Chapter 9 Major Histocompatibility Complex (MHC) Chapter 9 Major Histocompatibility Complex (MHC)
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
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.
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.
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.
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.
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
. 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
. Class gene region 1.Classical HLA class genes ------HLA-A,B,C Participate in endogenous antigen presenting and immune regulation.
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.
1. Classical class genes----HLA-DP,DQ,DR Participate in exogenous antigen presenting and immune regulation.. Class gene region
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
(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
. Class gene region 1. Encoded genes of complement ------C4B,C4A,Bf,C2
2. TNF genes family 3. Heat-shock protein(HSP) genes family
Part Genetic characteristics of HLA Haplotype inheritance Polymorphism Linkage disequilibrium
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.
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.
Part Molecular structure and distribution of HLA molecules
. 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
(3) Class HLA molecules have four regions Peptide binding region----α1, α2 IgSF region----α3, β2m Trans-membrane region Cytoplasmic region
(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)
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
(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)
. 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
Part Interaction between MHC molecule and antigenic peptide Class II MHC molecule- antigenic peptide complex Class I MHC molecule - antigenic peptide 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 antigen
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
. 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
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.
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.
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
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
1.Induce the differentiation of T cell to form T cell repertoire
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
Part Application of HLA in medicine HLA and transplantation
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
Some diseases are associated with HLA genotypes
HLA and forensic medicine: Paternity testing Criminal investigation