MHC Major Histocompatibility Complex I Concepts II Organization
MHC ( Major Histocompatibility Complex) I. Concepts II. Organization of MHC III. genetic characteristics of MHC IV. MHC molecules V. Interaction of antigenic peptides with MHC molecules VI. Biologic activities of MHC
Part I. Some concepts 1. Histocompatibility Ag Antigens which cause immune response to the graft and determine the survival of the graft. 2. MHS(Major histocompatibility antigen system ) A group of complex histocompatibility antigens which cause rapid and strong immunoreaction to the graft.
3. MHC (Major histocompatibility complex) A cluster of genes which encode for major histocompatibility antigens and relate to immune response.
4. HLA (human leucocyte antigen) The major histocompatibility antigens of human which are associated with histocompatibility and immune response. 5. HLA complex The MHC of human, a cluster of the genes which encode for HLA and relate to histocompatibility and immune response. 6. H-2 complex The MHC of mice
Part II. Organization of HLA complex Located on chromosome 6. ● Class I gene region 1. classical HLA I genes-------HLA-A, B, C gene loci 2. non-classical HLA I genes----HLA-E, F, G 3. MHC I chain-related genes ● Class II gene region 1. classical HLA II genes---HLA-DP, DQ, DR subregion (2 or more than 2 gene loci in each subregion) 2. genes associated with antigen processing ● Class III gene region complement genes-----C 4, C 2, B inflammation-associated genes----TNF, HSP 70
Located on chromosome 6. ● Class I gene region 1. classical HLA I genes-------HLA-A, B, C gene loci 2. non-classical HLA I genes----HLAE, F, G 3. MHC I chain-related genes
● Class II gene region 1. classical HLA II genes---HLA- DP, DQ, DR subregion (2 or more than 2 gene loci in each subregion) 2. genes associated with antigen processing
HLA-DM gene TAP gene(transporter associated with antigen processing) PSMB gene (Proteasome subunit, beta type) HLA-DOA and HLA-DOB genes
● Class III gene region complement genes-----C 4, C 2, B inflammation-associated genes---TNF, HSP 70
III. Genetic characteristics of MHC 1. Polymorphism: Multiple alleles In a population, there are multiple alleles at a gene locus of MHC Codominance The two alleles at a gene locus of MHC in the two homogenous chromosomes are expressed together.
2. Haplotype A gene combination which results from gene loci linked in a chromosome.
3. Linkage disequilibrium 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, that is , the distribution of haplotypes is not random in a population
Diversity -----MHC molecules are diverse. Diversity is generated by natural selection and show life-force.
Part IV. MHC molecules I) Molecular structure II) Distribution
I. Molecular Structure of HLA 1. HLA class I molecules 1) two separate polypeptide chains n MHC-encoded alpha (or heavy) chain; n non-MHC-encoded beta chain (beta 2 microglobulin) 2) Only alpha chain spans the membrane
3)The molecule has four domains 1 domain, 2 domain interact to form a peptide-binding region ( A peptide 8 -10 amino acids long sits in the groove. ) 3 domain , combining site of CD 8 2 microglobulin domain refered to as immunoglobulin-like region to maintain their proper conformation.
2. Class II HLA 1) two chains, and . both are MHC-encoded 2)both and chain span the membrane. 3) four domains 1 and 1 form the peptide-binding region 2 and 2 form the immunoglobulin-like region. 2 : Combining site of CD 4
II) Distribution of HLA molecules 1. class I molecules In human, all nucleate cells carry the class I antigens in variant amounts 2. class II molecules Activated Tcells, Professional antigen-presenting cells (macrophages, dentritic cells and B cells), Thymus epithelial cells et al.
Part V. Interaction of HLA molecules and antigen peptides 1. 2. 3. Combination of antigen peptide and antigen-binding groove Molecular basis of the interaction of HLA molecules and antigen peptides Characteristics of MHC moleculesantigen peptides interaction
1. Combination of antigen peptide and antigen binding groove
Class I MHC molecule A peptide 8 -10 amino acids long sits in the groove. The greatest variability in amino acids occurs in the 1 and 2 sequences n Class II MHC molecule A peptide 13 -17 amino acids long sits in the groove. n
2. Molecular basis of the interaction of HLA molecules and antigen peptides Anchor sites binding sites of an antigen peptide bound with antigen-binding grooves of MHC molecules anchor residues amino acids in the anchor sites bind to antigen- binding grooves of MHC molecules.
Anchor sites : places of the anchor residues
3. Characteristics of MHC molecules/anigen peptides interaction relative specificity (1) Specificity Certain MHC molecule recognizes corresponding consensus motif (2) Flexibility Amino acids “x” and anchor residue are variable Different MHC molecules can recognize similar consensus
Part VI. Biologic activities of HLA 1. induce the differentiation of T cell to form T cell repertoire 2. present antigens to initiate immune response n n Endogenous Ag is presented to CD 8 T cell by MHC class I molecule Exogenous Ag is presented to CD 4 T cell by MHC class II molecule
Application of HLA in medicine 1. HLA in transplantation 2. some diseases are associated with HLA genotypes
- Slides: 50