Lecture 11

Organized Notes: B Cell Development

1. Sites of B Cell Development

• Birds: Bursa of Fabricius (Box 2-4, Figure 3)

• Mammals: Bone Marrow (Figure 2-10)

2. B Cell Development Stages

• Hematopoietic Stem Cells (HSCs) to B Cell Progenitors (Figure 2-3)

• Cytokines and Cell-Cell Contact Required (Figure 9-2)

a. Progenitor B (Pro-B) Cells

• Express B220, Pax-5, CD19, RAG1/2, TdT

• Commitment to B cell lineage by Pax-5

• Ig Gene Rearrangement:

  • DH-JH recombination (first step)

  • VH-DJH recombination (second step)

  • Successful V(D)J recombination → Ig heavy chain protein

b. Large Pre-B Cells

• Pre-BCR Formation: Surrogate light chain (VpreB + λ5) assembles with heavy chain

• Pre-BCR signals via self-oligomerization (no ligand required)

• IL-7/IL-7Rα/γc signaling promotes cell division

c. Small Pre-B Cells

• IL-7Rα downregulation → cells stop dividing

• High RAG-1/2 expression → Light-chain gene recombination begins

d. Immature B Cells

• Express surface IgM (heavy + light chains)

• Igκ+:Igλ+ B cell ratio: 10:1 (mice), 6:4 (humans)

• Enter blood → migrate to lymphoid organs → Transitional B Cells

e. Allelic Exclusion

• Each B cell encodes only one antibody specificity

• The second Ig allele is rarely productively rearranged

• Two Ig alleles allow two attempts for successful rearrangement (Figure 6-15)

3. Transitional B Cells in the Spleen

• Transitional-1 B Cells (sIgM, CD93)

• Transitional-2 B Cells (sIgM, sIgD, CD93, CD21, CD23)

• BAFF/BAFFR signaling required for survival

• Central Tolerance: Transitional B cells encountering self-antigen undergo apoptosis (Figure 9-8)

4. Mature B Cells and Immune Deficiencies

• Types of mature B cells (Figure 18-2)

• Immunoglobulin Rearrangement and Disease

  • Aberrant RAG-mediated Ig gene rearrangement → B cell leukemia/lymphoma

  • Ig genes can fuse with oncogenes → cancer (e.g., Burkitt’s Lymphoma, ETV6-RUNX1)

  • Burkitt’s Lymphoma: IgH locus (Chr. 14) translocated to MYC gene (Chr. 8)

5. Precursor B Cell Leukemia (ALL)

• Acute Lymphoblastic Leukemia (ALL)

  • 80% of childhood cancers (ages 2-6)

  • Most are B cell lineage (4:1 ratio vs. T-ALL)

  • Large pre-B phenotype common

  • ETV6-RUNX1 translocation (t[12;21]) in 22% of pre-B-ALL cases

  • Promotes RAG-mediated chromosomal instability & mutations

  • ETV6-RUNX1 leukemia = 22% of all childhood leukemia cases (Mullighan et al., J. Clin Invest 2012)