Chapter 11 B-cell Generation, Activation, and Differentiation

1. Chapter 11 B-cell Generation, Activation, and Differentiation B cell T cell Initial contact between B and T cells Dec 19, 2006

2. 你需要學習的課題： • 人類及小鼠 B 細胞在骨髓中的成熟過程 • B 細胞的 negative selection • TD & TI 抗原 / B-1 & B-2 B 細胞 / • BCR signaling / B 細胞的 coreceptor complex • TH細胞如何影響 B 細胞的活化及增值 • 抗體反應 (humoral response)

3. Bone-Marrow Stromal Cells Are Required for Maturation of Progenitor B Cells into Precursor B Cells VLA-4: very late antigen 4 VCAM-1: vascular cell adhesion molecule 1 SCF: stem-cell factor direct contact is required.

4. B-cell Maturation Depends on Rearrangement of the Ig DNA in the Lymphoid Stem Cells Naïve B Cell RAG: recombination-activating genes (recombinases) TdT: terminal deoxynucleotidyl transferase

5. Pre-B Cell Receptor Heavy chain: m Chain Surrogate (代理者)light chain: VpreB (V-like sequence) l5 (C-like sequence) Iga/Igb

6. Sequential Expression of mIg and Surrogate L Chain During B-Cell Differentiation B-cell development in l5-/- mice is blocked at the pre-B stage.

7. Pre-TCR (pre-Ta / TCRb) Activates Signal Transduction Pathways

8. Sequence of Events and Characteristics of the Stages in B-cell Maturation in the Bone Marrow Sequence of Events and Characteristics of the Stages in B-cell Maturation in the Bone Marrow lymphoid pro-B pre-B immature mature stem cell cell cell B cell B cell mIgM + mIgD (IL-2Ra) CD45R: a protein tyrosine phosphatase CD19: part of the B-cell coreceptor CD43: leukosialin CD24: heat-stable antigen (HAS)

9. Negative Selection of Self-Reactive B Cells During Maturation in the Bone Marrow Ab against H-2Kk transgenes (H, L chain genes) ↓ H-2d/k or H-2d mice negative selection !!

10. Receptor Editing – secondary V(D)J recombination allows B lymphocytes to replace an inappropriate receptor with a new receptor

11. Overview of B-cell Development Sites of B-cell maturation – before birth: yolk sac fetal liver fetal bone marrow after birth: bone marrow e.g., spleen, lymph nodes

12. Mature Self-Reactive B Cells Can Be Negatively Selected in the Periphery HEL: hen egg lysozyme HEL-binding B cells are present.

13. Clonal Anergy in Mature Peripheral B Cells

14. Production of Double-transgenic Mice Expressing the H-2Kb Molecule and Anti-Kb Ab membrane form

15. Clonal Deletion of Self-reactive Mature Peripheral B Cells Kb-binding B cells are deleted.

16. B-Cell Activation and Proliferation

17. Thymus-Dependent (TD) and Thymus-Independent (TI) Ag Have Different Requirements for Response - The B cell response to TD Ags requires direct contact with TH cells. - Direct participation of TH cells is not required for TI Ags. (unknown mechanism) (crosslinking the mIg receptor) (helped by TH cytokines) Most type 1 TI (TI-1) Ags are polyclonal B-cell activators (mitogens); that is, they are able to activate B cells regardless of their antigenic specificity.

18. Two Distinct Signals for B-Cell Activation

19. B-1 and B-2 B Lymphocytes , therefore, no affinity maturation , class switching is not common Bind Ag with lower affinity Abs are multispecific

20. ITAM: immunoreceptor tyrosine-based activation motif(圖形)

21. Signal Transduction Pathways and • the Activation of B Cells • - Compartmentalization of function within receptor subunits • Activation by membrane-associated Src family protein • tyrosine kinases (Lyn, Blk, and Fyn) • Assembly of a large signaling complex with protein- • tyrosine-kinase activity (Syk) • Recruitment of other signal-transduction pathways • Changes in gene expression

22. Signal Transduction Pathways Activated by the BCR

24. The B-Cell-Coreceptor Complex Can Enhance B-Cell Responses : TAPA-1 (CD81), CR2 (CD21), and CD19 ITIM: immunoreceptor tyrosine inhibitorymotif

25. Sequence of Events in B-Cell Activation by a Thymus-Dependent Ag

27. Role of TH Cells in B-cell Activation 1. Formation of T-B conjugates 2. Contact-dependent help mediated by CD40/CD40L interaction CD40  signaling in B cells  activation of Lyn and Syk  PLC, IP3, DAG  transcription factors, such as NF-kB 3. Signals provided by TH-cell cytokines redistribution of Golgi apparatus and the microtubular-organizing center toward the junction with the B cell  Release of cytokines toward the Ag-specific B cell (directional or polarized release of cytokines) Initial contact between a T cell and B cell a T-B conjugate

28. The Humoral Response

29. Primary (1° ) and Secondary (2 ° ) Responses

31. In Vivo Sites for Induction of Humoral Response

32. B-cell Activation, Proliferation and Differentiation Occur in a Peripheral Lymph Node

33. 3 Important B-cell Differentiation Events Take Place in Germinal Centers 1. Affinity maturation 2. Class switch 3. Formation of plasma cells and memory cells

34. Cellular Events within Germinal Centers highly proliferative

35. The Frequency of Somatic Hypermutation Decreases with the Distance from the Rearranged V(D)J Gene 0.5 kb 1.5 kb

36. AID (activation-induced cytidine deaminase) Mediates Somatic Mutation AID – an RNA editing enzyme, deaminating selective cytidine in certain mRNAs, changing the cytosines into uracils – modifying DNA by the deamination of cytosine, resulting in formation of uracil

37. Variability

38. Cytokines Affect Proliferation and Class Switching of B Cells During the Differentiation of B Cells into Plasma Cells