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Major Histocompatibility Complex (MHC)

Chapter 6. Major Histocompatibility Complex (MHC). 主要组织相容性复合体. Outline.  Conception of termes related to MHC  Human MHC --- HLA complex  Characteristics of MHC

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Major Histocompatibility Complex (MHC)

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  1. Chapter 6 Major Histocompatibility Complex (MHC) 主要组织相容性复合体

  2. Outline Conception of termes related to MHC  Human MHC --- HLA complex  Characteristics of MHC  Interaction between MHC molecules and antigen-peptide  Functions of MHC molecules  HLA & clinical medicine

  3. Ⅰ. Conception of Terms Related to MHC 1.Histocompatibility antigen ---代表个体特异性的同种异型抗原称为组织相容性抗原 2.Major histocompatibility antigen ---引起强而迅速排斥反应的组织相容性抗原为主要组织相容性抗原

  4. 3.Major histocompatibility complex (MHC) A.Conception 位于同一染色体片段上,编码主要组织 相容性抗原的一组紧密连锁的基因群。 其编码的产物是参与抗原提呈和T细胞 激活的关键分子,在免疫应答的启动和 免疫调节中发挥重要作用 B.Nomemclature of MHC Mouse MHC: H-2 complex (Chromosome 17) Human MHC: HLA complex(Chromosome 6)

  5. HLA complex A.Conception of HLA complex 人类主要组织相容性抗原是存在所有有核细胞表面一组能识别和排斥外来组织的抗原,它首先在白细胞表面被发现且含量最高,故人类主要组织相容性抗原称为人白细胞抗原(human leukocyte Ag, HLA)。编码HLA的基因群称为HLA复合体 B.Location ---on the chromosome 6p 注意区别： *HLA complex & HLA antigen/molecule *Human MHC & HLA complex and MHC molecule & HLA antigen/molecule

  6. Ⅱ.Human MHC --- HLA complex A.Classical HLA gene B.Genes associated with immune function C.CYP21基因（21羟化酶基因） 1.Structure of HLA complex 2.Expressive products of classⅠ gene and classⅡgene ---HLA molecules

  7. 1.Structure of HLA complex A.Classical HLA gene ---ClassⅠgene and Class Ⅱ gene (HLA Ⅰa gene) HLA complex classⅠgenes Class Ⅱ genes HLA-B,HLA-C,HLA-A HLA-DP,HLA-DQ,HLA-DR

  8. B.Genes associated with immune function Genes encoding for C4 ,C2 and Bf (HLA-Ⅰb gene)  Non-classical classⅠgene f E GF  Inflammation related gene DO DO A Genes associated with Ag-processing and presenting •LMP2/7 (低分子量多肽) gene•TAP1/2 (抗原肽加工相关转运体) gene•HLA-DM gene•HLA-DO and TAP-associated protein gene

  9. 2.Expressive products of classⅠgene and classⅡgene ---HLA molecules Structure •consists of  chain and  chain•divided into four region peptide-binding cleft (肽结合槽) 2m *peptide-binding region 与抗原肽结合及被T细胞识别的部位 *Ig-like region 与T细胞表面CD8/CD4分子结合部位 *transmebrane region *cytolasmic region 15号染色体编码  Distribution

  10. Ⅲ.Characteristics of MHC 1.Polygenic properties (多基因性) 2.Haplotype (单元型) 3.Polymorphism (多态性) 4.Linkage disequilibrium (连锁不平衡)

  11. 1.Polygenic properties of MHC p53 多基因性:指MHC是由一组位置相邻(或紧密连锁)的基因座位(locus)组成 共有224个基因座位 每一个体的细胞表面均表达一组HLA分子(各具不同抗原肽结合特性) 2.Haplotype p58 A24 B12 DRB6 DQ3 连锁在同一条染色体上HLA不同基因座位等位基因的特定组合,称为单元型 allele

  12. 3. Polymorphismp57 haplotype a:A24-B12-DRB6-DQ3 b:A2-B32-DRB6-DQ8 群体中同一基因座位上存在两个以上等位基因的现象称多态性 A24 24 A 2 A2 HLA-A(151) 、 HLA-B (301) 、 HLA-DRB1(227) … 共1031个 (至2003.07.31止: A(282), B(537), DRB (418)……共1695个) B12 12 B 32 B32 DRB6 6 DRB 16 DRB16 DQ3 3 DQ 8 DQ8 a b phenotype (表型) （HLA-A* 0103）  random combination and co-dominance (共显性) expression of alleles  variation & selection pressure

  13. 4.linkage disequilibrium p58 ---两个或两个以上基因座位上的某些等位基因 同时出现于同一染色体上的几率高于随机出现的频率，此现象称为连锁不平衡 •北欧白人具特征性的单元型: A1-B8 •汉族人特征性的单元型： A2-B46-Cw3-DR9-DQ9-Dw23（南方人） A33-B17-Cw2-DR3-DQ2-Dw3 (北方人)

  14. 1.Molecular base of interaction Anchor position or “pocket” (锚定位) and anchor residue(锚定残基) Ⅳ.The Interaction between MHC molecules and antigen peptide ( p60概念) ---在抗原肽-MHC复合物中, 抗原肽的两个或两个以上专司与MHC分子结合的氨基酸残基(Y和I), 称为锚 定残基; MHC分子抗原结合糟中与抗原肽锚定残基相对应的氨基酸残基称为锚定位 Ag-peptide 酪氨酸 anchorresidue 异亮氨酸 “pocket” anchor position

  15. 2.Characteristics of interaction A.Relative specificity 抗原肽(8~10aa) (相对专一性） ---Different MHC molecules selectively bind different peptides that have specific anchor residue p61 表6-3 锚定残基 (不同MHC分子选择性结合具有特定锚定残基的不同抗原肽) 锚定位 B.Flexibility (包容性) 抗原肽(13~17aa) ---Given MHC molecule can present or recognize a group antigen peptide with consensue motif (特定MHC分子可提呈或识别带有特定共同基序的一群抗原肽) 锚定残基 锚定位

  16. 共同基序 xY*xxxxxV/I* xxxxY/F*xxL* H-2Kd H-2Kb Y:酪氨酸 I:异亮氨酸 V:缬氨酸 L:亮氨酸 F:苯丙氨酸 F: 苯丙氨酸 以上表明:与同一MHC分子结合的不同抗原肽,其锚定残基往往相同或相似(均显示一个特征性的共同基序)

  17. (14章) 2. Other functions of MHC molecules V . Functions of MHC molecules A. Take part in genetic control of immune- regulation (17章) B. Induce allogeneic graft rejection (23章) C. Take part in differentiation of T cell (12 章) D. Take part in restriction-recognition of T cell 1. Antigen processing and presenting (p54表:Ⅰ/Ⅱ类分子对CTL/Th的识别起限制作用)

  18. 24 A B CD8+T细胞 T 细胞 CD4+T细胞 受MHC-Ⅰ类分子限制 受MHC-Ⅱ类分子限制 Ag肽 2 靶细胞 APC MHC分子参与T细胞限制性识别 A.CD8+ T 细胞的TCR识别抗原肽的同时,需识别MHC-Ⅰ类分子 B.CD4+ T 细胞的TCR识别抗原肽的同时,需识别MHC-Ⅱ类分子 MHC限制性:指TCR在识别APC或靶细胞表面抗原肽的同时,还须识别与抗原肽结合成复合物的MHC分子的现象

  19. MHC分子的限制性识别 (anchor position)

  20. (key of success or failure, HLA typing) Ⅵ.HLA & Clinical Medicine (tumor,AID) 1.HLA & organ-transplantation 2.Abnormal expression of MHC molecules & clinical diseases 3.Association of HLA with diseases 4.HLA & legal medicine 5.HLA & transfusion (positive association and negative association)

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