Presentation is loading. Please wait.

Presentation is loading. Please wait.

Chapter 9 Major Histocompatibility Complex (MHC) Chapter 9 Major Histocompatibility Complex (MHC)

Similar presentations


Presentation on theme: "Chapter 9 Major Histocompatibility Complex (MHC) Chapter 9 Major Histocompatibility Complex (MHC)"— Presentation transcript:

1

2 Chapter 9 Major Histocompatibility Complex (MHC) Chapter 9 Major Histocompatibility Complex (MHC)

3 Contents Part Several important concepts Part Composition of HLA complex Part Genetic characteristics of HLA Part Molecular structure and distribution of HLA Part Interaction of MHC molecules and antigen peptide Part Biological functions of MHC Part Application of HLA in medicine Chapter 9 Major Histocompatibility Complex Chapter 9 Major Histocompatibility Complex

4 Part 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.

5 MHS(Major histocompatibility antigen system ) 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.

6 MHC (Major histocompatibility complex) A large 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.

7 HLA (Human leucocyte antigen) The MHS of human which is associated with allograft rejection, immune response, immune regulation 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.

8 H-2 complex: The MHC of mouse (chromsome 17)

9 Part Composition of HLA complex HLA complex is located 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

10 . Class gene region Classical HLA class genes HLA-A,B,C Non-classical HLA class genes-----HLA-E,F,G MHC 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

11 . Class gene region 1.Classical HLA class genes HLA-A,B,C Participate in endogenous antigen presenting and immune regulation.

12 2. Non-classical HLA class genes ----HLA-E,F,G Participate in immune regulation Associated with maternal-fetal immune tolerance. 3. MHC class chain-related genes(MIC) MICA,MICB,MICC,MICD,MICE Associated with cytotoxicity effect of NK cell.

13 1. Classical class genes----HLA-DP,DQ,DR Participate in exogenous antigen presenting and immune regulation.. Class gene region

14 2. Genes associated with antigen processing (1)The genes associated with endogenous antigen-processing and presenting TAP Transporter associated with antigen processing, LMP Large multifunctional proteasome, or low molecular weight polypeptide

15 (2) The genes associated with exogenous antigen-processing and presenting HLA-DM----Processing and presenting of exogenous Ag HLA-DO----Inhibit the function of HLA- DM

16 . Class gene region 1. Encoded genes of complement C4B,C4A,Bf,C2

17 2. TNF genes family 3. Heat-shock protein(HSP) genes family

18 Part Genetic characteristics of HLA Haplotype inheritance Polymorphism Linkage disequilibrium

19 1. Haplotype inheritance Haplotype Genotype Phenotype

20

21

22 2. Polymorphism Polymorphism means there are multiple alleles at a gene locus of MHC in a population so 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.

23

24

25 3. Linkage disequilibrium The distribution of haplotypes is not random in a population. The probability in which two or more than two alleles present together in one chromosome is greater than the probability in which they present randomly.

26 Part Molecular structure and distribution of HLA molecules

27 . Molecular Structure of HLA molecules 1. Class HLA molecules (1)Class HLA molecules contain two separate polypeptide chains HLA-encoded alpha (or heavy) chain Non-HLA-encoded beta chain (beta2 microglobulin,β2m)---15 chromosome (2) Only alpha chain is trans- membrane HLA

28 (3) Class HLA molecules have four regions Peptide binding region----α1, α2 IgSF region----α3, β2m Trans-membrane region Cytoplasmic region

29

30 (4) Function of each domain 1 and 2 domains: Interact to form a peptide- binding region which is a groove(cleft) having a "floor"of 8 beta-pleated strands and two "walls" with alpha-helices. ( Containing a peptide of 8-11 aa in the groove)

31

32 3 domain: Binding to CD8 on Tc cells 2 microglobulin domain: To maintain proper conformation of class HLA molecules. Trans-membrane region: Anchoring class HLA molecules Intra-membrane region: Transmitting the signal

33

34 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

35 (4) Class HLA molecules have four regions Peptide binding region----α1, β1 IgSF region----α2, β2 Trans-membrane region Cytoplasmic region

36

37 (5) Function of each domain α1 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 of 10-30aa in the groove)

38

39 2 and 2 domain : Form the immunoglobulin-like region. 2 domain can bind to CD4 on Th cells Trans-membrane region: Anchoring class HLA molecules Intra-membrane region: Transmitting the signal

40 βα

41 . Distribution of HLA molecules 1.Class HLA molecule: Expressed on nucleate cells 2.Class HLA molecule Expressed on professional antigen- presenting cell(macrophage, dentritic cell and B cell), activated T cell, thymus epithelial cell et al. 3.sHLA

42 Part Interaction between MHC molecule and antigenic peptide Class II MHC molecule- antigenic peptide complex Class I MHC molecule - antigenic peptide complex

43 . Molecular basis of interaction between MHC molecule and antigenic peptide

44 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 antigen

45 Certain 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

46

47

48 . Characteristics of interaction Relative specificity (1) Specificity: Certain MHC molecule recognizes corresponding consensus motif (2) Flexibility: Amino acids x and anchor residues are variable Different MHC molecules can recognize similar consensus motif

49 MHC restriction: T cell only recognize antigenic peptide combining with MHC molecules. That is to say, interaction of T cell and antigen-presenting cell(APC) or target cell need restriction by MHC molecules.

50 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 cell is restricted by class molecules.

51 CD4 + T cell(Th) CD8 + T cell(Tc) T cell Receptor Peptide MHC Class II T cell Receptor Peptide MHC Class I Antigen Presenting Cell Antigen Presenting Cell CD4CD8

52

53 Part Biological functions of MHC 1.Induce the differentiation and maturation of T cell to form functional T cell repertoire 2.Present antigen to initiate immune response

54 1.Induce the differentiation of T cell to form T cell repertoire

55 2. Present antigen to initiate immune response Endogenous antigen: antigens synthesized within cells Exogenous antigen: antigens comes outside the cell Endogenous Ag is presented to CD8 + T cell by MHC class molecule Exogenous Ag is presented to CD4 + T cell by MHC class molecule

56 CD8 + T cell

57 CD4 + T cell

58 Part Application of HLA in medicine HLA and transplantation

59 Mixed lymphocyte reaction to determine identity of class II HLA antigens between a potential donor and recipient. Lymphocytes from the donor are irradiated or treated with mitomycin C. If the class II antigens on the two cell populations are different, the recipient cells will divide rapidly and take up large quantities of radioactive nucleotides into the newly synthesized nuclear DNA. The amount of radioactive nucleotide uptake is roughly proportionate to the MHC class II differences between the donor and recipient lymphocytes. MLR

60 Some diseases are associated with HLA genotypes

61 HLA and forensic medicine: Paternity testing Criminal investigation


Download ppt "Chapter 9 Major Histocompatibility Complex (MHC) Chapter 9 Major Histocompatibility Complex (MHC)"

Similar presentations


Ads by Google