B cell activation and antibody production Flashcards
(32 cards)
Activation results from
antigen binding to antigen specific membrane IgM and IgD on mature, naïve B cells
A single B cell can generate
5000 plasma cells that produce > 1012 Ab
molecules per day (1,000,000,000,000)
The type and amount of Ab produced depends on:
Antigen driving response
T cell involvement
Prior antigen exposure
Anatomic site of infection
Antibody responses to peptide antigen require
internalization, processing
and presentation to CD4+ helper T lymphocytes and TH can then costimulate and further activate B cells
what Ab responses do not require T cell costimulation
Ab response to polysaccharides, some lipids and NA with repeating, multivalent, non-protein determinants do not require T cell costimulation for activation
- May activate many BCR simultaneously
- involves B1 cells or marginal zoneB cells and short lived plasma cells
typical in helper T –
dependent humoral responses
Isotype switching and affinity maturation
Most mature naïve B cells are
follicular B cells located in lymph nodes
–>Enter follicles, or B cell zones, of lymph nodes
Guided by cytokines
Antigen Delivery
many forms and routes
- Most antigens from tissues arrive in lymph nodes through lymphatic system. (small, soluble antigens). they enter B cell zone via conduits
- Subcapsular macrophages in lymph nodes capture large microbes and antigen-antibody complexes and deliver to follicles
- Many large antigens enter the lymph node from lymphatics and are not captured by subcapsular macrophages and are too large to enter conduits so they are Captured by resident dendritic cells and transported to follicles for B cell activation
- Antigens in immune complexes may bind to complement receptors on marginal zone B cells
(These cells transfer antigen to follicular B cells)
5.Blood-borne microbes captured
by plasmacytoid dendritic cells
are transported to spleen for
potential delivery to marginal zone B cells - Polysaccharide antigens can be
captured by macrophages in
marginal zone (spleen) and
transferred to Marginal zone B cells
Antigen binding to BCR results in two main processes
- Signal transduction for activation
2. Receptor internalizations of the bound antigen =Antigen processing and presentation to T helper cells
Antigen binding can initiate activation but Usually requires additional stimuli including to allow proliferation and differentiation of naive B cells
Complement proteins
pattern recognition receptors
and in the case of protein antigens, helper T cells
complement activation of B cells. the plasma protein is activated by 1 of 2 ways
-usually seen with microbes which activate this system with direct binding in the absence of antibodies by the alternative and lectin pathways
or
-in the presence of antibodies (Antigen-Ab complex) by the classical pathway
- Protein antigens can be bound by pre-
existing Abs, or Abs produced early in
the response
complement activation results in complement fragments being generated that bind to the microbes
Complement activation cleaves complement proteins
C3 (key component) cleavage = C3b and C3a
C3b binds to microbe or antigen-Ab complex.
C3b cleaved to C3d which remains on microbial surface
-the C3d fragment on antigen is recognized by the type 2 complement receptor on the B cells called CR2(aka CD21), which functions as a coreceptor for B cells as it enhances the strength of B cell signalling
C3d-antigen or C3d-antigen-Ab complex
bind to B cells through
Ig AND CR2
Enhances activation signals
Myeloid cells activated through PRR
help B cell activation indirectly in two ways:
Dendritic cells contribute to T cell activation and Secrete cytokines to induce T- independent activation
Antigen-mediated crosslinking of BCR by different types of antigens induces distinct cellular events
Multivalent antigens initiate B cell proliferation and differentiation
vs
Protein antigens prepare B cells for T interaction
Some activated B cells differentiate into short-lived plasma cells and the Survival of B cells is promoted by
the production of anti-apoptotic proteins (Bcl-2)
B cell activation by antigen binding results in:
Increases MHC II expression
and
B7 costimulator expression
-Activated B cells express more receptors for T cell derived cytokines and may move from follicles to T cell location
*therefore antigen stimulated B cells are more efficient activators of helper T cells compared to naive B cells
protein antigens require processing by B cells and present them to helper T cells via MHC 11
-both TCR and BCR recognize protein antigen in peripheral lymphoid organs and then come together to initiate humoral immune response:
Antigen taken up by DC and presented to naïve T cells, Helper T cell activation results and then Activated helper T migrate toward follicle (B cell zone) and express CD40L (T cells also secrete cytokines that promote isotope switching). B cells in follicle are activated by antigen (soluble or displayed). B cells process antigen and migrate toward T cell zone and then
activated Helper T cells and B cells interact and B cells become activated. B cells undergo low level isotype switching, somatic mutation and generate short-lived plasma cells. Some activated T cells differentiate into T follicule cells. Activated B cells and T cells migrate back into the follicle and form germinal centres where the more specialized antibody responses are induced and include:
Extensive B cell proliferation Isotype switching Somatic mutation Affinity maturation Memory B cell generation Induction of long-lived plasma cells that migrate to bone marrow
A protein antigen that elicits a T-dependent B cell response uses two epitopes to fully activate B cells
- Surface epitope on native protein
recognized by BCR
2.Linear internal epitope recognized by TCR
Germinal Centre in lymphoid follicles is site of:
Affinity maturation
Isotype switching
Generation of memory B cells
Long-lived plasma cell differentiation
describe the more slowly developing but more effective germinal center response
activation mediated by B-T cell interaction
-TFH cells begin to develop 4-7 days after antigen exposure (Triggered by B cells)
Some progeny of IgD and IgM expression B cells undergo isotype switching following CD40L and cytokine activation
IFN-γ induces switching to IgG
and
IL-4 induces switching to IgE
(cytokines from activated helper T cells)
Isotype switching involves
the process called switch recombination in which the Ig heavy chain in B cells is cut and recombined such that a previously formed VDJ exon that encodes the V domain is placed adjacent to a downstream C region, and the intervening DNA is deleted (old heavy
chain constant region is replaced but the variable region remains the same)
Affinity Maturation
result of somatic mutations of Ig genes followed by
selective survival of B cells with the highest affinities for the antigen
(Antigen recognition stimulates Bcl-2 expression)
(leads to increased affinity of antibodies for a particular antigen)->-As the process progresses the affinities get higher and higher
-Generates Abs that more efficiently neutralize and eliminate microbes
Only generated in T-dependent B cell activation
