1. MHC Histocompatibility Ags 1-Minor Histocompatibility Complex HLA 2-Major Histocompatiblity Complex H- 2

2. Major Histocompatibility Complex (MHC)  What is MHC? –HLA –H-2 –Minor histocompatibility antigens  What is MHC? –HLA –H-2 –Minor histocompatibility antigens

3. Significance of the MHC  role in immune response  role in organ transplantation  role in predisposition to disease  role in immune response  role in organ transplantation  role in predisposition to disease

4. Major Histocompatibility Complex: History Transplantation: autograft or autologus(syngraft) no regection allograft or allogenic graft rejection

5. Genetic barriers to transplantation autologous: in the same individual isologous: between genetically Identical individuals, i.e., identical twins (inbred animals) homologous: between individuals of the same species heterologous: between individuals different species autologous: in the same individual isologous: between genetically Identical individuals, i.e., identical twins (inbred animals) homologous: between individuals of the same species heterologous: between individuals different species

6. The laws of transplantation

8. The mouse MHC genes

9. Mouse MHC H-2K H-2 I-A= DP II human H-2D H-2 I-E = DR human H-2L

10. HLA Detection 1-by serologicaly 2-by mixed leukocyte reaction(MLR)

11. Cytotoxic T lymphocyte (CTL) generation CD4 + TH 1 CD8 + CTL CD8 + preCTL

12. The human MHC genes

13. Polymorphism of MHC genes

14.  Class-I expressed on all nucleated cells in man, and also on erythrocytes in mice.  Class-II expressed primarily on antigen presenting cells (dendritic cells, macrophages and B cells) Differential expression of MHC antigens

15. PROPERTIES MHC Immune responses: antibody formation Highly polymorphic Bind peptide: recognized by T cells: Th__MHCII Tc__MHCI Co_dominant Three-dimensional structure determined by X-ray crystallography

16. Structure of Class I MHC NH 2 Alloantigenic sites CHO NH 2 COOH P α1 α2 α3 β2 OH Plasma membrane Disulfide bridge Papain cleavage Cytoplasm NH 2

18. Structure of Class I MHC Two polypeptide chains, a long α chain and a short β chain, called β2 microglobulin Four regions: 1.Peptide-binding region - a groove formed from α1 and α2 domains of the α chain : 8-10 residue,greatest variability,anchor site 2. Immunoglobulin-like region = highly conserved α3 domain that homologus to Ig domain and non-covalently bound to beta2 Mic- site to which CD8 on T cell binds

19. Structure of Class I MHC (continued) 3.Transmembrane region – stretch of hydrophobic amino acids spanning membrane 4.Cytoplasmic region – contains sites for phosphorylation and binding to cytoskeletal elements

20. Structure of Class I MHC NH 2 Alloantigenic sites CHO NH 2 COOH P α1 α2 α3 β2 OH Plasma membrane Disulfide bridge Papain cleavage Cytoplasm NH 2

21. Structure of Class I MHC Peptide-binding Region a “groove” composed of an α-helix on two opposite walls and eight β-pleated sheets forming the floor residues lining groove most polymorphic peptide in groove 8-10 amino acids long specific amino acid on peptide required for “anchor site” in groove

22. Variability For Polymorphism

23. Structure of Class II MHC Plasma membrane Cytoplasm CHO NH 2 COOH α1 α2β2 β1

25. Structure of Class II MHC Two polypeptide chains, α and β, of roughly equal length. Four regions: 1.Peptide-binding region – a groove formed from the α1 and β1 domains of the α and β chains – site of polymorphism 2.Immunoglobulin-like region – conserved α2 and β2 domains – β2 is site to which CD4 on T cell binds