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. Pre-BCR vs BCR
Figure 4-4
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 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. What could cause an absence of B cells?
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