B-CELLS…
•
•
•
•
Origin…
Development…
SelectionS
ActivationS
•Progenitor B cells (pro-B-cells)
bearing a CD45R marker develop
– in the bone marrow – into
immature and then mature B cells.
•Then, they migrate to peripheral
lymph nodes.
•Those developmental events are
physically and physiologically
distinct; the former are antigen
independent; the latter are antigen
dependent.
NEGATIVE selection:
• crosslinkage of mIgM on immature
B cells can cause cells to die within
the bone marrow
• aka: CLONAL DELETION
Nota bene:
• Prior to clonal deletion, development is
antigen independent.
• Negative selection and positive
selection are antigen dependent.
• Recognition of the ANTIGEN in the
periphery leads to positive selection…
•
aka CLONAL EXPANSION
SELECTION does not equal ACTIVATION…
Recall that a B-CELL needs a signal from a T-HELPER CELL
SELECTION does not equal ACTIVATION…
Recall that a B-CELL needs a signal from a T-HELPER CELL
Signaling is synergistic…
Consider how
cytokines
function.
Remember their
potency
and locality.
SELECTION does not equal ACTIVATION…
Recall that a B-CELL needs a signal from a T-HELPER CELL
Activation….
• Activation occurs when a B-cell associates with a T-helper cell
through a ternary complex; this association establishes
specificity (the B-cell will have processed the antigen and presented it
through MHC-II, thus selecting a specific T-helper cell lineage).
• Pairing between B7 on the B-cell and CD28 on the T-helper cell
constitutes a co-stimulatory signal which will activate the Thelper cell. (The identities of the co-stimulatory proteins are “specific”; but
these same proteins are involved regardless of the identity of the antigen).
• The T-helper cell , once activated, synthesizes CD40L. Now,
pairing occurs between CD40 on the B-cell and CD40L on the
T-helper cell . This association constitutes a co-stimulatory
signal which activates the B-cell.
• Thus, there is “mutuality” between the B-cell activating the Thelper cell and the activated T-helper cell, in turn, activating the
B-cell.
• (This “mutuality” should not obscure that the process is “antigen-driven.”)
• Cytokines of various types are secreted by T-helper
cell and are received by differentiating B-cells.
• The various cytokines affect what immunoglobulin
isotypes will be produced by plasma cells.
Where is activation happening?
And what is happening?
The primary response is initiated in the
paracortex.
T-cells respond to processed antigen
that is typically delivered from a site
of origin by dendritic cells.
B-cells see the same antigen in an
unprocessed form in the lymph.
The T-cells and B-cells, now both
activated, form associations which
allow proper signaling.
The B-cells migrate to the periphery of
the paracortex and form foci where
they mature into plasma cells which
secrete, first, IgM and then IgG.
Some B-cells – along with some Thelper cell’s – migrate to primary
follicles in the cortex.
Primary follicles develop into secondary follicles
The secondary
follicles have
an area of
proliferation
(a germinal
center)
where Bcells
proliferate
and
differentiate.
Follicular dendritic cells… not an APC!
The follicular dendritic cells do not originate in
the bone marrow and do not have MHC-II.
Rather, the follicular dendritic cell contains Fc
receptors, receptors which can capture
immunoglobulins through their constant
region.
Thus, the follicular dendritic cells
become decorated with Ab
complexed to whole (unprocessed)
antigen. Stated another way, these
follicles have a rich supply of the
filtered antigen
The dendrites are fragile and can
break in to (non-nucleated) beads
(about 0.3-0.4 µm in diameter); these
beads are called “iccosomes”
(immune-complex coated bodies);
they can persist for several months.
How do the primary and secondary
responses differ?
How do the primary and secondary
The secondary response is
responses differ?
more intense because:
(i) there are more memory
cells specific for an antigen
than there are naive cells,
(ii) the immunoglobulins of
memory cells have
experienced affinity
maturation and bind to
antigen more strongly,
(iii) memory cells have a
much more extensive
exposure to antigen
(presented by follicular
dendritic cells), and
(iv) activation of memory cells
requires a less strong
stimulation.