Basic events during B cell development
Stem
cells
Pre-B expansion
and antigen selection
Allelic exclusion
Pro-B
“A”
Pro-B
“B”
Pro-B
“C”
Pre-B
“D”
None
DJ
VDJ
VDJ-C(m)
IgH (m) heavy chain
rearrangement
Immature
B cells
VDJ-C(m) + VLCL
IgM
Mature
A,B,C… = Hardy Fractions
Peripheral B cells
Bone Marrow
But:
not all mature B cells
are the same
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
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
Spleen
PerC
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…
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
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
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
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 selfreplenishing population
Single lineage model of B cell development
Peripheral B cells
Stem
cell
B-1a
Pro-B
“A”
Pro-B
“B”
Pro-B
“C”
Self-replenishing
Special
Specialantigens
antigens
(self,
(self,repetitive,
repetitive,bacterial)
bacterial)
B-1b
DHDJ
Pre-B
“D”
Self-replenishing
Immature
B
B-2
De novo replacement
Normal pre-B expansion
and antigen selection
(follicular + MZ)
Multi-lineage model of B cell development
Fetal
liver
Feedback loop
in mice 3-6 weeks
Stem
cell
B-1a
X
Self-replenishing
Stem
cell
B-1b
X
Self-replenishing
Stem
cell
Adult
BM
B-2
Pre-B
expansion
De novo replacement (follicular + MZ)
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 expansion
and antigen selection
Allelic exclusion
Pro-B
“A”
Pro-B
“B”
Pro-B
“C”
Pre-B
“D”
None
DJ
VDJ
VDJ-C(m)
IgH (m) heavy chain
rearrangement
Immature
B cells
VDJ-C(m) + VLCL
IgM
Mature
A,B,C… = Hardy Fractions
Peripheral B cells
IgH allelic exclusion in B cells
“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
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 selfreplenishing 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