2Chapter 9 Major Histocompatibility Complex ContentsPartⅠ Several important conceptsPartⅡ Composition of HLA complexPartⅢ Genetic characteristics of HLAPartⅣ Molecular structure and distribution of HLAPartⅤ Interaction of MHC molecules and antigen peptidePartⅥ Biological functions of MHCPartⅦ Application of HLA in medicine
3PartⅠ Several important concepts Transplantation antigen(Histocompatibility antigen): Antigens which cause immune response to the graft and determine the survival of the graft.They are alloantigen which is specific for each individual.
4MHS(Major histocompatibility antigen system )： A group of complex histocompatibility antigens which cause rapid and strong immunoreaction to the graft.mHS(Minor histocompatibility antigen system)：A group of complex histocompatibility antigens which cause slow and weak immunoreaction to the graft.
5MHC (Major histocompatibility complex)： A large cluster of linked genes located in some chromosome of human or other mammals encode for MHS and relate to allograft rejection, immune response, immune regulation and cell-cell recognition.
6HLA (Human leucocyte antigen)： The MHS of human which is associated with allograft rejection, immune response, immune regulation and cell-cell recognition.HLA complex：The MHC of human,a cluster of the genes which encode for HLA and relate to allograft rejectionimmune response, immune regulation and cell-cell recognition.
8PartⅡ Composition of HLA complex HLA complex is located on chromosome 6and divided into three regionsClass IIClass IIIClass IDP DQ DR C4B C4A Bf C2 HSP TNF B C E A F GRING DP DM LMP2 LMP DQ DRB2 A2 B1 A A B TAP1 TAP B2 A2 B3 B1 A B* A第六对 染色体
9Ⅰ. ClassⅠgene region Ⅱ. Class Ⅱ gene region Ⅲ. Class Ⅲ gene region Classical HLA classⅠgenes HLA-A,B,CNon-classical HLA classⅠgenes-----HLA-E,F,GMHC classⅠ chain related genesⅡ. Class Ⅱ gene regionClassical HLA classⅡ genes---HLA-DP,DQ,DRGenes associated with antigen processingⅢ. Class Ⅲ gene regionComplement genes-----C4,C2,BfInflammation-associated genes----TNF,HSP70
10Ⅰ. Class Ⅰ gene region Classical HLA class Ⅰ genes ------HLA-A,B,C Participate in endogenous antigen presenting and immune regulation.
112. Non-classical HLA classⅠ genes ----HLA-E,F,GParticipate in immune regulationAssociated with maternal-fetal immune tolerance.3. MHC classⅠchain-related genes(MIC)MICA,MICB,MICC,MICD,MICEAssociated with cytotoxicity effect of NK cell.
12Ⅱ. Class Ⅱ gene region 1. Classical class Ⅱ genes----HLA-DP,DQ,DR Participate in exogenous antigen presenting and immune regulation.
132. Genes associated with antigen processing The genes associated with endogenousantigen-processing and presentingTAP（Transporter associated with antigen processing,抗原加工相关转运体）LMP（Large multifunctional proteasome,巨大多功能蛋白酶体）or （ low molecular weight polypeptide 低分子量多肽）
14(2) The genes associated with exogenous antigen-processing and presentingHLA-DM----Processing and presenting of exogenous AgHLA-DO----Inhibit the function of HLA-DM
15Ⅲ. Class Ⅲ gene region 1. Encoded genes of complement ------C4B,C4A,Bf,C2
162. TNF genes family3. Heat-shock protein(HSP) genes family
17PartⅢ Genetic characteristics of HLA Haplotype inheritancePolymorphismLinkage disequilibrium
212. PolymorphismPolymorphism means there are multiple alleles at a gene locus of MHC in a population so that an individual may have variant allele.------multiple allele------codominance: The two alleles at a gene locus of MHC in the two homogenous chromosomes are expressed together.
243. Linkage disequilibrium The distribution of haplotypes is not random in a population.The probability in which two or more than two alleles present together in one chromosome is greater than the probability in which they present randomly.
25PartⅣ Molecular structure and distribution of HLA molecules
26Ⅰ. Molecular Structure of HLA molecules 1. Class Ⅰ HLA molecules(1)Class Ⅰ HLA molecules contain two separate polypeptide chainsHLA-encoded alpha (or heavy) chainNon-HLA-encoded beta chain (beta2 microglobulin,β2m)---15 chromosome(2) Only alpha chain is trans-membraneHLA
27(3) Class Ⅰ HLA molecules have four regions Peptide binding region----α1, α2IgSF region----α3, β2mTrans-membrane regionCytoplasmic region
29(4) Function of each domain 1 and 2 domains: Interact to form a peptide-binding region which is a groove(cleft) having a "floor"of 8 beta-pleated strands and two "walls" with alpha-helices.( Containing a peptide of aa in the groove)
313 domain: Binding to CD8 on Tc cells 2 microglobulin domain: To maintain proper conformation of class Ⅰ HLA molecules.Trans-membrane region: Anchoring class Ⅰ HLA moleculesIntra-membrane region: Transmitting the signal
36(5) Function of each domain α1 and 1: Interact to form the peptide-binding region which is a groove having a "floor" of 8 beta-pleated strands and two "walls" with alpha-helices.(Containing a peptide of 10-30aa in the groove)
40Ⅱ. Distribution of HLA molecules 1.Class Ⅰ HLA molecule:Expressed on nucleate cells2.Class Ⅱ HLA moleculeExpressed on professional antigen-presenting cell(macrophage, dentritic cell and B cell), activated T cell, thymus epithelial cell et al.3.sHLA
41PartⅤ Interaction between MHC molecule and antigenic peptide Class I MHC molecule -antigenic peptide complexClass II MHC molecule-antigenic peptide complex
42Ⅰ. Molecular basis of interaction between MHC molecule and antigenic peptide
43Interaction between MHC and antigen Anchor sites: Two or more sites on antigenic peptide bind to “groove” or “pocket” of MHC molecules.Anchor residues: The amino acid residues on anchor sites of antigenic peptide.
44Antigenic peptides which can combine with Interaction between MHC and antigenCertain MHC molecule binds the corresponding anchor residue of antigenic peptides.Antigenic peptides which can combine withthe same kind of MHC molecule have same or similar anchor sites and anchor residues(consensus motif).
47Ⅱ. Characteristics of interaction Relative specificity(1) Specificity:Certain MHC molecule recognizes corresponding consensus motif(2) Flexibility:Amino acids “x” and anchor residues are variableDifferent MHC molecules can recognize similar consensus motif
48MHC restriction:T cell only recognize antigenic peptide combining with MHC molecules.That is to say, interaction of T cell and antigen-presenting cell(APC) or target cell need restriction by MHC molecules.
49Interaction of Th(CD4+T) cell and antigen-presenting cell (APC) is restricted by class Ⅱ molecules. Interaction of Tc(CD8+T) cell and antigen-presenting cell (APC) or target cell is restricted by class Ⅰ molecules.
50CD8+T cell(Tc) CD4+T cell(Th) T cell Receptor Peptide MHC Class II Antigen PresentingCellCD4CD8
52PartⅥ Biological functions of MHC 1.Induce the differentiation and maturation of T cell to form functional T cell repertoire2.Present antigen to initiate immune response
531.Induce the differentiation of T cell to form T cell repertoire
542. Present antigen to initiate immune response Endogenous antigen: antigens synthesized within cellsExogenous antigen: antigens comes outside the cellEndogenous Ag is presented to CD8+ T cell by MHC class Ⅰ moleculeExogenous Ag is presented to CD4+ T cell by MHC class Ⅱ molecule
57PartⅦ Application of HLA in medicine HLA and transplantation
58MLRMixed lymphocyte reaction to determine identity of class II HLA antigens between a potential donor and recipient.Lymphocytes from the donor are irradiated or treated with mitomycin C. If the class II antigens on the two cell populations are different, the recipient cells will divide rapidly and take up large quantities of radioactive nucleotides into the newly synthesized nuclear DNA. The amount of radioactive nucleotide uptake is roughly proportionate to the MHC class II differences between the donor and recipient lymphocytes.