L16 Genetic Polymorphism and MHC Molecules PDF

Genetic polymorphism and its significance for MHC molecules Learning Objectives On completion of this session you should be able to 1) Understand the basis of MHC genetic polymorphism. 2) Comprehend how MHC polymorphism and polygeny contributes to the diversity of peptide presentation. 3) Expla...

Genetic polymorphism and its significance for MHC molecules Learning Objectives On completion of this session you should be able to 1) Understand the basis of MHC genetic polymorphism. 2) Comprehend how MHC polymorphism and polygeny contributes to the diversity of peptide presentation. 3) Explain how the combination of polygeny and polymorphism in MHC molecules provides a robust defence against pathogen evasion. MHC Genes - Organisation & Polymorphism 1) The arrangement of MHC genes ensures that a broad spectrum of peptides can be bound to T cells 2) This ensures that all antigenic peptides are recognised and pathogens destroyed 3) Pathogens have the potential to evade immune detection by mutating structural genes 4) The MHC “counters” this in 2 ways: 1. through POLYGENY 5) 2. through POLYMORPHISM Polygenic nature of MHC 1) Polygeny - the existence of multiple, functionally equivalent genes 2) There are several MHC class I and II genes encoding proteins with different peptide binding specificities 3) These proteins are also referred to as HLA (Human Leucocyte Antigen) class I and II molecules 4) Class I Region: 5) Three gene loci encode class I molecules - HLA-A, HLA-B, HLA-C 6) These encode for class I a chains 7) b2 Microglobulin are encoded by genes on chromosome 15 Polygenic nature of MHC 1) Class II Region: 2) There are at least 3 class II regions designated HLA-DR, HLA- DQ and HLA-DP 3) HLA-DR Subregion: 1 x a chain gene (DRA) 9 x b chain genes designated DRB1 - 9 Of these, 5 (DRB2, DRB6, DRB7, DRB8, DRB9) are pseudogenes DRB1, DRB3, DRB4 and DRB5 encode separate DR molecules Polygenic nature of MHC 1) The presence of these genes is restricted to certain haplotypes: 2) Haplotype B genes DR1 DRB1, (DRB6) DR51 DRB1, DRB5 (DRB6, DRB9) DR52 DRB1, DRB3 (DRB2) DR8 DRB1 DR53 DRB1, DRB4 (DRB7, DRB8, DRB9) Polygenic nature of MHC 1) HLA-DQ Subregion: 2 x a chain genes (DQA1 and DQA2) 3 x b chain genes (DQB1, DQB2, DQB3) DQB3 is a pseudogene. DQA2 and DQB2 may be functional 2) HLA-DP Subregion: 2 x a chain genes (DPA1, DPA2) 2 x b chain genes (DPB1, DPB2) DPA2 and DPB2 are pseudogenes 3) Other Genes Expressed in the Class II Region: 2 x TAP genes - encode for TAP transporter units 2 x LMP genes - encode for proteosome subunits Polygenic nature of MHC 1) Class III Region: 2) Contains genes encoding for: 1. Complement components C2, C4, factor B 2. TNF cytokines 3) Class Ib Region: 4) Comprises genes that encode for class I-like proteins which are thought to act as differentiation antigens during embryogenesis Polygenic nature of MHC Polymorphic nature of the MHC 1) Polymorphism: variation within a single gene and its products 2) Polymorphism increases further the number of MHC molecules expressed by an individual 3) There is co-dominant expression of allelic variants by heterozygous individuals 4) MHC expresses by an individual does not change over time but they may differ significantly from those expressed. By another individual of the same species 5) Polygeny and polymorphism result in the expression of 6 MHC class I and 6 - 8 MHC class II molecules Polymorphism + polygeny Polymorphic nature of the MHC 1) Allelic variants of MHC proteins can differ by up to 20 amino acid residues 2) Variations are restricted to: 1. Outer surface - recognised by TCR and restricts antigen recognition by T cells i.e. MHC restriction 2. Binding cleft - determines peptide binding properties (TCR ligand) 3) MHC genes are inherited as an intact set of alleles i.e a haplotype MHC alleles Summary 1. Understanding the basis of MHC genetic polymorphism reveals the presence of multiple alleles for each MHC gene, allowing for diverse peptide presentation. 2. MHC polymorphism, with its numerous alleles, and polygeny, with multiple genes within an individual, collectively enhance the variety of peptides presented to T cells. 3. This combination creates a robust defence against pathogen evasion, as pathogens that mutate to escape one individual's MHC molecules can still be recognised by others. 4. Together, polygeny and polymorphism ensure effective immune surveillance and response, maintaining a strong defence against infections across individuals and populations.