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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

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

slide3

But:

not all mature B cells are the same

phenotype
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
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
ig isotype production
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
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
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
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
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
single lineage model of b cell development

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

multi lineage model of b cell development

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

slide15

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 development16
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

allelic exclusion
“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

slide19

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

slide20

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
slide21

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