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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 sam

2、e individualisograft : between genetically Identical individuals, i.e., identical twins (inbred animals)allograft : between individuals of the same speciesxenograft: between individuals different species,5,What are

3、Histocompatibility Antigen?,● Responsible for rejection of transplanted tumors (…origins of inbred laboratory animals, mouse H-2),● Control rejection of transplanted organs in humans; HLA, “tissue-typing”,6,● Graft rejec

4、tion 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 Ana

5、lysis of Graft Rejection and its Genetics - MHC,,,,,7,,● Mediate cell/cell interactions during the development and execution of immune responses,8,Histocompatibility Genes Many genes are involved, >30 named lo

6、ci in mice One group of linked genes predominates in every vertebrate species: Major Histocompatibility Complex, “MHC” Mouse – “H-2” Human – “HLA” 编码主要组织相容性抗原的一组紧密连锁的

7、 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?

8、What are the autoimmune diseases that are associated with particular types of MHC genotypes?,Big questions?,10,Introduction,General Organization and Inheritance of the MHCMHC Molecules and GenesCellular Distributi

9、on of MHC MoleculesMHC and Immune ResponsivenessMHC and Disease Susceptibility,11,Significance of the MHC,role in immune responserole in organ transplantationrole in predisposition to disease,12,§1 MHC Genes,13

10、,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 ca

11、lled the human leukocyte anitgens (HLA) and are equivalent to the mouse H-2 molecules,,15,,,,,MHC(H-2)/HLA复合体(1980NP),Benacerraf(1920~),Snell(1903~1996),Dausset(1916~),16,Schematic maps of MHC loci,17,Human HLA complex

12、and Gene products,18,,,,Properties of MHC - Polymorphism (多态性),,,Polymorphism: presence of multiple alternative forms (alleles) of a gene.,19,Polymorphism allows the population can handle a variety of pathogens.,20,The s

13、et 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 the cellular leve

14、l, 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

15、(连锁不平衡),The difference between the frequency observed for a particular combination of alleles and that expected from the frequencies of the individual alleles,23,§2 MHC Molecules,24,1. Structure and Properties,2

16、5,,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 man.Class II expressed primarily on B cells, macrophages,

17、 dendritic cells ,etc.,Features of Class I and Class II MHC Molecules,,Peptide-binding by class I and class II molecules,Peptide-binding domain α1/α2 α1/β1Nature of cleft

18、 closed open General size of peptides 8-10 aa 13-17 aa,Class I,Class II,,,,31,MHC class I accommodatepeptides of 8-10 amino acids,Nature of pr

19、esented 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-bi

20、nding groove of MHC molecules,34,Anchor residue of antigenic peptide,,HLA-A*0201:x-L/M-x-x-x-x-x-x-L/V,35,Each classІ and classII MHC molecule has a single peptide-binding cleft that can accommodate many different peptid

21、es---flexibility(包容性)..The association of antigenic peptides and MHC molecules is a saturable, low-affinity interaction.The MHC molecules of an individual do not discriminate between foreign peptides and self antigen

22、peptides.,Characteristics of Peptide-MHC Interactions,36,If a microbe had proteins such that none of its peptides can bind to MHC, what’s the result?If a microbe mutates to avoid MHC binding of its peptides it would be

23、 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

24、simple or small proteins and the MHC.,Surprising, but true,37,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

25、,,TCRs bind short antigen peptides but not whole antigen proteins. Antigen processing is required to present antigen peptides to TCR.,40,Antigen presentation,Roles in Adaptive Immune Response,41,Figure 3-30,,T cell recep

26、tor 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

27、,44,MHC molecules 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 in

28、fections.,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,

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