M AJOR H ISTOCOMPATIBILITY C OMPLEX

1. MHC MAJORHISTOCOMPATIBILITYCOMPLEX • definition and basic features • structure of MHC class I and II molecules • structure and organization of MHC genes • inheritance and expression of MHC genes

2. FUNCTION OF MHC MOLECULE(s) Presentation of antigens to T lymphocytes

3. GPLA H-2 DLA MHC FLA RT-1 SLA

4. HLA Human Leukocyte Antigens

5. BASIC FEATURES of MHC • polygenicity (> 200 genes) • polymorfism(genes within species have • alternative variants – alleles)

6. George Snell Jean Dausset Baruj Benacerraf 1980

7. Stucture of class I and class II MHC molecules

12. Anchoring amino acids Cleft of MHC

14. TISSUE DISTRIBUTION AND NOMENCLATURE OF MHC ALL NUCLEATED CELLS DENDRITIC CELLS MACROFAGES B CELLS A a DP a b b2m a a DQ b B b2m a a b DR C b2m MHC class I MHC class II

15. CD4+ T cell (helper) CD8+ T cell (cytotoxic) TCR TCR CD8 CD4 MHC I MHC II A P C A P C

16. Peter C. Doherty Rolf M. Zinkernagel 1996

17. Figure 5-12 Nomenklature and genetic organization of HLA

18. HLA 6. chromosome centromere telomere DR TNF DQ DP C4BC4ABf C2 B A B A B A B C E A F G IIclass III class I class

19. Regions: II III I HLA-A HLA-B HLA-C HLA chr. 6

20. HLA-C HLA-A HLA-B HLA-B HLA-C HLA-A molecules cell membrane chromosome genes

21. Regions II III I chr. 6 DQA DQB DRA DRB DPA DPB

22. DP beta DP alfa DQ beta DR beta DQ alfa DR alfa DQ molecule DR molecule molecules cell membrane DP molecule DQA DQB DRA DRB DPA DPB chromosome genes

25. Figure 5-14 part 1 of 2

33. PROCESSING AND PRESENTATION OF PROTEIN ANTIGENS Antigen processing peptide derivation out of native proteins Antigen presentation Displaying peptidesin complex with self MHC on the cell surface

34. Features of antigens recognized by T lymphocytes • Peptide antigens 2. Linear determinantes 3. On the cell surface within own MHC

35. Two pathways of antigen processing and presentation • MHC class I pathway • MHC class IIpathway

36. COMMON FEATURES OF BOTH PATHWAY OF ANTIGEN PROCESSING AND PRESENTATION • peptide antigens are formed by proteolytic cleavage in the APC’s organelles • peptide binding to MHC occurs before they appear on the cell surface • organelles and enzymes of general protein metabolism are used • no distinction of foreign from self proteins

40. MHC class I pathway

44. The Nobel Prize in Chemistry 2004 "for the discovery of ubiquitin-mediated protein degradation"

45. MHC class II pathway

48. 1. Human MHC class I molecules are a. MHC class I 2. Human MHC class II molecules are b. CD8+ T-lymphocytes 3. Processing and presentation of antigens is necessary for c. HLA-A, HLA-B, HLA-C 4. Exogenous antigens that enter the cell by endocytosis are presented within d. CD4+ T-lymphocytes 5. Endogenouslysynthesized (within the cell) antigensare presented in e. dendritic cells, macrophages and B lymphocytes 6. Peptides derived from endogenous proteins that form the complex with MHC class I are formed in f. MHC class II 7. MHC class I presents the peptides to g. recognition by T lymphocytes 8. MHC class II presents the peptides to h. all nucleated cells 9. MHC class I molecules are expressed on i. proteasome 10. MHC class II molecules are expressed on j. HLA-DR, HLA-DP, HLA-DQ c j g f a i b d h e 1.____ 2.____ 3.____ 4.____ 5.____ 6.____ 7.____ 8.____ 9.____ 10.____