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Basic events during B cell development

Stem cells. Pre-B expansion and antigen selection. Allelic exclusion. Pro-B “B”. Pro-B “C”. Pro-B “A”. Pre-B “D”. Immature B cells. DJ. VDJ. VDJ-C( m ) + V L C L IgM. None . VDJ-C( m ). IgH ( m ) heavy chain rearrangement. Mature Peripheral B cells.

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Basic events during B cell development

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  1. Stem cells Pre-B expansion and antigen selection Allelic exclusion Pro-B “B” Pro-B “C” Pro-B “A” Pre-B “D” Immature B cells DJ VDJ VDJ-C(m) + VLCL IgM None VDJ-C(m) IgH (m) heavy chainrearrangement Mature Peripheral B cells Basic events during B cell development A,B,C… = Hardy Fractions

  2. Bone Marrow

  3. But: not all mature B cells are the same

  4. Phenotype Phenotypic differences distinguish four kinds of B cells • B-1a: CD5+, IgMbr, IgDdull, MAC-1+ in PerC • B-1b: like B-1a but CD5- • B-2 follicular: CD5-, CD23+, IgMdull, IgDbr • B-2 marginal zone: CD5-, CD23+, IgMbr, IgDdull

  5. Location • B-1a: Peritoneal and pleural cavities; gut • B-1b: Peritoneal and pleural cavities • B-2 follicular: spleen, lymph nodes, PerC • B-2 MZ: spleen

  6. Spleen

  7. PerC

  8. Ig Isotype production • B-1a: IgM >> IgG3 > IgA >IgG2 >IgG1 • B-1b: IgM > IgE > IgG1 > IgG2 • B-2 follicular: IgM, IgG1, IgG2… • B-2 marginal zone: IgM, IgG1…

  9. Function: adaptive responses • Made in response to antigenic stimulation • Usually T dependent • Differentiate to IgG memory cells • Usually made by B-2, but B-1 clearly respond

  10. Function: natural antibodies • Made by B-1 • Produced and secreted without (known) specific antigenic stimulation • Cytokines increase secretion • IL-9 increases IgE and IgG1 production by B-1b • IL-5 increases secretion by B-1a (?) • Production is T-independent in the ordinary sense • Differentiation to IgG producing cells has been reported in pathologic conditions

  11. Ontogeny • B-1a: Arise in fetus and neonate • B-1b: Arise in neonate; adult?? • B-2 follicular: Arise around weaning • B-2 MZ: Strains differ but mostly after weaning

  12. Subset maintenance • B-2 are replenished by de novo development from progenitors in BM throughout life • B-1 cells develop de novo during fetal and neonatal life but persist thereafter as a self-replenishing population

  13. Self-replenishing Single lineage model of B cell development Stem cell Peripheral B cells B-1a Pro-B “A” Pro-B “B” B-1b Special antigens (self, repetitive, bacterial) DHDJ Special antigens (self, repetitive, bacterial) Self-replenishing Pro-B “C” Pre-B “D” Immature B B-2 (follicular + MZ) De novo replacement Normal pre-B expansion and antigen selection

  14. Self-replenishing Multi-lineage model of B cell development Fetal liver Feedback loop in mice 3-6 weeks Stem cell B-1a X Stem cell B-1b X Self-replenishing Stem cell B-2 (follicular + MZ) De novo replacement Pre-B expansion AdultBM

  15. So how do we determine which hypothesis is valid? Study B cell progenitors activity in mixture-transfer experiments Use Ig allotype expression to mark the mature progeny B cells

  16. Basic events during B cell development Stem cells Pre-B expansion and antigen selection Allelic exclusion Pro-B “B” Pro-B “C” Pro-B “A” Pre-B “D” Immature B cells DJ VDJ VDJ-C(m) + VLCL IgM None VDJ-C(m) IgH (m) heavy chainrearrangement Mature Peripheral B cells A,B,C… = Hardy Fractions

  17. IgH allelic exclusion in B cells

  18. “Allelic” exclusion The IgH of the antibody molecules produced by an individual B cell are all encoded by a single VDJ-C rearrangement that occurred on one of the two parental chromosomes

  19. So how do we determine which hypothesis is valid? Study B cell progenitors activity in mixture-transfer experiments Use Ig allotype expression to mark the mature progeny B cells

  20. Results of mixture-transfer studies • B-2 are replenished by de novo development from progenitors in BM throughout life • Adult BM readily regenerates the entire B-2 population in adoptive recipients • B-1 cells develop de novo during fetal and neonatal life but persist thereafter as a self-replenishing population • Adult BM regenerates only a few B-1 cells, mainly B-1b • Fetal and neonatal progenitor sources fully regenerate the B-1 population

  21. Results of mixture-transfer studies • Mixtures of progenitors (B220-) from adult BM and fetal sources fully regenerate the B-1 population • Virtually all B-1 cells are derived from the fetal source Therefore: 1) BM does not contain cells that inhibit B-1 development; and, 2) Fetal sources do not provide support for the development of cryptic progenitors for B-1 cells We conclude that BM (essentially) lacks progenitors for B-1 cells

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