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

Bone Marrow

But:

not all mature B cells are the same

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

Spleen

PerC

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

IgH allelic exclusion in B cells

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