HISTOCOMPATIBILITYCOMPLEX(主要组织相容性复合体)

1、HISTOCOMPATIBILITYCOMPLEX(HISTOCOMPATIBILITYCOMPLEX(主要主要组织相容性复合体组织相容性复合体) )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 M

2、HC locus also includes genes encoding cytokines, molecules involved in antigen processing, and complement proteins.H-2 complex: murine MHCsHLA: human MHC which is known as the human leucocytes antigen system. Three classes of MHC genes closely linked on chromosome Classgene Classgene ClassgeneThe or

3、ganization of murine and human MHCMouse H-2 complex:Classgene: K, DL class molecules (chainClassgene: I class molecules (chain)Classgene: S complement, TNFSKID/LChr. 17centromereH-2Human HLA complex:DP DN DO DQ DR B C E A GHLA complexcentromereChr. 6classlociProteins encodingHLA class ClassicalB, C,

4、 AHLA class moleculesNon-classicalE, F, GHLA classClassicalDP, DQ, DRHLA class ImoleculesNon-classicalDN, DOHLA class Complement, TNF, HSPGenetics of MHC Polygenic Polymorphic Haplotype inherited CodominantHLA-molecules The structure and function of MHC moleculesStructureTwo polypeptide chain: H-cha

5、in 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 CD8Cellular distibutionClass molecules are expressed on all nucleated cells (all cells except for RBC )Exists in the form ofMembra

6、ne bound moleculesSoluble moleculesFunctionAntigen 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 lymphocytes) .Involve in tran

7、splant rejectionT cell development in thymusCytosolic pathogen (Endogenous antigen)Intravesicular pathogen (exogenous antigen)HLA-moleculesStructure Heterodimers of andglycoprotein chains. Each chain has 2domains(1, 2 and 1, 2)1 and 1 form the binding groove. (the polymorphic region)CD4 bind to 2 do

8、main2. Cellular distribution class molecules are expressed on B cells M Dendritic cells Vascular endothelial cellsFunctions Antigen processing and presenting (exogeneous pathway):both pathogens in cellular vesicles and those come from outside the cell are presented on MHC class molecules of APCs and

9、 are transported to the cell surface where they can be recognized by CD4 + T cellInvolve in transplant rejectionRegulation of immune responseT cell development in the thymusNon-classical HLA (HLA-b)Differentiation or activation statesDisease CytokinesFactors influencing the expression of HLA molecul

10、esHLAHLA与疾病的关系与疾病的关系 一一R.R (relative riskR.R (relative risk，相对危险率，相对危险率) ) R.R R.R值越大相关性越强。值越大相关性越强。 二举例二举例 1. 1.强直性脊柱炎与强直性脊柱炎与B27 B27 2. 2.胰岛素依赖性糖尿病胰岛素依赖性糖尿病IDDMIDDM与与DR3DR3、DR4DR4 Significance of MHCControl of immune response MHC restriction:The ability of T lymphocytes to respond only when they a

11、re presented with the appropriate antigen in association with either “self MHC class or classmolecules.Ir gene (immune response gene)血清学血清学细胞学细胞学分子生物学分子生物学实验方法实验方法补体介导的微补体介导的微量细胞毒试验量细胞毒试验混合淋巴细混合淋巴细胞培养法胞培养法（MLC)MLC)分子生物学分子生物学技术技术原理原理抗体抗体(HLA(HLA分型分型) ) + + 淋巴细胞淋巴细胞( (受受者者) + ) + 补体补体淋巴细胞受损淋巴细胞受损 判定结果判定结果（细胞死亡百（细胞死亡百分率）分率）单向法单向法双向法双向法比较供、受比较供、受者编码者编码HLAHLA抗原基因的抗原基因的 DNADNA序列，序列，判定供、受判定供、受者间的相似者间的相似程度。程度。主要应用主要应用检测检测HLA-AHLA-A、B B、C C抗原抗原检测检测DRDR抗原抗原 HLAHLA分型法原理及应用分型法原理及应用Graft rejection and tissue matching Auto