Chapter 11- B-cell generation, activation, differentiation

1. Chapter 11- B-cell generation, activation, differentiation • Where we’re going • Similar to Ch 10- T cell • Steps involved in the generation process • Evidence for elimination/tolerance induction of self-reactive cells in bone marrow and periphery. • MORE signal transduction! • T-independent and dependent antigens • Differentiation in the lymph nodes- affinity maturation/somatic hypermutation.

3. Stromal cells are important! Signals from the c-Kit-SCF bindin results in IL7 receptors, which stimulates development

4. ??? I don’t think so

5. The maturation sequence • - Progenitor- Ig alpha and beta- for signal transduction (long tails) • Pre-B cell- mIgM heavy chain, and surrogate light chain • Naïve /immature- light chain- mIgM, but no IgD. • “mature”- IgD.

6. In periphery In B.M.

7. Self-reactive B cells commit suicide in the bone marrow • But- not all self-ag’s are in the B.M. • So, there’s anergy induced in the periphery

8. So what happens to a B cell if it binds to a self-Ag in the BM?

9. Mice are transgenics- most B cells engineered to express anti-K^k mIgM these mostly die in the BM

10. Mice are transgenics- most B cells engineered to express anti-K mIgM. Now we see no K^k MHCI; so the anti-K^k survive

11. Mice are transgenics- most B cells engineered to express anti-K mIgM. The rest of the story- a few do survive- they have the original mu heavy chain, but have activated a different light chain, and no longer react to MHCI K^k.

12. It also happens in the periphery

13. HEL only expressed in liver- should be a recipe for autoimmune disease!

14. These have Anti-HEL B cells in the periphery, and they’re inactive- mIgM is downregulated! These have Anti-HEL B cells in the periphery, and they’re active Other work (fig. 11-13) showed that reactive cells were deleted in the periphery.

15. T-independent, and T-dependent Two types of antigens

16. TI-1& 2- LPS, capsule- large, not complex- gives both signals

17. These are important!

18. Cross-linking may take a lot of Ag! They are activated, and then become phosphorylated!

19. The text and the figure differ somewhat in detail. There may be mutual activations between ITAMs and Blk, Lyn, Fyn, and Syk's got to be involved!

20. The Co-receptor story • While the BCR works fine, it can be made up to 100X more sensitive with the co-receptor. • Interaction with the innate system- Ag+ C3d- a fragment from the complement system, which can bind bacteria, other pathogens non-specifically (we'll get to it later)

21. No cross-linking needed

22. Signal 2- some interesting interactions! Signal 1 stimulates >MHCII, and B7- so it can both give signal 2 to it's appropriate T cell, and receive signal 2!

23. The secondary response • Faster, more intense • Higher affinity • Class switching- G, A, maybe E • Due to memory cells- B and T.

24. Log scale!

26. What happens to the activated B cells • Some make Ab right away • Others- there's a lot, remember, due to proliferation- undergo affinity maturation • Happens in the germinal centers

29. It’s not that the CDR’s get particularly mutated, it’s that the VDJ region’s hit hard; selection does the rest.

32. Things to know • Maturation: antigen independent and dependent parts. • Pro-pre-immature, Naïve but mature, surrogate light chain, Ig alpha & beta • Experimental demonstration of negative selection and peripheral anergy. • The activation story- The first few steps (through activation of syk), some 2nd messengers: Ca++, G protein activation, PLC ,IP3, DAG. • TI and TD antigens- characteristics of response, examples • Affinity maturation: centroblasts, centrocytes, follicular dendritic cells, what happens in dark and light zones. • Class switching- caused by cytokines.