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Chapter 8- MHC’s & Antigen Presentation

Chapter 8- MHC’s & Antigen Presentation. Where we’re going in this MHC I and II functions review Genes for these proteins Structure in detail, and how that relates to Ag presentation MHC’s and disease Antigen presentation- some details, plus learning about processing in the Golgi.

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Chapter 8- MHC’s & Antigen Presentation

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  1. Chapter 8- MHC’s & Antigen Presentation • Where we’re going in this • MHC I and II functions review • Genes for these proteins • Structure in detail, and how that relates to Ag presentation • MHC’s and disease • Antigen presentation- some details, plus learning about processing in the Golgi

  2. We need to be able to present lots of different peptides. For this we need a somewhat generic binding, and much diversity.

  3. More details in to come!

  4. More details in to come!

  5. “the nomenclature is somewhat confusing” HA!! MASSIVE UNDERSTATEMENT!! 2 MB! 2 copies of each! 4 MB! Classical MHC’s- there are others as well

  6. A digression into mouse genetics • The MHC genes typically are a package deal- Haplotypes • We have inbred strains of mice- these are homozygous at the MHC’s, and have sets of MHC’s.

  7. Mouse MHC terms • Syngeneic- identical- a mouse strain • Congenic- the same except at one location- for our purposes, the same MHC haplotype- E.g., B10.A: a B10 mouse with a type A haplotype These terms will come into play later!

  8. Strains are produce by breeding; useful in determining the effects of MHC’s on immune response

  9. OK- back to MHCs- structure of MHC I

  10. MHC I structure

  11. Ends are closed; holds peptide of 8-10 AA’s

  12. MHCII- not only a dimer, but a dimer of dimers Open cleft- hold 13-18 AA peptides http://www.ncbi.nlm.nih.gov/Structure/mmdb/mmdbsrv.cgi?uid=7120

  13. Different MHCI’s

  14. With MHC I, the peptide can bulge; not so with MHCII

  15. Diversity! Multiple genes, now MANY alleles! • MHC genes are polymorphic: • Human MHC I- HLA A: 370 • HLA B: 660 • HLA C: 190 • Lots of diversity in MHC II as well- DP, DQ, DR genes, and among the alpha and beta subunits. • Total theoretical diversity of 4 X 1019 !

  16. Linkage disequilibrium • The diversity isn’t as great as theoretically expected • Some alleles are found together more than you would expect: • HLA-A1- 0.16; HLA B8- 0.09; • Expecte 0.16X 0.09= 0.014; actual is 0.088- they are found together >6X as often as expected.

  17. Diversity- so what? • Differences in immune responsiveness • Some MHC’s linked to disease susceptibility

  18. Many are autoimmune

  19. So a completely heterozygous mouse would have 8 different MHC II molecules and six different MHC I molecules on its cell surfaces.

  20. What to know • I won’t test on this, but it’ll be helpful to know • - H2 D,L,&K are MHC I’s in mice • HLA A,B,C are MHC I’s in people • Three MCH I genes in mice and people • Three MCH II genes in people, 2 in mice. • They are polygenic and polymorphic • Structure of I and II’s- effect on size and types of peptides bound. • Effects on immune response and disease susceptibility, and why that might be.

  21. MHC Restriction • Tough concept • Fundamentally, T cells only recognize Ag presented by the MHC’s that they were trained to recognize in the thymus.

  22. These do exogenous Ag presentation Th cells Uptake of 3[H]thymidine

  23. For this experiment, the Ag that’s presented is not seen- wrong MHC! These are seen as self

  24. Antigen Processing and Presentation

  25. Processing: Breaking up the antigen into pieces that fit into the MHC I or II groove. • Presentation: putting the peptides on the groove. • Again, endogenous and exogenous antigens

  26. These are MHC II APC’s Non-pro’s get activated by inflammation!

  27. “The TUNNEL OF DEATH!”

  28. LMP’s- induced by infection, make production of MHC I peptides more likely

  29. ERp57- ER protease, mw 57K- exoprotease, trims down to ~8 AA’s! These are Chaperone proteins

  30. Now- onto exogenous- receptor- mediated endocytosis, OR phagocytosis

  31. HLA-DM- non-classical MHC- catalyst for exchange of CLIP for peptide

  32. What to know • Definitions- processing, presentation, MHC restriction- evidence for the latter. • Tell the story of antigen presentation, beginning with the antigen until it’s on the surface of the cell- • MHCI- roles of ubiquitin, LMP’s, proteasome, TAP, tapasin, calreticulin, calnexin (chaperones) • MHC II- roles of invariant chain, CLIP, MHC DM, endocytic processing.

  33. Review for Exam II • I’ve updated the learning objectives- I’ll go over them.

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