Transcript B cells - UCLA.edu

B CELL DEVELOPMENT AND ACTIVATION
• In healthy people, there are mature B cells with the capacity to
make antibodies to virtually any antigen.
• Bone marrow is the primary lymphoid organ in which B cell
development occurs.
• Bone marrow is the primary
lymphoid organ in which B
cell development occurs.
• Following initial development
in bone marrow, mature B
cells migrate to various
secondary lymphoid
tissues, including lymph
nodes, spleen, gut-associated
lymphoid tissue and blood.
• There, mature B cells can
interact with antigen, become
activated, and further
differentiate into antibodysecreting cells
• B and T cells undergo distinct differentiation pathways.
• B cells are generated in the bone marrow, with mature B cells,
which are ready to respond to antigen, then exiting and migrating to
lymph nodes and spleen.
• The development of B cells, starting from hematopoietic
stem cells and ending with cells that produce antibodies, can
be divided into four phases:
Phase 1 – development of B cells in bone marrow
• This first phase of B cell development is the generation of B
cells in bone marrow.
• There, stem cells develop into pro-B cells, then pre-B cells,
and finally mature B cells, which exit the bone marrow and
migrate to secondary lymphoid organs.
• This phase of B cell development is not driven by contact with
antigen: antigen independent.
• The DNA rearrangements that result in a functional cellsurface immunoglobulin molecule occur during this phase.
Phase 1 – development of B cells in bone marrow:
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• Stem cells have both their H-chain and L-chain genes in germline, un-rearranged configuration
• The earliest cell that has made the commitment to the B cell
lineage is the pro-B cell: pro-B cells have begun to rearrange
their H-chain gene.
• Once a B lineage cell expresses cell surface H-chain (m) it is
defined as a pre-B cell.
• However, the early pre-B cell receptor is not the final form of
surface immunoglobulin: H-chain + surrogate light chain
(molecule that mimics L-chain)
• Further DNA rearrangements result in the formation of a functional
L-chain, then IgM (H-chain + L-chain) is expressed on the cell
surface.
• When a cell has productive rearrangements of both H- and Lchains) it becomes an immature B cell:
• These surface IgM-positive cells are ready to leave the bone
marrow, go to secondary lymphoid organs, and interact with
antigen.
• This first phase of B cell development in bone marrow is
dependent on association with stromal cells.
• Stromal cells are non-lymphoid cells that provide an appropriate
microenvironment for B cell development.
• Bone marrow stromal cells produce both cell surface-stimulatory
molecules, as well as growth factors and cytokines, which help
drive B cell development.
• For a B cell to survive this
phase of development, it
must have productive
rearrangements of both
H-chain and L-chain.
• Failure to do this results
in cell death - cells that
have unproductive
rearrangements (such
as rearrangements that
are not in a correct
reading frame) are
eliminated.
• A given B cell can
undergo repeated
rearrangements.
• The rearrangements that result in functional H- and L-chains
occur in a specific order:
• Expression of a functional
B cell receptor protein on
the cell surface stops
further rearrangement of
the gene encoding that
product:
Phase 2 – elimination of self-reactive cells
• Once B cells have reached the stage of immature B cells, they
are able to interact with antigen – they express a functional cell
surface receptor for antigen, and have the potential to be
stimulated to become antibody-secreting cells.
• Since the DNA rearrangements that result in functional H-chain
and L-chain are not antigen-driven, a fraction of immature B
cells will have a BCR that, by chance, reacts with some
component of self - self antigen reactive cells
• These immature B cells are removed by clonal deletion, either
in the bone marrow, or shortly after leaving the bone marrow.
• Encounter with
self-antigen results
in apoptosis
(death), or anergy
(unresponsiveness)
• B cells that survive
this step express
surface IgD as well
as IgM:
mature B cells
• How do these immature B cells know that the antigen that they’re
binding is a self Ag? They don’t:
– B cells are more susceptible to anergy at this stage in
development
– They become anergic if they don’t receive a co-stimulatory
signal:
• Therefore, signaling via the BCR alone is not sufficient to activate
the B cell • Second signals (co-stimulatory signals) are necessary for
activation.
Phase 2 – elimination of self-reactive B cells,
generation of mature IgM+, IgD+ cells:
Phase 3 – activation of B cells on contact with antigen
• Following the generation of a
functional B cell receptor for
Ag, and the removal of selfreactive cells, mature Agresponsive B cells
(IgM+, IgD+) emigrate from
bone marrow.
• These mature B cells go to
secondary lymphoid
organs.
• In the lymph node, B cells gather in primary lymphoid follicles,
where they receive viability-promoting signals, interacting with
follicular dendritic cells, and wait for antigen
• B cells enter
lymph nodes
via high
endothelial
venules (HEV)
to reach
these primary
follicles.
• B cells can
recirculate out
via the lymphatic
circulation, and
back into blood.
• B cells can interact with an
antigen that is bound to the
surface of follicular dendritic
cells in the lymph nodes.
• These cells trap and concentrate
antigen, maximizing the
interaction of antigen with B cells
• Antigen-specific B cells are detained in the T cell-areas, where
they interact with antigen, and with antigen-specific activated
helper T cells. Stimulated antigen-specific B cells then proliferate
and differentiate, eventually forming plasma cells and germinal
centers:
• Binding of antigen to the B
cell’s antigen receptor
results in an initial
activation signal (first
signal) if there is receptor
cross-linking.
• Cross-linking of the B cell
receptor results in a
cascade of intracellular
signals, which results in the
induction of specific gene
expression leading to
cellular proliferation and
differentiation.
• However, signaling via the BCR alone is not sufficient to activate
the B cell -
• Second signals (co-stimulatory signals) are necessary for
activation.
activation
signal
activation
signal
Laâbi, Y. and A. Strasser. Science 289:883, 2000
Phase 4 – differentiation to antibody-secreting cells
• Some of the progeny of these antigen-activated B cells
differentiate into plasma cells, which are antibody-secreting
cells.
• Plasma cells:
– terminally-differentiated cells
– derived from activated B cells or
memory cells
– loaded with endoplasmic reticulum
– devoted to protein (antibody)
synthesis
– no longer express surface
immunoglobulin or MHC class II
– no longer responsive to antigen
contact
– live for several weeks
– migrate away from the site of initial
contact with helper T cells, either to
the medullary cords of the lymph
nodes or to the bone marrow
• Other antigen activated B cells give rise to germinal centers
(GC), zones of proliferating activated B cells:
• These germinal centers (GC) contains:
– proliferating (D - centroblasts) B cells
– differentiating (L - centrocytes) B cells
• Germinal centers are where isotype switching and somatic
hypermutation occur.
• Somatic hypermutation:
– rapid mutation (hypermutation)
of immunoglobulin genes
– results in antigen-binding
affinity that is higher, or lower,
than its original binding affinity
– selection by antigen results in
the generation of BCR with
increased affinity for antigen
• Only those B cells that have
enhanced their antigen receptor’s
binding affinity survive.
• This selection process involves competition for both antigen
and for helper T cells.
• Antigen is trapped on the surface of follicular dendritic cells in
the form of immune complexes (antigen + antibody
complexes).
• B cells that bind to Ag with high affinity live, others die by
apoptosis.
• Centrocytes interact with T cells by presenting processed
antigen to them via their MHC class II molecules.
• Centrocytes that receive co-signaling (via CD40, MHC class II
and cytokines), as well as signaling via their antigen receptor
survive
• Centrocytes that do not bind antigen and T cells with sufficient
affinity die by apoptosis.
• These germinal centers (GC) contains:
– proliferating (D - centroblasts) B cells
– differentiating (L - centrocytes) B cells
• Isotype switching - change in the type of H-chain that is
used by a given B cell, also occurs in germinal centers:
• Isotype switching involves DNA rearrangements - replacement of
one H-chain class gene with another
• Isotype switching also occurs in germinal centers
• Isotype switching is guided by the pattern of cytokines that are
produced by helper T cells:
• These somatically mutated and
isotype switched B cells can then
continue to differentiate into memory
cells or plasma cells, producing:
– IgG or other switched isotypes
– much higher affinity Ab, due to
somatic hypermutation increasing
the antigen binding affinity
Together, these processes result in a 1-2 log increase in the number
of antigen-specific B cells (clonal selection and expansion), an
increase in antibody binding affinity for antigen
(somatic hypermutation), and the expression of new Ig subclasses
(Ig isotype switching):
• Other germinal center B cells develop into memory B cells:
– quiescent
– Increased in frequency following primary responses
– long-lived
– posses high-affinity, isotype-switched antigen receptors
– form a pool of cells ready to mount a rapid secondary
antibody response, on subsequent exposure to antigen
• The combined result of
somatic hypermutation,
isotype switching, and the
generation of memory
cells, is the creation of a
pool of cells that can
respond rapidly and
vigorously to subsequent
contact with antigen, with
high-affinity, IgG and IgA
antibodies.
B cell cancers
mirror these
different stages
of B cell
development