CHAPTER 11. THE MAJOR HISTOCOMPATIBILITY COMPLEX(主要组织相容性复合体)

1、CHAPTER 11THE MAJOR HISTOCOMPATIBILITY COMPLEX,Introduction,Major histocompatibility antigen system Major histocompatibility complex: A large genetic locus that includes the highly polymorphic genes encoding the peptide-binding molecules recognized by T lymphocytes. The MHC locus also includes genes

2、 encoding cytokines, molecules involved in antigen processing, and complement proteins. H-2 complex: murine MHCs HLA: human MHC which is known as the human leucocytes antigen system.,Three classes of MHC genes closely linked on chromosome Classgene Classgene Classgene,The organization of murine and

3、human MHC,Mouse H-2 complex: Classgene: K, DL class molecules (chain） Classgene: I class molecules (chain) Classgene: S complement, TNF,Human HLA complex:,Genetics of MHC,Polygenic Polymorphic,Haplotype inherited Codominant,HLA-molecules,The structure and function of MHC molecules,Structure Two poly

4、peptide chain: H-chain and 2-microglobulin (not coded by the MHC) Heavy chain has 3 domains:1,2,3. Heavy chain 1and2 domains form the binding groove (the polymorphic region) 3 domain bind to CD8,Cellular distibution Class molecules are expressed on all nucleated cells (all cells except for RBC ) Exi

5、sts in the form of Membrane bound molecules Soluble molecules,Function Antigen processing and presenting (endogeneous pathway) peptides generated in the cytosol (eg. Virus antigen) become associated with MHC class molecules which move to the surface and can be recognized by CD8+ T cell (cytotoxic T

6、lymphocytes) . Involve in transplant rejection T cell development in thymus,Cytosolic pathogen (Endogenous antigen),Intravesicular pathogen (exogenous antigen),HLA-molecules,Structure Heterodimers of andglycoprotein chains. Each chain has 2domains(1, 2 and 1, 2) 1 and 1 form the binding groove. (the

7、 polymorphic region) CD4 bind to 2 domain,2. Cellular distribution class molecules are expressed on B cells M Dendritic cells Vascular endothelial cells,Functions Antigen processing and presenting (exogeneous pathway): both pathogens in cellular vesicles and those come from outside the cell are pres

8、ented on MHC class molecules of APCs and are transported to the cell surface where they can be recognized by CD4 + T cell Involve in transplant rejection Regulation of immune response T cell development in the thymus,Non-classical HLA (HLA-b),Differentiation or activation states Disease Cytokines,Fa

9、ctors influencing the expression of HLA molecules,（1）内源性抗原提呈：抗原 靶细胞 组成HLA类分子-抗原肽复合物 表达于细胞膜表面 CD8+T细胞识别。 （2）外源性抗原提呈：抗原 APC HLA类分子-抗原肽复合物 表达于细胞膜表面 CD4+T细胞识别。,HLA与疾病的关系 （一）R.R (relative risk，相对危险率) R.R值越大相关性越强。 （二）举例 1.强直性脊柱炎与B27 2.胰岛素依赖性糖尿病（IDDM）与DR3、DR4,病人（Ag+/Ag-）,对照（Ag+/Ag-）,Significance of MHC,Con

10、trol of immune response MHC restriction: The ability of T lymphocytes to respond only when they are presented with the appropriate antigen in association with either “self” MHC class or classmolecules. Ir gene (immune response gene),HLA分型法原理及应用,Graft rejection and tissue matching Autoimmune disease susceptibility