Lecture 19 November 16 th 2010

1. Lecture 19 November 16th 2010 Quiz 2 scheduled for November 23rd not November 18th

2. New clues to effective HIV vaccine Created: Monday, November 08, 2010 Print Slight differences in five HLA amino acids may explain why certain people resist the human immunodeficiency virus, US researchers said in a study that lends new clues about how to make an Aids vaccine. "For a long time, we've known that some people progress extremely rapidly when they get infected, and others can stay well for three decades and never need treatment and still look entirely well," said Dr. Bruce Walker of Massachusetts General Hospital and Harvard University, whose study appeared online in Science. Specific amino acids in the human leukocyte antigen (HLA)-B peptide binding groove predicted protective and risk HLA alleles to persistent HIV infection.

3. In mice termed histocompatibility antigens (H-2 antigens). In humans termed human leukocyte antigens (HLA).

4. So how do MHC molecules work ? T helper and cytotoxic cells go around the body checking the pockets of the MHC molecules their TCR recognizes. If the pocket is empty they do nothing. If a CD8+ cells finds something in the pocket of a MHC 1 molecule it recognizes, it kills the cell bearing this MHC1. If a CD4+ cells finds something in the pocket of a MHC2 molecule it recognizes, it produces cytokines that can enhance immune functions of that cell and it can trigger the class switch if the cell is a B lymphocyte.

10. EMPTY

11. The pocket of a MHC 1 molecule can contain a fragment of antigen.

12. MHC1

17. What is eluted from a class 1 MHC ?

23. Peptides in MHC2 can slide across binding region to fit.

25. So how do peptides get into MHC1 and MHC2 class molecules? • Class 1 molecules use the Endogenous pathway. • Class 2 molecules use the Exogenous pathway.

26. No infection on a normal day…..

27. Normally MHC 1 assembled in RER and is unoccupied.

28. IN RER, MHC1 molecules are produced and assembled

29. What if cell becomes infected or altered ? • Viral infection • Bacterial infection • Some normal cellular proteins • Transformation

30. Endogenous Pathway

31. Endogenous Pathway using Ubiquination Pathway

32. If foreign antigens are in cell, tagged by ubiquitin and brought to proteosomes.

33. LMP2, LMP 7, LMP 10 are proteases associated with ~10% of proteasomes And produce peptide fragments 8-10 AA in length- perfect for MHC1 binding site. Small peptides migrate to Transporter-associated with antigen processing = TAP on RER.

34. Viral, tumor, bacterial protein MHC class 1 pathway

36. Precisely 8-10 AA in length

40. CD8+T cell murdered cell

41. Third method of Cytotoxic T cell killing

42. cytotoxic T cell tumor cell

43. First method of cytotoxic T cell killing of target cells

44. MHC 2 molecules on surface • Everyday MHC 2 molecules produced and transported to the membrane of antigen presenting cells. • What does this look like on a good day when there is no infection …..

47. B cell, Macrophage Dendritic cell not in the presence of antigen.

48. What if B cells binds antigen ?What if dendritic cell pinocytoses antigen ?What if macrophage phagocytosis antigen ? Antigen is internalized, processed and presented on the surface of the cell bound to MHC 2 molecules and can be recognized only by CD 4+ T helper cells