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B Cell Development in Bone Marrow and Peripheral Lymphoid Tissue: Part 1

B Cell Development in Bone Marrow and Peripheral Lymphoid Tissue: Part 1. March 20, 2009 11:00-12:00. THE FOUR PHASES OF B CELL DEVELOPMENT. Ag Ind. Ag dependency depends on your definition of antigen. Ag Dep. Ag Dep. B CELLS DEVELOP FROM A HEMATOPOIETIC STEM CELL.

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B Cell Development in Bone Marrow and Peripheral Lymphoid Tissue: Part 1

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  1. B Cell Development in Bone Marrow and Peripheral Lymphoid Tissue: Part 1 March 20, 2009 11:00-12:00

  2. THE FOUR PHASES OF B CELL DEVELOPMENT Ag Ind Ag dependency depends on your definition of antigen Ag Dep Ag Dep

  3. B CELLS DEVELOP FROM A HEMATOPOIETIC STEM CELL

  4. DEVELOPMENT IN THE BONE MARROW IS CONTACT DEPENDENT Key players: Cell Adhesion molecules (CAMs); Integrins (VLA-4) Kit (receptor on pro-B) and SCF (kit ligand) IL-7

  5. B CELL DEVELOPMENT STAGES ARE DEFINED BY STATUS OF Ig GENES BCR Membrane Ig on pre-B cells does not have light chain B cell development in bone marrow is complete when both IgM and IgD are expressed

  6. Figure 4-4 Pre-BCR vs BCR Both Pre-BCR and BCR Can Deliver a Signal

  7. Ig REARRANGEMENT OCCURS IN A DEFINED ORDER Productive rearrangements result in ability to generate functional protein Introduction of stop codons during joining can result in inability to generate a functional protein….unproductive rearrangement

  8. LIGHT CHAINS CAN REARRANGE MULTIPLE TIMES The combination of 2L chains and multiple opportunity for rearrangement means 85% of pre-B cells can grow up Overall <half of B lineage cells make it

  9. CONSEQUENCES OF GENE REARRANGEMENT Heavy chain expression with surrogate light chain stops heavy chain rearrangement Successful light chain rearrangement ends rearrangement End Result: Monospecific B Cells

  10. EXPRESSION OF PROTEINS INVOLVED IN REARRANGEMENT IS DEVELOPMENTALLY CONTROLLED TdT is not expressed during light chain rearrangement

  11. ABERRANT B CELL DEVELOPMENT LEADS TO CLINICAL PROBLEMS

  12. CASE 3: IMMUNODEFICIENCY HPI:CE is a 1 year old boy who presents with 1 day of fever, cough and dyspnea. The mother recorded a fever of 102.3 F and notes increased irritability, rhinorrhea, frequent ear pulling, diarrhea and vomiting. The cough began yesterday and has progressed to rapid breathing. This is his sixth respiratory tract infection in the last 5 months, which includes one episode of bronchitis, three episodes of otitis media, and one episode of pneumonia requiring hospitalization. How would you test for a B cell deficiency? What are potential causes for absence of B cells?

  13. PRINCIPALS OF FACS ANALYSIS

  14. Normal CE What could cause an absence of B cells?

  15. Pre-BCR Signaling Is Required for B Cell Development Pre BCR Signaling requires Btk

  16. CE’s Family Tree

  17. ABERRANT REARRANGEMENTS LEAD TO B CELL TUMORS Ig genes can get spliced into other chromosomes…translocation Translocation can juxtapose Ig with a proto-oncogene (myc, BCL2) Proto-oncogenes are involved in cell growth Dysregulation of proto-oncogene leads to tumor

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