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1、CHAPTER 11THE MAJOR HISTOCOMPATIBILITY COMPLEXI.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 MHCsHLA:human MHC which is known as the human leucocytes antigen system.Three classes of MHC genes closely linked on chromosome Classgene Classgene ClassgeneII.The organization of murine and human
3、MHC1.Mouse H-2 complex:Classgene:K,DL class molecules(chain）Classgene:I class molecules(chain)Classgene:S complement,TNFSKID/LChr.17centromereH-22.Human HLA complex:DP DN DO DQ DR B C E A GHLA complexcentromereChr.6classlociProteins encodingHLA class ClassicalB,C,AHLA class moleculesNon-classicalE,F
4、,GHLA classClassicalDP,DQ,DRHLA class ImoleculesNon-classicalDN,DOHLA class Complement,TNF,HSPV.Genetics of MHCPolygenicPolymorphicHaplotype inherited CodominantA.HLA-molecules III.The structure and function of MHC molecules1.StructureTwo polypeptide chain:H-chain and 2-microglobulin(not coded by th
5、e MHC)Heavy chain has 3 domains:1,2,3.Heavy chain 1and2 domains form the binding groove(the polymorphic region)3 domain bind to CD82.Cellular distibutionClass molecules are expressed on all nucleated cells(all cells except for RBC)Exists in the form ofMembrane bound moleculesSoluble molecules2.Funct
6、ioni.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 lymphocytes).ii.Involve in transplant rejectioniii.T cell development in
7、thymusB.HLA-molecules1.Structure 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 domain2.Cellular distributionclass molecules are expressed on B cells M Dendritic cells Vascular endothelial cells3.Functi
8、ons i.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 are transported to the cell surface where they can be recognized by CD4+T cellii.Involve in transplant rejectioniii.Re
9、gulation of immune responseiv.T cell development in the thymusC.Non-classical HLA(HLA-b)1.Differentiation or activation states2.Disease 3.CytokinesIV.Factors influencing the expression of HLA molecules （1 1）内源性抗原提呈：抗原）内源性抗原提呈：抗原 靶细胞靶细胞 组成组成HLAHLA类分子类分子-抗原肽复合物抗原肽复合物 表达于细表达于细胞膜表面胞膜表面 CD8+TCD8+T细胞识别。细胞
10、识别。（2 2）外源性抗原提呈：）外源性抗原提呈：抗原抗原 APC APC HLAHLA类分子类分子-抗原肽复合物抗原肽复合物 表达于细胞表达于细胞膜表面膜表面 CD4+TCD4+T细胞识别细胞识别。HLAHLA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 病人（病人（病人（病人（Ag+/
11、Ag-Ag+/Ag-Ag+/Ag-Ag+/Ag-）对照（对照（对照（对照（Ag+/Ag-Ag+/Ag-Ag+/Ag-Ag+/Ag-）VI.Significance of MHC1.Control 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(i
12、mmune 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)+)+补体补体淋淋巴细胞受损巴细胞受损 判定结果（细判定结果（细胞死亡百分率）胞死亡百分率）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
13、-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2.Graft rejection and tissue matching 3.Autoimmune disease susceptibilitySummuryKey pointsThe definitions of MHC and HLA.The composition of HLA gene complexThe structure,distribution and functions of MHC class and molecules.9、静夜四无邻，荒居旧业贫。5月-235月-23Tue
14、sday,May 23,202310、雨中黄叶树，灯下白头人。13:05:0013:05:0013:055/23/2023 1:05:00 PM11、以我独沈久，愧君相见频。5月-2313:05:0013:05May-2323-May-2312、故人江海别，几度隔山川。13:05:0013:05:0013:05Tuesday,May 23,202313、乍见翻疑梦，相悲各问年。5月-235月-2313:05:0013:05:00May 23,202314、他乡生白发，旧国见青山。23 五月 20231:05:00 下午13:05:005月-2315、比不了得就不比，得不到的就不要。五月 231
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