1、Major Histocompatibility Complex,Department of Immunology Tianjin Medical University,2,OUTCOMES ?,What are Histocompatibility?,3,What are Histocompatibility?,4,Genetic barriers to transplantation,autograft : in the same individualisograft : between genetically Identical individuals, i.e., identical
2、twins (inbred animals)allograft : between individuals of the same speciesxenograft: between individuals different species,5,What are Histocompatibility Antigen?, Responsible for rejection of transplanted tumors (origins of inbred laboratory animals, mouse H-2), Control rejection of transplanted orga
3、ns in humans; HLA, “tissue-typing”,6, Graft rejection results from genetic differences between donor and recipient Immune system recognizes “foreign” cell surface antigens Most important transplantation antigens are glycoproteins encoded by the MHC,Experimental Analysis of Graft Rejection and its Ge
4、netics - MHC,7, Mediate cell/cell interactions during the development and execution of immune responses,8,Histocompatibility Genes Many genes are involved, 30 named loci in mice One group of linked genes predominates in every vertebrate species: Major Histocompatibility Complex, “MHC” Mouse “H-2” Hu
5、man “HLA” 编码主要组织相容性抗原的一组紧密连锁的 基因群，主要功能是以其产物向T细胞呈递 抗原肽,9,Different individuals with different susceptibility to diseases,why?How TCR recognizes antigens?Why MHC molecules are the major antigens responsible for transplantation rejections?What are the autoimmune diseases that are associated with partic
6、ular types of MHC genotypes?,Big questions?,10,Introduction,General Organization and Inheritance of the MHCMHC Molecules and GenesCellular Distribution of MHC MoleculesMHC and Immune ResponsivenessMHC and Disease Susceptibility,11,Significance of the MHC,role in immune responserole in organ transpla
7、ntationrole in predisposition to disease,12,1 MHC Genes,13,Discovery of the Mouse MHC,14,Mice Chromosome 17 contains the major histocompatibility complex(H-2 gene).(1948)Humans Chromosome 6 contains the major histocompatibility complex(MHC).(1954)Human MHC molecules are called the human leukocyte an
8、itgens (HLA) and are equivalent to the mouse H-2 molecules,15,MHC（H-2）/HLA复合体(1980NP),Benacerraf（1920）,Snell（19031996）,Dausset（1916）,16,Schematic maps of MHC loci,17,Human HLA complex and Gene products,18,Properties of MHC - Polymorphism （多态性）,Polymorphism: presence of multiple alternative forms (al
9、leles) of a gene.,19,Polymorphism allows the population can handle a variety of pathogens.,20,The set of alleles that an individual carries at each locus on a single chromosome.Haplotype is transmitted as a single unit in most cases.,Properties of MHC Haplotype(单元型）,21,MHC genes are co-dominant at t
10、he cellular level, that is, both maternal and paternal gene products are expressed in the same cells. There is no allelic exclusion in their expression.,Properties of MHC Codominance（共显性）,22,Properties of MHC Linkage disequilibrium（连锁不平衡）,The difference between the frequency observed for a particula
11、r combination of alleles and that expected from the frequencies of the individual alleles,23,2 MHC Molecules,24,1. Structure and Properties,25,1. Structure and Properties,26,Structure of MHC molecules,27,28,Figure 3-22,2.Distribution of MHC class I and II,Class I expressed on all nucleated cells in
12、man.Class II expressed primarily on B cells, macrophages, dendritic cells ,etc.,Features of Class I and Class II MHC Molecules,Peptide-binding by class I and class II molecules,Peptide-binding domain 1/2 1/1Nature of cleft closed open General size of peptides 8-10 aa 13-17 aa,Class I,Class II,31,MHC
13、 class I accommodatepeptides of 8-10 amino acids,Nature of presented peptides,MHC class II accommodatepeptides of 13 amino acids,32,The peptide-binding groove of MHC molecules,3.Characteristics of Peptide-MHC Interactions,33,Binding of Peptides to MHC Molecules,The peptide-binding groove of MHC mole
14、cules,34,Anchor residue of antigenic peptide,HLA-A*0201：x-L/M-x-x-x-x-x-x-L/V,35,Each class and classII MHC molecule has a single peptide-binding cleft that can accommodate many different peptides-flexibility(包容性）.The association of antigenic peptides and MHC molecules is a saturable, low-affinity i
15、nteraction.The MHC molecules of an individual do not discriminate between foreign peptides and self antigen peptides.,Characteristics of Peptide-MHC Interactions,36,If a microbe had proteins such that none of its peptides can bind to MHC, whats the result?If a microbe mutates to avoid MHC binding of
16、 its peptides it would be a disaster!These considerations probably explain the polymorphism in MHC (large number of alleles within the populations)This specificity of MHC binding also explains the link between antigen non-responsiveness to simple or small proteins and the MHC.,Surprising, but true,3
17、7,REVIEW,human MHC I and II genes.Structures, distributions and functions of MHC I and II molecules. Properties of MHC,3 Functions of MHC,39,Figure 3-9,TCRs bind short antigen peptides but not whole antigen proteins. Antigen processing is required to present antigen peptides to TCR.,40,Antigen prese
18、ntation,Roles in Adaptive Immune Response,41,Figure 3-30,T cell receptor recognition of antigens is MHC-restricted,Roles in Adaptive Immune Response,Self-MHC restriction,42,Self-MHC restriction,Roles in Adaptive Immune Response,43,Role of MHC in selection,Roles in Adaptive Immune Response,44,MHC mol
19、ecules are essential,Bare Lymphocyte Syndrome-congenital deficiency of either class I or class II molecules. Patients lack killer cell or helper cell responses and are prone to many types of opportunistic infections.,45,Roles in Innate Immune Response,46, 4 Clinical importance of HLA antigens,MHC and Disease Susceptibility,Association关联,PositiveAssociation正关联,Negative Association负关联,Relative Risk(RR)相对风险比,47,48,目的要求掌握MHC/HLA的基本概念；经典HLA类、类分子的编码基因、分子结构、组织分布及功能特点熟悉MHC分子的生物学功能及遗传特征了解HLA与临床医学的关系,
