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Basic events during B cell development
Stem cells
Pre-B“D”
Pre-B expansion and antigen selection
Immature B cells
Mature
Peripheral B cells
IgH () heavy chainrearrangement
VDJ-C() + VLCL
IgM
VDJ-C()
Pro-B“A”
Pro-B“C”
Pro-B“B”
None DJ VDJ
Allelic exclusion
A,B,C… = Hardy Fractions
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
Phenotype
B-1a: Peritoneal and pleural cavities; gut
B-1b: Peritoneal and pleural cavities
B-2 follicular: spleen, lymph nodes, PerC
B-2 MZ: spleen
Location
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…
Ig Isotype production
Made in response to antigenic stimulation
Usually T dependent
Differentiate to IgG memory cells
Usually made by B-2, but B-1 clearly respond
Function: adaptive responses
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
Function: natural antibodies
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
Ontogeny
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
Subset maintenance
Single lineage model of B cell development
Stem cell
Pre-B“D”
B-1a
B-1b
B-2 (follicular + MZ)
Self-replenishing
Self-replenishing
De novo replacement
Normal pre-B expansion and antigen selection
Pro-B“A”
Pro-B“C”
Pro-B“B”
Immature B
Peripheral B cells
DHDJSpecial antigens
(self, repetitive, bacterial)Special antigens
(self, repetitive, bacterial)
Multi-lineage model of B cell development
Stem cell
Stem cell
AdultBM
Fetal liver Feedback loop
in mice 3-6 weeks
X
X B-1a
B-1b
B-2 (follicular + MZ)
Self-replenishing
Self-replenishing
De novo replacementPre-B
expansion
Stem cell
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
Basic events during B cell development
Stem cells
Pre-B“D”
Pre-B expansion and antigen selection
Immature B cells
Mature
Peripheral B cells
IgH () heavy chainrearrangement
VDJ-C() + VLCL
IgM
VDJ-C()
Pro-B“A”
Pro-B“C”
Pro-B“B”
None DJ VDJ
Allelic exclusion
A,B,C… = Hardy Fractions
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
“Allelic” exclusion
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
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
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