5. MHC.ppt
- 1. 5. MHC molecules: Recognition of antigens 1
- 2. 2 Major Histocompatibility Complex (MHC)
- 3. • Difficulty during transplantation…rejection • Immune responses: antibody formation, TH, CTL • Highly polymorphic √ • Bind peptide…….. recognized by T cells 3
- 4. • Are self antigen (autoantigen) • Found on all cells of nucleated humans and all vertebrates cells • Discovered during transplantation experiment in mice – Transplanted organ is accepted sometimes (genetically the same) and rejected some other time (genetically different) – The answer was given by George Snell: the tissue of donor and recipient are incompatible – Closely related gene: Major histocompatibility complex (MHC) 4
- 5. MHC Genes The human MHC genome is called HLA (Human Leukocyte Antigen-HLA)….tightly linked cluster of genes The mouse MHC genome is H-2. • MHC class I = HLA-A, HLA-B & HLA-C • MHC class II = HLA-DP, HLA-DQ, &HLA-DR (D region) • MHC class III = Complement factors C2, C4,& Factor B • Genes encoding in this MHC III do not play any role in antigen presentation. 5
- 6. MHC is Polygenic and Polymorphic It is polygenic because it has several genes for each class (3 for class-I, 6 for class-II). It is polymorphic due to the relatively large number of alleles within each MHC class within the species. 6
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- 8. Polymorphism of MHC Molecules 8
- 9. Importance of MHC polymorphism • Polymorphism and polygeny – is the generation of a highly diverse repertoire of MHC molecules capable of presenting a large variety of Ag peptides to T cells 9
- 10. MHC gene inheritance to offspring • Most individuals are heterozygous in terms of MHC inheritance. • For each MHC genes every individual inherits one MHC allele from each parent, maternal and paternal. • The MHC molecules are expressed co-dominantly • In any mating, four possible combinations of haplotypes can be found in the progenies, for each MHC gene. 10
- 11. Classification and structure of MHC • 2 types of polymorphic genes, the class I and II encodes two groups of structurally distinct but homologous proteins. • MHC class-I is made up of two polypeptide chains: One large called and one small called 2 microglobulin, it is not polymorphic. • The chain has 3 extracellular domains (1, 2 & 3), a transmembrane and a cytoplasmic segment. 11
- 12. The 1 and 2 domains form a cleft where the Ag fragment of antigen binds. The 2 microglobulin has only one extracellular domain No transmembrane portion No cytoplasmic tail Immunoglobulin-like region: highly conserved α3 domain - site to which CD8 on T cell binds 12
- 13. NH2 Alloantigenic sites CHO NH2 COOH P α1 α2 α3 β2 OH Plasma membrane Disulfide bridge Papain cleavage Cytoplasm NH2 13
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- 15. MHC Class-II molecules o Composed of two polypeptide chains and . o Each chain has two extracellular domains 1 2 and 1 and 2 o A transmembrane segment o A cytoplasmic tail o The 1 and 1 domains form the cleft for the Ag fragment oImmunoglobulin-like region – conserved α2 and β2 domains – β2 is site to which CD4 on T cell binds 15
- 16. Plasma membrane Cytoplasm CHO CHO CHO NH2 NH2 COOH COOH α1 α2 β2 β1 16
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- 19. Class I or II MHC: Interaction with Peptides • Has a broad specificity • Has a single peptide binding cleft • The peptide sequences that bind to MHC molecules are distinct from those recognized by T cells • The affinity of peptide-MHC interactions is much lower than that of antigen-antibody binding • Peptide-MHC complexes persist long due to low rate of Dissociation • MHC molecules don’t discriminate between self and non Self antigens 19
- 20. Genomic of MHC molecules In Humans, MHC is located on the short arm of chromosome 6 and -2 Microglobulin is encoded by a gene on chromosome 15 MHC of human occupies ~3500kb • MHC-I are in the most telomeric region and MHC-II are in the most centromeric region of HLA locus • Other genes in the class II locus -TAP 1 and 2 - subunits of a cytosolic protease complex (Proteasome) - HLA-DM 20
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- 22. •MHC class III = Between class I and II gene • Complement factors C2, C4,& Factor B • Genes encoding in this MHC III do not play any role in antigen presentation 22
- 23. Expression of MHC molecules • MHC-I expressed on all nucleated cells • MHC-II expressed on APCs: Macrophages, B cells and Dendritic cells • Expression of MHC molecules is increased by cytokines!! produced during innate and adaptive immune responses Interferon , , , Tumor necrosis factor (TNF) and lymphotoxin increases expression of class I molecules Interferon : stimulates expression of class II molecules?? 23
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- 26. Both of them have a peptide-binding groove with a wall of 2 α helices and a floor of 8 β-pleated sheets Close-ended groove for class I MHC requires an 8-10 amino acid-length peptide to bind Open-ended groove for Class II MHC lets it bind a peptide 13-25 amino acids long Peptide-binding site for MHC-I and MHC-II are structurally similar 26
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- 28. Properties of MHC o are membrane-bound, recognition by T cells requires cell-cell contact. o Peptide/antigen from cytosol attach to class I MHC and is recognized by CD8+ cells. o Peptide from vesicles associates with class II MHC and is recognized by CD4 cells. 28
- 29. o Though there is a high degree of polymorphism (MCH) for a species, an individual has maximum of six different class I MHC products and maybe more class II MHC products (12). o Antigen must associate with a given MHC of that individual, otherwise no immune response can occur. 29
- 30. o Mature T cells must have a T cell receptor that recognizes the peptide associated with self MHC . o Each MHC molecule has only one binding site o Different peptide/antigen can bind a given MHC molecule, degenerate o All bind to the same site, but only one at a time. 30
- 31. o MHC polymorphism is determined at germline. There is no recombinational mechanism for generating diversity o Cytokines increase level of expression of MHC. o `controlled by transcription factors o Alleles for MHC genes are co-dominant. Each MHC gene product is expressed on the cell surface of an individual nucleated cell. 31
- 32. MHC & Immune responsiveness • The MHC polymorphism within a species will generate a diversity of binding specificities, and thus different patterns of responsiveness to antigens. • The absence of an MHC molecule that can bind and present a given peptide, or the absence of T-cell receptors that can recognize a given peptide–MHC molecule complex, could result in the absence of immune responsiveness. • Some HLA alleles occur at a much higher frequency in those suffering from certain diseases than in the general population: autoimmune disorders, certain viral diseases, disorders of the complement system, some neurologic disorders, and several different allergies. 32
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