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The MHC complex: genetics, function and disease association

The MHC complex: genetics, function and disease association. Lecturer: Adelheid Cerwenka, PhD, D080, Innate Immunity Sources: Janeway: Immunobiology, 5th edition Kuby: Immunology, 4th edition Klein/Horejsi:Immunology 2nd edition. Only complementary surfaces fit together. MHC-structure.

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The MHC complex: genetics, function and disease association

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  1. The MHC complex: genetics, function and disease association Lecturer: Adelheid Cerwenka, PhD, D080, Innate Immunity Sources: Janeway: Immunobiology, 5th edition Kuby: Immunology, 4th edition Klein/Horejsi:Immunology 2nd edition

  2. Only complementary surfaces fit together

  3. MHC-structure Major Histocompatibility Complex (MHC): linked cluster of genes, which products play a role in intercellular recognition between self and nonself. The MHC is a region of multiple loci that play major roles in determining, whether transplanted tissue is accepted as self (histocompatible) or rejected as foreign (histoincompatible)

  4. The concept of Histocompatibility A skin-graft transplanted from A donor to a genetically identical recipient is accepted, to a genetically disparate recipient is rejected

  5. Nomenclature • MHC = MajorHistocombitibiliy Complex • Minor Histocompatibility Antigens: proteins, which are cell surface expressed and their peptides are loaded into MHC molecules • MHC is a generic name • HLA = Human Leucocyte Antigen, eg SLA = Swine Leucocyte Antigen • Mouse: MHC has an historical name = H2 (H-2) stands for histocompatibility 2

  6. Table of contents • Introduction • Structure of MHC I and II molecules • Genetic organisation of the MHC • Polymorphisms of MHC alleles • MHC and disease

  7. Communication of cells in the body 1.) Cell cell contact via cell surface receptors: cell surface proteins have been classified as CDs (=cluster of differentiation) CD2 T cell DC MHC TCR CD28 B7 2.) Cell to cell contact via soluble mediators such as cytokines (interleukins-IL) or chemokines (CCR, CXCR) IFN-g T cell DC MHC TCR CD28 B7 IL-12

  8. Host defense Against intracellular infection by mycobacteria Against intracellular infection by viruses

  9. MHC class I molecules present antigen derived from proteins in the cytosol

  10. MHC class II molecules present antigen originating in intracellular vesicles

  11. MHC molecules on the cell surface display peptide fragments

  12. Structure of MHC class I Computer graphic representation and ribbon diagramms of of the human MHC class I molecule HLA-A2. Heterodimer: a chain (43 kDa): polymorphic b2-microglobin (12 kDa): non-polymorphic, non-covalently bound a1 and a2: peptide binding, cleft formed by single structure a3: transmembrane

  13. Structure of MHC class II Computer graphic representation and ribbon diagramms of of the human MHC class II molecule, HLA-DRI Heterodimer, 2 transmembrane chains: a chain (34 kDa) b-chain (29 kDa) b1 and a1: peptide binding, not joined by covalent bond A2 and b2 : transmembrane Peptide binding groove is the MHC class II molecules is open at both ends

  14. Peptide binding sites and binding sites for CD4 or CD8 on MHC class I and MHC class II b chain (white) a- Chain (white) a chain (purple) b2- Microglobuline (purple) Base of b2 domain (green) Base of a3 domain (green) The binding sites for CD4 and CD8 on MHC class II molecules or MHC class I lie in the immunoglobulin domain, nearest to the membrane

  15. Peptides bind to MHC I molecules through structurally related anchor molecules Free amino and carboxy termini are stabilizing contacts Peptides eluted from two different MHC class I molecules are shown. Anchor residues in green: Not identical but related: eg: F and Y are both aromatic amino acids V, L and I are large hydrophobic amino acids MHC class I without peptide instable Pockets in the MHC molecules are lined by polymorphic amino acids.

  16. Peptides that bind MHC class II are variable in length and anchor residues lie at various distances from the ends of the peptide Peptides that bind to mouse MHC II Ak allele, or human MHC II HLA-DR3 Peptides that bind to MHC class II are at least 13-17 AA long, Ends of peptides are not conserved. Ends do not bind, binding pockets more permissive Blue: negatively charged residue D, aspartic acid, E glutamic acid, green: hydrophobic residues

  17. The expression of MHC molecules differs between tissues MHC class I: Expressed on all nucleated cells MHC class II: Expressed on surface of APCs (antigen presenting cells) Viruses can infect all types of cells Plasmodia (malaria) live in red blood cells

  18. Regulation of MHC class I expression Expression of MHC class I regulated by sequences upstream of the coding part. MHC enhancer segment: enhancer A, IRE interferon response element, enhancer B MHC class I expression can be regulated by Interferon (IFN-g). IFN-g also induces the key components of the intracellular machinery that enables peptides to be loaded onto MHC class I molecules

  19. T cells bearing a gd T cell receptor • gd T cells are not restricted by classical MHC molecules • They may be specialized to bind certain types of ligands (heatshock proteins, mycobacterial lipid antigens) directly or presented by non-classical MHC molecules.

  20. Conclusion: Structure of MHC molecules • MHC class I and II molecules have different structure, different distribution on cells in the body, and different function • Peptides, that bind to MHC class I or II are derived of different compartments and are of different length • The expression of MHC class I molecules can be regulated by interferon-g.

  21. Genetic organisation of MHC

  22. MHC diversity MHC is polygenic means that it contains several different MHC class I and class II genes MHC is polymorphic (poly=many Morphic=shape, structure): means that there are multiple variants of a gene within a population as a whole

  23. Genetic organisation of the MHC Human chromosome 6 Mouse chromosome 17

  24. Detailed map of the human MHC MHC class IB genes =Non-classical MHC Molecules =Non-conventional MHC Class I molecules

  25. Function of non-conventional MHC molecules • Ligands of inhibitory (HLA-G) or activating (MIC) Natural Killer cell receptors • Presentation of non-conventional peptides to ?? Cells:In mice, the H-2M locus encodes a nonconventional MHC class I molecule that present peptides that have a formylated methionin (eg also found in prokaryotic organisms such as mycobacterium tuberculosis, listeria, Salmonella) • Presentation of lipid antigens (CD1)

  26. MHC class I receptors on human Natural killer cells Receptors……………………………Ligands effect KIR receptors (Killer immunoglobulin receptors)…HLA-C mostly inhib. NKG2A/CD94………………………..HLA-E mostly inhib. NKG2D……………………………….MIC activ.

  27. a1 a2 a3 b2m MHC class I-like ligands for the activating receptor NKG2D human NKG2D-ligands Classical MHC I mouse NKG2D-ligands human MICA, B a1 a2 ULBP-human RAE-1-like RAE-1, H60 a3 b2m a1 a2 a1 a2

  28. a1 a2 a3 MHC class I related chain (MIC): ligands for human NKG2D • polymorphic • MIC = non-conventional MHC molecule • Expression absent from healthy tissue,overexpressed on tumors and in the gut epithelium • A soluble form of MICA is found in the serum of cancer patients • Expression induced by heat shock, viral infection and bacteria

  29. Lymphomas expressing mouse homologues of MIC molecules (RAE-1) are rejected Lymphoma cells +RAE-1 Lymphoma cells

  30. Polymorphism of MHC genes The figures are the numbers of alleles currently officially assigned by the WHO 100 different class I or class II alleles in mice H-2 complex: theoretical diversity is: 100 (K) x 100 (IAa)x 100 (IEa) x 100 (IEb) x 100 (D)=1012 Linkage disequilibrium occurs in human

  31. Expression of MHC alleles is co dominant 4 possible combinations of haplotypes are found in the offspring, there being one chance in four that an individual will share both haplotypes with a sibling.

  32. Diversity of MHC molecules expressed by an individual Polygeny the presence of several different related genes With similar function ensures that each individual produces a number of different MHC molecules

  33. Allelic variation occurs at specific sites within MHC molecules Allelic variability is clustered at specific sites within domains

  34. Gene conversion and new alleles Sequences can be transferred from one gene to a similar but different gene by a process know as gene conversion. This can occur by a misalignment of two paired homologous chromosomes When there are many copies of similar genes arrayed in tandem. Polymorphisms have been actively selected during evolution.

  35. MHC restriction The antigen specific T cell receptor recognizes a complex of antigenic peptide and MHC.

  36. History: MHC restriction Zinkernagel and Dohety 1975, JEM, 141:502

  37. Many T cells respond to superantigens Superantigens (produced by bacteria and viruses) can bind independently to MHC class II molecules and TCR, binding to the Vb domain of the TCR. Stapphylococcal enterotoxins (SE) cause food poisoning and toxic shock syndrome

  38. Conclusion: Polymorphism of MHC • Extensive polymorphism can extend the range of antigens to which the immune system can respond. • It is an advantage for the survival of the species • It has evolved to outflank evasive strategies of pathogens. • Pathogens are clever: they can evade detection or can suppress host responses. • Exposure to select for expression of particular MHC alleles: strong association of HLA-B53 with recovery from malaria • Why not more MHC loci? For maintenance of self-tolerance

  39. Cheetah were bred from limited breeding stock: limited polymorphism. Disadvantage for survival?

  40. MHC-dependent mate preferences in humans ??

  41. MHC and transplantation

  42. Mating of inbred mouse strains with different MHC haplotypes

  43. Various MHC molecules expressed on antigen presenting cells of a heterozygous H-2 k/d mouse Diversity generated by these mechanisms presumably increases the number of antigenic peptides that can be presented and thus is advantageous to the organism.

  44. Skin transplantion between between different mouse strains with same or different MHC haplotype

  45. T cells (CD4 and CD8 T cells) can transfer allograft rejection (1950. Mitchison) Nude mice (have no T cells) even accept xenografts

  46. Even complete matching does not ensure graft survival 1.) HLA typing not precise, complex polymorphisms, only siblings inherit the same haplotypes 2.) Minor histocompatibility antigens exist, peptides from polymorphic proteins presented by the MHC molecules on the graft. Although MHC genotype can be matched, polymorphism in any other gene can graft rejection.

  47. Minor H antigens

  48. 2 different ways of graft recognition

  49. Initiation of graft rejection: Dynamics of graft rejection

  50. Hyper acute graft rejection Preexisting antibody against donor graft antigens can cause hyperacute graft rejection

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