60-B Cell Development Flashcards
B cell development
from hematopoietic stem cell
commitment to B cell lineage
turning on or off transcription factors driven by cytokines and receptor-ligand interactions
b cell maturation
bone marrow
Fetal development of b cell
liver to spleen to bone marrow
clonal representation
each b cell clone expresses many copies of a unique, single BCR
central tolerance
mature b cells are purged of self reactivity
VDJ recombination
heavy chain at pro b cell stage
VJ recombination
light chain at pre b cell stage
allelic exclusion
only 1 successful VDJ and VJ chain recombination is allowed
ensures only 1 unique BCR per B cell clone
goal of recombination
create diverse set of Vh and Vl regions for antigen binding pocket
heavy chain
VDJ and constant
chromosome 14
kappa light chain
VJ and constant
chromosome 2
lambda light chain
V and JC pairs, up to 7, only 4 functional
chromosome 22
productive rearrangement
in frame contiguous
successful recombination
out of frame shifts reading frame
Heavy chain recombination
D to J recombination, successful recombination occurs on both chromosomes
V to DJ recombination, successful recombination allowed on only 1 chromosome
steps in recombination
elements randomly selected
brought into close proximity with recombinase complex
intervening DNA is cleaved and eliminated
cut DNA ends are ligated
end product of VDJ recombination
mu heavy chain protien
defines cell as now being pre B cell
proteins made by pre b cell
surrogate light chain complex, made of VpreB and lambda 5
pre b cell complex
surrogate light chain binds with mu heavy chain protein to make pre b cell complex expression
block further VDJ recombination and initiate VJ recombination
allelic exclusion for VDJ
out of frame DJ for one or both loci
non productive VDJ at one or both loci
pre b cell complex to close other heavy chain
non productive VDJ at both b cell
cannot develop and dies
allelic exclusion at light chain
transcription and translation of light chains, paired with mu heavy chain and expressed as complete BCR
stops rearrangement at kappa and lambda
stops surrogate light chain production
non productive at both kappa
lambda loci now open
non productive at both lambda
cell dies
complete BCR
pairing of mu heavy chain with light chain to stop all further recombination
recombinatorial diversity
random association of VDJ or VJ
junctional diversity
open ends of DNA during recombination can be tampered with
add nucleic acids using TdT or remove nuclei acids using nucleases
makes new coding sequence for Ag binding pocket
recombination is unbiased
BCR recognize self Ags as much as foreign Ags
must purge self reactive immature B cells “central tolerance”
3 outcomes of central tolerance
apoptosis
anergy/cell paralysis
positive selection
apoptosis purging
high affinity for self, strong BCR signal, apoptosis
cell anergy purging
low affinity for self, modest BCR signal, paralysis
positive selection purging
lack of Ag binding, no affinity for self, exit to periphery
B1 B cells
primitive population, early in ontogeny, fetal derived
enriched in serosal lined cavities (pleural and peritoneal), use restricted set of Vh regions
express CD19, CD20, IgM and IgD
high IgM, low IgD
B2 B cells
generated throughout life from bone marrow
express CD19, CD20, IgM, and IgD
marginal zone and follicular cells
marginal zone b cells
reside in spleen
t cell independent responses
high IgM, low IgD
follicular b cells
reside in all secondary lymphoid organs
t cell dependent
high IgD, low IgM
B1 B cell reproduction
self renewal, steady state mitosis creating identical daughter cells to preserve restricted Vh
function of B1 B cells
spontaneously differentiate into plasma cells
secrete natural Abs (IgM)
do not require stimulation from pathogens
marginal zones
only in spleen border between follicle and red pulp sample blood first coming into spleen appear late in development (2 years) t cell independent responses rapid Ab response against bacteria
follicular zones
follicles of SLO (spleen, nodes, MALT)
present early in life
t cell dependent responses and germinal center reaction
give rise to memory b cells and long term plasma cells
distinct zones in SLO
segregation of T and B cells driven by chemokines
B cells migrate to?
follicles, secretion of CXCL13 by dendritic cells
CXCR5 on b cells binds to 13
T cells migrate to?
t cell zones, secretion of CCL19 and CCL21 by reticular cells
CCR7 on t cells bind to 19 and 21
