、HSP gene family: HSP70 transcript factor gene family: I-B,ZNF173,Naming of HLA alleles,allele alleleLocus group numberHLA-A* 02 01 1HLA-A* 02 01 2HLA-A* 24 02 1 02L (low level of expression) HLA-DRB4* 01 03 1 02N (null allele)silent polymorphismpolymorphism In introns or in exon flanking regions,The
12、 genetics of the HLA,1. PolygenyEach person inherits multiple class and class genes.2. Polymorphism Multiple allele: The phenomenon of having multiple stable forms of one gene in the population. These genes are co-dominantly expressed.,EMBL-EBI HLA Sequence Database (http:/www.ebi.ac.uk/imgt/hla/sta
13、ts.html) HLA alleles: 3,201 (class I:2,215, class II: 986) (last updated:07/2008 )HLA-A 673 alleles HLA-DPA1 27 HLA-B 1077 HLA-DPB1 128 HLA-C 360 HLA-DQA1 34 HLA-E 9 HLA-DQB1 93 HLA-F 21 HLA-DRA 3 HLA-G 36 HLA-DRB 669 HLA-DRB1 585HLA-DRB3 45HLA-DRB4 13HLA-DRB5 18,The significance of MHC polymorphism
14、:Almost all of the polymorphism among MHC alleles involves amino acid residues located in and around the peptide-binding groove. As a result, each allelic form has its own unique peptide-binding properties.,The significance of MHC polymorphism: 1) to affect the ability to make immune responses, including the level of antibody production, resistance or susceptibility to infectious diseases, resistance or susceptibility to autoimmune disease and allergies. 2) to ensure survival of the population as a whole when they encounter any new pathogen.,
