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IMMUNOLOGY Major Histocompatibility Complex (MHC) and its encoding molecules Xiaojian Wang 0571-88206268 科研楼B819 [email protected] MHC 1. Introduction 2. Structure of MHC genes and products 3. Polymorphism of MHC 4. Interactions of MHC molecules with antigenic peptides 5. Biological function of MHC molecules 6. MHC and clinical medicine Introduction MHC 1. Histocompatibility antigen The Ags primarily responsible for rejection of genetically different tissues are known as histocompatibility Ags. Histocompatibility The ability to accept grafts between individuals. 2. Histocompatibility antigen system Major histocompatibility antigen Minor histocompatibility antigen MHC 3.Major histocompatibility complex,MHC A cluster of genes on chromosome 6 in humans, encoding major histocompatibility antigen which regulates immune response. 4. Human: Human leukocyte antigens (HLA) mouse: H-2 Mouse Ir基因 MHC = H-2 human MHC = HLA Mouse MHC = H-2 1996 Nobel Prize (MHC restriction) MHC Organization and Structure of MHC Genes and Products 1. Organization of MHC genes 2. Products of MHC class I and MHC class II genes---HLA molecules 3. Immune function related genes MHC 1. Organization of MHC genes H-2 I K Ⅰ AβAα S EβEα C4 Bf C2 D IA IE Ⅱ Ⅱ Chromosome 17 (mouse) Ⅲ Ⅰ L Ⅰ MHC Organization of MHC genes HLA DP DQ DR BA BA BB A Ⅱ Ⅱ Ⅱ C4 B C A B A Bf C2 Ⅲ Chromosome 6 (human)6p21.31 ⅠⅠ Ⅰ Organization of MHC genes MHC 2. Products of MHC class I and class II genes---HLA molecules 1) HLA class I molecules MHC 1) HLA class I molecules Genes: A, B, C Distribution: every nucleated cell Structure: α chain (45kD) β2m (12kD) chromosome 15 peptide-binding cleft: α1+α2 CD8 binding: α3 Function: recognize and present the endogenous Ags to CD8+ T cells MHC HLA class I molecule MHC Structure of HLA I molecule HLA I molecule 2) HLA class II molecules MHC MHC 2) HLA class II molecules Genes: DR, DQ, DP Distribution: APC (B, DC, MΦ) thymic epithelial cell, activated T cell Structure: α chain (35kD) β chain (28kD) peptide-binding cleft: α1+β1 CD4 binding: β2 Function: recognize and present the exogenous Ags to CD4+ T cells MHC Structure of HLA II molecule HLA class II molecule MHC Structure of HLA molecule HLA-Ⅰ、Ⅱ类抗原的分布 组织 MHC I类分子 MHC II类分子 T细胞 B细胞 巨噬细胞 树突状细胞 +++ +++ +++ +++ +/+++ ++ +++ 胸腺上皮细胞 肝细胞 肾脏细胞 脑细胞 红细胞 滋养层细胞 + +++ + +- +++ - MHC 3. Immune function related genes 1. Serum complement coded genes HLA class III C4B, C4A,Bf, C2 2. Antigen presenting function related genes HLA class II LMP (proteasome subunit beta type, psmb):LMP2/7 encoding proteosome beta subunit Function: process endogenous Ag TAP (transporter associated with Ag processing): TAP1, TAP2 Function: transport endogenous Ag peptides Tapasin (TAP associated protein) Function: : participate in the endogenous pathways , help the assemble of the MHCI in ER MHC HLA-DM: DMA and DMB participate in the exogenous pathways, help the peptide binding to the MHCII HLA-DO: negative regulation to DM The function of HLA-DM HLA-DM catalyses the removal of CLIP HLA-DM Replaces CLIP with a peptide antigen using a catalytic mechanism (i.e. efficient at substoichiometric levels) Discovered using mutant cell lines that failed to present antigen HLA-DR HLA-DM MIIC compartment HLA-DO may also play a role in peptide exchange Sequence in cytoplasmic tail retains HLA-DM in endosomes MHC 3. Non-classic class I gene (HLA Ib) HLA-E, HLA-G: inhibit NK cell activity *HLA-E: 结合NK细胞和部分CTL细胞表面的C型凝集素受体超家族 CD94/NKG2家族.抑制NK 细胞功能 表达于各种组织细胞,在羊膜和滋养层细胞表面高表达。 功能: A.生理状态下NK处于抑制状态。 B.母胎耐受 *HLA-G:由α链和β2m组成,有15种等位基因。 分布:主要分布于母胎界面绒毛外滋养层细胞, 受体:杀伤细胞免疫球蛋白样受体(KIR)家族和白细 胞免疫球蛋白样受体(LIR)家族的某些成员。 功能:在母胎耐受中发挥功能。 MHC 4. Inflammation related genes TNF gene family: TNF, LTA, LTB Transcript factor gene family: I-κBL, ZNF173 MIC family: MIC A(高多态性), 激活NK 细胞性 MIC B Heat shock protein gene family: HSP70 Immune function related genes Ag processing-related genes Complement encoding genes Inflammationrelated genes Non-classical MHC I genes MHC Polymorphism of MHC Concept of polymorphism The phenomenon of having multiple allels at given genetic locus in the population 1.Mutiple-allele EMBL-EBI HLA Sequence Database (http://www.ebi.ac.uk/imgt/hla/stats.html) HLA alleles: 3,201 (class I:2,215, class II: 986) (last updated:07/2010 ) HLA-A HLA-B HLA-C HLA-E HLA-F HLA-G 673 alleles 1077 360 9 21 36 HLA-DPA1 HLA-DPB1 HLA-DQA1 HLA-DQB1 HLA-DRA HLA-DRB HLA-DRB1 HLA-DRB3 HLA-DRB4 HLA-DRB5 27 128 34 93 3 669 585 45 13 18 Naming of HLA alleles allele allele Locus group number HLA-A* 02 01 HLA-DRB1* 1102 2. Codominant expression: MHC genes are codominantly expressed in each individual (therefore each individual has 6 class I and 6 class II MHC molecules), which means the alleles inherited from both parents are expressed equally. This maximizes the number of MHC molecules available to bind peptides for presentation to T cells. Linkage disequilibrium and haplotype Linkage disequilibrium: the phenomenon that certain MHC alleles at different loci are inherited together more frequently than would be predicted by random assortment. e.g., DRB1*0901 DQB1*0701 15.6% 21.9% 11.3% (0.156×0.219=3.4%) the set of MHC alleles on each chromosome A2-B46-Cw3-DR9-DQ9-Dw23 MHC HLA多态性 *产生基础为变异,涉及基因突变、基因重组(染色体 同源部分的交换)和基因转换(染色体非同源部分 DNA片段的转移)等。 *MHC变异属于偶发事件,这些偶发变异能否以新等位 基因的形式被遗传下来,取决于自然选择。 例如:HLA-B53在抗疟疾流行中的作用 白种人和黄种人频率低不到1%,中非人高达28-40%, 当地疟疾患者中B53的频率明显降低(17%)——B53 具有保护作用。 白种人和黄种人群中,没有持续的疟疾流行,B53基因 不显示“优越性”,没有保留下来。在中非的疟疾流行 区,B53的保护作用引起阳性自然选择效应,构成选择 压力,使得B53基因频率上升。 MHC The significance of MHC polymorphism: Almost all of the polymorphism among MHC alleles involves amino acid residues located in and around the peptide-binding groove. As a result, each allelic form has its own unique peptidebinding properties. Affect the ability to make immune responses (e.g. resistance or susceptibility to infectious diseases) MHC Interactions of MHC molecules with antigenic peptides 1. Molecular basis (1) Antigen-binding cleft class I Molecules: 1/2 closed at both ends 8~10 amino acids class II Molecules: 1/1 open at both ends 13~17 amino acids Cleft geometry -chain -chain Peptide 2-M MHC class I accommodate peptides of 8-10 amino acids Peptide -chain MHC class II accommodate peptides of 13-17 amino acids HLA-Ⅰ,Ⅱ类分子抗原肽复合物的三维图 MHC (2) Anchor site and anchor residue anchor site anchor residue consensus motif MHC 2. Characteristics of peptide-MHC binding (1) Specificity: special anchor residue The important point is that peptide binding by a given MHC protein. (2) Flexibility: a series of antigenic peptides with consensus motif can be presented by a given MHC molecule. is somewhat selective but mush less specific than antigen binding by a TCR or an Ig. HLA molecules bind to different peptides with the same consensus binding motif Consensus binding motif HLA molecules 1 2 Class I A*0201 X X X X X X X B*2705 X L M R X X X X X X X X I L E V Y X N S T Q V X X Class II DRB1*0405 I F Y V 3 4 5 6 7 8 9 L V L F E D Biological function of MHC 1. Participate in the adaptive immune response serving as presenting molecules antigen 1) T cells recognize both the antigenic peptide and MHC molecules by TCR (double recognition) MHCI present endogenous antigen MHCII present enxogenous antigen CLIP:Class IIassociated invariant chain peptide 2) MHC molecules can present both autoantigens and allogenic MHC molecules 3) MHC molecules participate in selection and differentiation of T cells in the thymus. 4) MHC is the crucial determinant of disease susceptibility in different individuals; 5) MHC contributes to the genetic heterogeneity of the population 2. Participate in the innate immunity serving as regulatory molecules 1) Classical MHC class III genes encode complement, hereby participating in complement reaction and the pathogenesis of some immune diseases. 2) Non-classical HLA class I molecules (HLA-E, G) regulate the activity of NK cells. 3) Inflammation related genes initiate and control inflammation. They also play a role in stress. (such as HSP). MHC HLA/MHC and clinical medicine 1. HLA and transplantation HLA typing; cross-match 2. Abnormal expression of HLA Tumor: class I molecule↓ Autoimmune diseases: class II molecule↑ 3. HLA and disease susceptibility Ankylosing apondylitis: B27 58%-97% 4. HLA and medical jurisprudence 一、 HLA与器官移植 * HLA等位基因的匹配程度直接影响器官移植的 成败。 * HLA分子相同的同卵双生子之间进行移植, 可 长期存活;亲子之间有一条单倍型相同, 存活率 也较高;无关人群之间进行器官移植, 存活率就 较低,需进行HLA配型。 HLA-DR对移植排斥最为重要,其次是HLA-B 和HLA-A。 二、HLA分子的异常表达和临床疾病 *恶变细胞表达I类分子下调或缺如,造成免疫逃逸; *自身免疫性疾病中,原先不表达II类分子的组织细胞诱 导表达II类分子,导致免疫应答的异常激活和病理作 用。 如胰岛素依赖性糖尿病中的胰岛β细胞、乳糜泻中的肠 道细胞、萎缩性胃炎中的胃壁细胞等。 三、HLA与疾病的关联 1、HLA是机体对疾病易感的主要免疫遗传成分 * 某些特定HLA型别的个体易感某一疾病(阳性关联) 或对该疾病有较强的抵抗力(阴性关联)。 *与HLA关联的疾病大部分为自身免疫性疾病。 *如HLA-B27与强直性脊柱炎呈阳性关联,高达58-97%, 而健康人群仅为1-8%。相对风险程度(RR)为55~ 376。 四. HLA与输血反应 抗HLA 五. HLA与亲子鉴定和法医学 利用HLA系统的多基因性和多态性进行亲子鉴 定和法医学鉴定。 MHC more…? Thanks for your attention! 思考题(MHC): 问答题: 1. MHC分子的生物学功能。 2. HLA 1 类和II 类抗原的结构,组织分布和功能特点