phase 1
generation of diverse and clonally expressed B-cell receptors in the bone marrow
phase 2
alteration, elimination or inactivation of B-cell receptors that bind to components of human body.
*negative selection
phase 3
promotion of a fraction of immature B cells to become mature B cells in the secondary lymphoid tissues
* positive selection
phase 4
recirculation of mature B cells between lymph, blood, and secondary lymphoid tissues
phase 5
activation and clonal expansion of B cells by pathogen-derived antigens in the secondary lymphoid tissues
phase 6
differentiation to antibody-secreting plasma cells and memory B cells in secondary lymphoid tissue
are B cells stockpiled?
NO, they are constantly replaced
30 billion/day
half life is 50-100 days thus population is winnowed down
when does the D-J of the heavy chain rearrange?
Early pro-B cell
when dos the DJ-V of the heavy chain rearrange?
Late pro-B cell
what is the first checkpoint of B cell development?
after the heavy chain has rearranged
Late pro-B cell
when is the heavy chain made?
Large pre-B cell
when does the V-J rearrange of the light chain?
small pre-B cell
when is the second checkpoint of B cell maturation?
after the light chain has rearranged
small pre-B cell
What is expressed on the surface of an immature B cell?
IgM
what is the order of B cell development?
early pro, late pro, large pre, small pre, immature
Stromal cells interact and drive B cell development how?
- express adhesion molecules and growth factors
- B cell receptor expression changes with progression through development
- Pro-B cells are programmed to die in the absence of survival signals
Does the D-J rearrange happen on both chromosomes?
yes
*early pro-B cell
If the V-DJ doesn’t happen on one chromosome what happens?
it gets another chance on the other chromosome, if this also fails then the cell dies. Junctional diversity errors result in non successful formation of heavy chain
*Late pro-B cell
Early Pro-B cell
RAG proteins activated
heavy chain D and J segments joined
occurs on both chromosomes
Late-Pro-B cell
heavy V and DJ segments joined
occurs sequentially on chromosomes
two chances for RAR
*first checkpoint happens now for functional heavy chain
what is the pre B cell receptor?
causes transition form Pro to Pre B cell
it is expressed in the ER
**surrogate light chain expressed and ensures a light chain can bind
Ig alpha and beta expressed(allows signaling)
Ig alpha and beta
checkpoint clearance
turns of RAG proteins
initiates cell division
-Allelic exclusion(heavy chain only from one chromosome)
why is allelic exclusion important?
ensures specificity of the heavy chain not allowing for a mixture of heavy chain production
Once the late pro-B cell has made it through the checkpoint and transitions into a Large -Pre-B cell what happens?
cell division:
100 small pre-B cells
RAG genes activated
unique recombination per cell(light chain)
small Pre-B cells light chains are rearranged sequentially how?
4-5 recombinations per chromosome
kappa then lambda
-approxiamately 85% of small pre-B cells survive
-Functional antibody expressed on the cell surface (IgM)
what are the two checkpoints in B cell developement?
- functional heavy chain(pre B cell receptor) and happens between early and late Pro B-cells
- functional light chain
- *both signal through Ig alpha and beta
what is negative selection
exposure to self antigen and ensures tolerance
- central tolerance(bone marrow)
- peripheral tolerance(soluble self antigen)
if a B cell binds to self what happens?
has a chance to rearrange again, if this fails again then it under goes apoptosis
what are the 3 fates negative selection
- light chain reorganization
- apoptosis
- anergy(nonfunctional cells)
Immature B cells migrate to lymphoid tissues through what?
a High endothelial venule (HEV)
Where do B cells mature?
in secondary lymphoid tissues and reside in the the primary lymphoid follicles
what draws immature B cells to secondary lymphoid tissues?
CCL 21 and CCL19 released by stromal dendritic cells
what does CXCL 13 do?
attracts B cells into the primary follicle
what drives the maturation of B cells in the primary follicle?
interactions with follicular dendritic cells and cytokines via BAFF
**positive selection
A mature naive B cell has what expression of IgD and IgM?
increased IgD
decreased IgM
*now can circulate in lymph, blood, and secondary tissues
Positive selection of B cell
lymph node localization
BAFF signaling
what are the steps of B cell activation
4 steps
- antigen exposure in cortex
- interaction with T cell (isotype of Ab)
- migration to germinal center
- plasma cell production and memory cells
