1. Principles of Immunology B Cell Development 3/16/06 “Hard work has a future payoff but laziness pays off now.” Anonymous

2. Word/Terms List  Class switching  Clonal deletion  Naïve B cells  Stromal cells  TD antigens  TI antigens

3. B Cell Development  Maturation-Stem cells to mature, naïve B cells  Activation-Ag binding; initiation of cell changes  Differentiation-Cell division and changes into effector B cells (plasma cells) and memory B cells

4. Lymphopoiesis  Occurs in yolk sac, fetal liver then bone marrow throughout rest of life  Mature, naïve B cells released into circulation  B cell production occurs throughout life; does not wane as does T cell production  About 5 million produced per day  Only 10% of B cells mature  Naïve B cells survive about one week  Undergo negative selection

5. B Cell Maturation  Hematopoietic stem cells(HSC)  Lymphoid stem cell (progenitor)  B cell progenitor (pro-B cell)  Pre-B cell  Immature B cell  Mature, naïve B cell

8. B Cell Changes  Pro B cells Rearrangement of Ig heavy chain genes (D to J joining followed by V to DJ) Not all rearrangements result in complete mu variable region sequences Expression of CD45R and CD19 Further maturation is dependent on direct interaction with BM stromal cells c-Kit on pro B is activated by SCF on stromal cells

10. B Cell Changes  Pre B cells Cell division occurs Rearrangement of Ig light chain genes (V to J joining) Expression of IL7 receptor Expression of mu heavy chains in association with Ig alpha-Ig beta heterodimer Pre B cell receptor uses surrogate light chains Shuts down further Ig gene rearrangement

12. B Cell Changes  Immature B cells IgM expressed on surface B cell receptor appears Cells interact with self Ags Negative selection (clonal deletion) occurs

13. B Cell Changes  Mature B cells Migrate out of bone marrow Both IgM and IgD expressed on surface Cell division occurs Rearrangement of Ig light chain genes (V to J joining) Expression of IL7 receptor Expression of mu heavy chains in association with Ig alpha-Ig beta heterodimer Pre B cell receptor uses surrogate light chains Shuts down further Ig gene rearrangement

14. B Cell Activation  Triggered by combining with Ag Two types of Ags that activate B cells  Thymus dependent Ag e.g. soluble proteins  Thymus independent Ag Type 1, e.g. LPS Type 2, e.g. capsular polysaccharides The reaction to thymus independent antigens is not as strong, memory cells are not produced and class switching does not occur

15. B Cell Activation  Activation signals Two signals required In TI Ags both signals occur post antigen binding without T helper cells In TD Ags, Ag binding provides one signal and CD40/CD40L ligand on T helper cell provides the second

17. B Cell Activation  Signaling pathways Similar to T cell signaling  Protein tyrosine kinase (Src)  Phosphorylated tyrosines on ITAMS dock the Syk kinase  Ultimate effects are on gene expression  Co receptor Three protein complex Provides signals that modify B cell

19. B Cell/T Cell Interaction  B cells as Ag binding and Ag presenting cells  B cells are able to react to lower concentrations of Ag  Co-stimulation with CD40/CD40L  Role of interleukins (IL2,4,5)

21. B Cell Subsets  B1 CD5 marker More responsive to CHO Ags Seen in peritoneum  B2 Most B cells (95%) Drive the Ag response in secondary lymphoid organs

22. Humoral Response  Effector cells and memory cells  Naïve B cells vs. memory cells, primary vs. secondary response