醫(yī)學(xué)免疫學(xué)英文教學(xué)課件：Chapter 9 MHC

1、 Chapter 9Major Histocompatibility Complex(MHC)ContentsPart Several important conceptsPart Composition of HLA complexPart Genetic characteristics of HLAPart Molecular structure and distribution of HLAPart Interaction of MHC molecules and antigen peptidePart Biological functions of MHCPart Applicatio

2、n of HLA in medicinePart Several important concepts Transplantation antigen(Histocompatibility antigen): Antigens which cause immune response to the graft and determine the survival of the graft.They are alloantigen which is specific for each individual. MHS(Major histocompatibility antigen system )

3、： A group of complex histocompatibility antigens which cause rapid and strong immunoreaction to the graft. mHS(Minor histocompatibility antigen system)： A group of complex histocompatibility antigens which cause slow and weak immunoreaction to the graft. MHC (Major histocompatibility complex)： A lar

4、ge cluster of linked genes located in some chromosome of human or other mammals encode for MHS and relate to allograft rejection, immune response, immune regulation and cell-cell recognition.Nobel Prize in Physiology or Medicine 1980George D. Snell (1/3), Jean Dausset (1/3) Discoveries concerning ge

5、netically determined structures on the cell surface that regulate immunological reactions H-genes (histocompatibility genes), H-2 gene Human transplantation antigens (HLA) -MHCHLA (Human leucocyte antigen)： The MHS of human which is associated with allograft rejection, immune response, immune regula

6、tion and cell-cell recognition.HLA complex： The MHC of human,a cluster of the genes which encode for HLA and relate to allograft rejection immune response, immune regulation and cell-cell recognition. H-2 complex: The MHC of mouse (chromsome 17)Part Composition of HLA complex HLA complex is located

7、on chromosome 6 and divided into three regions Class IIClass IIIClass I DP DQ DR C4B C4A Bf C2 HSP TNF B C E A F G RING DP DM LMP2 LMP7 DQ DR B2 A2 B1 A1 A B TAP1 TAP2 B2 A2 B3 B1 A1 B* A Class II Class III Class I第六對 染色體. Classgene region Classical HLA classgenes-HLA-A,B,C Non-classical HLA classge

8、nes-HLA-E,F,GMHC class chain related genes. Class gene region Classical HLA class genes-HLA-DP,DQ,DR Genes associated with antigen processing. Class gene region Complement genes-C4,C2,Bf Inflammation-associated genes-TNF,HSP70. Class gene region Classical HLA class genes -HLA-A,B,C Participate in en

9、dogenous antigen presenting and immune regulation.2. Non-classical HLA class genes -HLA-E,F,GParticipate in immune regulationAssociated with maternal-fetal immune tolerance.3. MHC classchain-related genes(MIC)MICA,MICB,MICC,MICD,MICEAssociated with cytotoxicity effect of NK cell.1. Classical class g

10、enes-HLA-DP,DQ,DR Participate in exogenous antigen presenting and immune regulation. Class gene region 2. Genes associated with antigen processing The genes associated with endogenous antigen-processing and presenting TAP（Transporter associated with antigen processing,抗原加工相關(guān)轉(zhuǎn)運(yùn)體） LMP（Large multifunct

11、ional proteasome,巨大多功能蛋白酶體）or （ low molecular weight polypeptide 低分子量多肽） (2) The genes associated with exogenous antigen-processing and presentingHLA-DM-Processing and presenting of exogenous AgHLA-DO-Inhibit the function of HLA-DM. Class gene region 1. Encoded genes of complement -C4B,C4A,Bf,C2 2.

12、TNF genes family3. Heat-shock protein(HSP) genes familyPart Genetic characteristics of HLA Haplotype inheritancePolymorphismLinkage disequilibrium1. Haplotype inheritanceHaplotype GenotypePhenotype2. Polymorphism Polymorphism means there are multiple alleles at a gene locus of MHC in a population so

13、 that an individual may have variant allele. -multiple allele -codominance: The two alleles at a gene locus of MHC in the two homogenous chromosomes are expressed together.3. Linkage disequilibriumThe distribution of haplotypes is not random in a population. The probability in which two or more than

14、 two alleles present together in one chromosome is greater than the probability in which they present randomly.Part Molecular structure and distribution of HLA molecules . Molecular Structure of HLA molecules1. Class HLA molecules(1)Class HLA molecules contain two separate polypeptide chainsHLA-enco

15、ded alpha (or heavy) chain Non-HLA-encoded beta chain (beta2 microglobulin,2m)-15 chromosome(2) Only alpha chain is trans-membraneHLA(3) Class HLA molecules have four regionsPeptide binding region-1, 2IgSF region-3, 2mTrans-membrane regionCytoplasmic region(4) Function of each domain1 and 2 domains:

16、 Interact to form a peptide-binding region which is a groove(cleft) having a floorof 8 beta-pleated strands and two walls with alpha-helices. ( Containing a peptide of 8-11 aa in the groove) 3 domain: Binding to CD8 on Tc cells2 microglobulin domain: To maintain proper conformation of class HLA mole

17、cules.Trans-membrane region: Anchoring class HLA molecules Intra-membrane region: Transmitting the signal 2. Class HLA molecules(1) Class HLA molecules consist of a non-covalent complex of two chains: and .(2) Both and chain span the membrane.(3) Both and chain are HLA-encoded HLA(4) Class HLA molec

18、ules have four regionsPeptide binding region-1, 1IgSF region-2, 2Trans-membrane regionCytoplasmic region(5) Function of each domain1 and 1: Interact to form the peptide-binding region which is a groove having a floor of 8 beta-pleated strands and two walls with alpha-helices. (Containing a peptide o

19、f 10-30aa in the groove) 2 and 2 domain : Form the immunoglobulin-like region. 2 domain can bind to CD4 on Th cellsTrans-membrane region: Anchoring class HLA molecules Intra-membrane region: Transmitting the signal. Distribution of HLA molecules1.Class HLA molecule: Expressed on nucleate cells2.Clas

20、s HLA molecule Expressed on professional antigen-presenting cell(macrophage, dentritic cell and B cell), activated T cell, thymus epithelial cell et al. 3.sHLAPart Interaction between MHC molecule and antigenic peptide Class II MHC molecule-antigenic peptide complexClass I MHC molecule -antigenic pe

21、ptide complex. Molecular basis of interaction between MHC molecule and antigenic peptide Anchor sites: Two or more sites on antigenic peptide bind to “groove” or “pocket” of MHC molecules.Anchor residues: The amino acid residues on anchor sites of antigenic peptide.Interaction between MHC and antige

22、nCertain MHC molecule binds the corresponding anchor residue of antigenic peptides.Antigenic peptides which can combine with the same kind of MHC molecule have same or similar anchor sites and anchor residues (consensus motif).Interaction between MHC and antigen. Characteristics of interaction Relat

23、ive specificity (1) Specificity: Certain MHC molecule recognizes corresponding consensus motif (2) Flexibility:Amino acids “x” and anchor residues are variableDifferent MHC molecules can recognize similar consensus motifMHC restriction: T cell only recognize antigenic peptide combining with MHC mole

24、cules. That is to say, interaction of T cell and antigen-presenting cell(APC) or target cell need restriction by MHC molecules. Interaction of Th(CD4+T) cell and antigen-presenting cell (APC) is restricted by class molecules.Interaction of Tc(CD8+T) cell and antigen-presenting cell (APC) or target c

25、ell is restricted by class molecules.CD4+T cell(Th)CD8+T cell(Tc)T cellReceptorPeptideMHCClass IIT cellReceptorPeptideMHCClass IAntigen PresentingCellAntigen PresentingCellCD4CD8Part Biological functions of MHC 1.Induce the differentiation and maturation of T cell to form functional T cell repertoire2.Present antigen to initiate immune response1.Induce the differentiation of T cell to form T cell repertoire2. Present antigen to initiate immune responseEndogenous antigen: antigens synthesized within cellsExogenous antigen: antigens comes outside the c