B Cell Development and Activation Flashcards
mature naive B cells possess what surface markers?
IgM and IgD Ig-alpha and Ig-beta CD19 and CD20 CR2 MHC Class I and II
where do mature naive B cells migrate?
most to secondary lymphoid organs
-lymph nodes and spleen
enter through HEVs and circulate for weeks
if not activated, die by apoptosis
B-1 cells
develop from the fetal liver-derived stem cells
-find in the GALT
respond to non-protein antigen in mucosa
have the CD5 marker**
B-2 cells
develop from B cells produced after birth
are follicular and marginal
follicular B cells
subset of B-2 cells
**major subset
re-circulating cells (surveillance)
margin B cells
subset of B-2 cells
reside in the spleen
don’t recirculate
more likely to respond to blood-borne polysaccharides**
what is necessary for signal transduction of B cells?
Ig alpha and beta dimer is necessary
primary lymphoid follicles
contain follicular dendritic cells (FDCs)
-present antigen, but not like other APCs
naive B cells interact with the FDCs to be activated
competition for survival signals?
not enough FDCs to activate all B cells - those not activated will die
naive B cells express what?
L selectin
CCR-7
LFA1
CXCR4
**allow for B cell homing
these surface molecules activate integrins
L selectin
on naive B cells binds Pnad (Peripheral node addressin)
CCR7
on naive B cells
binds CXCL19 or CXCL21
LFA1
on naive B cells
binds ICAM-1
CXCR4
on naive B cells
binds CXC12
CXCL13
secreted by FDCs
mediate the follicle migration of naive B cells
What two signals does B cell activation require?
antigen recognition by membrane Ig
-must have repeating epitopes
first signal for B cell activation
antigen recognition by membrane IgG
-must crosslink 2 or more BCRs
signaling occurs through Ig alpha and beta tails
another way B cells can get first signal?
through the B cell co-receptor
pathogen bound with C3d
-binds CR2
-CR2 and CD19 cytoplasmic
results in a 1000x more intense signal
BCR co-receptor complex
CD19
CD81
CR2
lg-alpha and Ig-beta
**does not require the crosslinking of membrane bound Ig to initiate response
activated B cells what to alter chemokine receptors?
activated in the primary follicle area
downregulate CXCR5 and increase CCR7
-can leave the follicle and go to para-cortex
activated T cells what to alter chemokine receptors?
in the para-cortex/cortex area
down-regulate CCR7 and increase CXCR5
allows B and T cells to meet and interact
second signal of B cell activation
two critical ligand pairs
- B7/CD28
- CD40/CD40L
B7
upregulated by stimulation of B cell
-can bind to CD28 on T cells
**first signal of T cell was the TCR MHC class II interaction
allows T cells to perform effector function
activation of T cell results in what?
increase in expression of CD40L
can interact with CD40 on B cell
provudes signal 2 for the B cell
Important concept for B and T cell interaction
CD40L ( T cells) and B7 (B cells) are dependent on antigen stimulation
only lymphocytes specifically interacting with antigen will be activates
**maintains specificity
CD40 expression on B cell?
constitutively expressed
Class switching in the germinal center
cytokines from T cells provide the switch for this
IL-4 = IgE
IFN-gamma = IgG2a
TGF-beta and IL-5 = IgA
second function is B cell proliferation
cytokine that stimulates IgE production?
IL-4
cytokine that stimulates IgG2a production?
IFN-gamma
cytokine that stimulates IgA production?
TGF-beta and IL-5
what signaling triggers isotype switching?
CD40:C40L and cytokines
increase the accessibility of the DNA at specific C regions
rearrange VDJ gene segment recombines with a downstream C region (intervening DNA deleted)
T-dependent antigens?
peptides (proteins only)
activation-induced deaminase?
key enzyme in isotype switching
-expressed in response to CD40 signaling
Ig in naive B cells
IgM and IgD
Ig in naive B cell with LPS
no class switching occurs
Ig in naive B cell with LPS and IL-4
switching at gamma and epsilon
**keep in mind, will only produce one C region
Ig in naive B cell with LPS and TGF-beta
switching at gamma and alpha
**keep in mind, will only produce one C region
affinity maturation
aka somatic hypermutation
under activity of AID
-converts Cs to Us
introduces point mutations into V regions of gene
what is required for affinity maturation?
CD40/CD40L
T-dependent antigen required
what happens to the selected B cells?
move back to the germinal center
-B cell now has higher affinity
interacts with FDCs and TfH cells
**only the cells with high affinity antigen receptors are selected to survive
TfH
T follicular helper cells
do T cell receptors undergo affinity maturation?
NO!
over time what happens to the number of somatic mutations?
increases toward end of primary response and with every subsequent exposure (secondary and tertiary response)
Plasma Cells
terminally differentiated antibody secreting B cells
lose CD19 and 20 expression
identified by CD27**
high secretion rate (hundreds to thousands per second)
survive for long periods of time and capable of mounting the secondary response
CD27
marker for plasma B cells
T dependent antigens
require T cell help (contact dependent)
proteins
specific for the epitope
T independent antigens
don’t require T cell help
bacterial cell wall like LPS activation
no memory
feedback of B cell response?
**IgG binds the IgG receptor and inhibits antibody production
by binding the Ig-alpha and Ig-beta dimers
natural antibodies?
IgM
produced by B-1 and margin zone B cells
specific for bacteria in area
cross react with blood alloantigens
