Immune system: how life fight against invaders!

1. Immune system: how life fight against invaders! 4-18-2016

2. Multicellular organism: the heaven of bacteria/virus and parasites

3. The three layers of vertebrate immune defenses.

4. 血清療法的發明人！ Using horse serum against diphtheria toxin to treat patients. http://nobelprize.org/nobel_prizes/medicine/laureates/1901/

5. 血清療法帶來的新思維 抗白喉毒素血清中的有效成分是什麼？ 怎麼產生的？為什麼可以解毒？

7. 抗毒素(抗体)與毒素(抗原)結合，帶引出二個重要的概念：抗毒素(抗体)與毒素(抗原)結合，帶引出二個重要的概念： 1, 結構的辨識 (specificity)； 2, 分子問的親和力(affinity)。 “antitoxines represent nothing more than side-chains reproduced in excess during regeneration, and therefore pushed off from the protoplasm, and so coming to exist in a free state…….”

8. http://nobelprize.org/nobel_prizes/medicine/laureates/1908/

9. Challenge of acquired immunity 1, how tospecifically recognize infinite different foreign molecules; 2, how to distinguish self from non-self!

10. Conceptual framework of acquired immunity • Clonal selection hypothesis • Variation: randomly generated. • Inheritance. • Selection by foreign antigens.

12. Normal median survival time of A strain skin on CBA mice is 11 days. Injected CBA mice in utero with tissues from A strain mice, then grafted with A strain skin at adult. Three of them accepted for more than 2 months(tolerance) Transfer of lymphoid tissue from CBA donors immunized with A strain tissue caused rapid rejection of the previously tolerated grafts.

15. Cooper MD, Raymond DA, Peterson RD, South MA, Good RA. The functions of the thymus system and the bursa system in the chicken. J Exp Med. 1966;123:75–102.

16. Cells of the adapted immune system • Lymphocytes • B cells • Plasma cells (Ab producing) • T cells • Cytotoxic (CTL) • Helper (Th) • Th1 • Th2 • Th17 • T-reg

18. The basic structure of an immunoglobulin molecule.

20. Hybridization of labeled RNA probes, specific for the entire k gene (V ＋Ｃ) and for the 3’ end that encodes the C region, to fraction of digested DNA separated by agarose gel electrophoresis. N. Hozumi and S. Tonegawa, 1976, Proc. Nat’l. Acad. Sci. USA 73:3629.

21. For light chain variable region : 30 V X 5 J = 150. For heavy chain variable region: 45 V X 23 D X 6 J = 6,000. 150 X 6,000 = One million plus 1,000 X from imprecision junction and 1,000 X from hypermutation Total variation is around 100 billion!

23. Organization of the major histocompatibility complex in mice and humans. Snell GD & Higgins GF 1951, "Alleles at the histocompatibility-2 locus in the mouse as determined by tumor transplantation", Genetics36:306–310

24. How T cell recognizes specific antigen? Through cell surface receptor namely T cell receptor (TCR)

25. Organization and recombination of TCR loci.

26. Zinkernagel-Doherty experiment demonstrating that MHC restriction is required for activation of a cytotoxic T-cell response.

27. Ag If T cell receptor can recognize antigen directly, what role of MHC played in TCR recognition? TCR T cell

28. Figure 23.22 Peptide binding and MHC restriction.

30. Signals involved in T-cell activation and termination.

31. Perforin- and granzyme-mediated cell killing by cytotoxic T cells.

32. Why T cell need MHC for its antigen recognition?

33. Collaboration between T and B cells is required to initiate the production of antibodies.

34. Collaboration between T and B cells is required to initiate the production of antibodies

37. How memory T cells are generated? Science 315: 1673-4; 2007

38. How tumor cells suppress cytotoxic T cells? Can w e block such inhibitory pathway to reactivate T cells to kill tumor cell?

41. MHC pathway of antigen processing and presentation.

42. Class II MHC pathway of antigen processing and presentation.

43. Positive and negative selection of the T cell repertoire: To expand T cell population and to eliminate clones recognize self antigen

44. Innate immune system • Pattern recognition receptor • LPS for Toll-like receptor • dsRNA/ DNA for interferons induction • Complement proteins • Phagocytes (cells) (e.g., macrophages) • Natural killer (NK) cells

46. Figure 2-18 The three pathways of complement activation converge Combination of adaptive and innate immune responses Innate immunity Innate immunity

47. Macrophages can engulf and digest bacteria Macrophage about to eat a bacterium http://www.biochemweb.org/neutrophil.shtml

48. Arm race between immunity and pathogens Pathogens have also developed ways to remove some of the cell’s critical proteins, often so that they can escape detection by the immune system. For example, in the adaptive immune system, T lymphocytes (T cells) recognize viral fragments (peptides) bound to MHC proteins. It’s hard for a virus to hide out in a cell if the cell surface MHC proteins contain viral fragments that can be recognized by T cells. What’s a virus to do? Get rid of the host MHC proteins!

49. For every strategy a virus comes up with, the immune system (usually) has an answer… Natural killer cells recognize cells that do not express adequate levels of MHC proteins on their surface. They respond to “missing self”.

50. Natural killer (NK) cells • Identify targets based on “missing self” • Two types of NK receptors: inhibitory and activating • If inhibitory receptor recognizes a self protein (a class I MHC molecule) on a target cell, the NK cell is turned OFF even if activating receptor binds a ligand on the same target cell • If activating receptor binds a ligand, but inhibitory receptor does not (target cell has down-regulated class I MHC proteins), NK cells kill • Many virally-infected cells and tumor cells down-regulate expression of class I MHC molecules (NK cells important for preventing cancers)