Antigen Presenting Cells (APCs)
385
9.3.1
B Cell/Follicular DC Contacts
Some of the mutations generated dur-
ing somatic mutations in immunoglobulin
genes are likely to be useful because anti-
bodies with higher afFnity are generated.
However, the majority of the mutations
may lead to a decline or even loss of antigen
binding or to recognition of self-antigen.
Therefore, the next step in the process of
afFnity maturation is the selection of the
useful, high-afFnity B cells that do not
react with self.
To this end, follicular dendritic cells
(±DCs) are required to engage hyper-
mutated B cells. ±DCs have long cyto-
plasmic processes that form a network
around which germinal centers are formed
(±ig. 9). ±DCs do not express MHC class
II molecules, and hence, are not related
to classical DCs, but they express several
complement receptors, ±c receptors, and
CD40L. These receptors bind and display
intact antigen that are decorated with Ig or
complement factors. Signals generated by
antigen binding – mediated by ±DCs – to
surface Ig on the B cell block a default cell
death pathway by inducing antiapoptotic
protein of the Bcl family.
With increasing numbers of antigen-
speciFc antibodies being available, more
and more of the antigen is captured,
and thus, the concentration of available
antigen in the germinal center decreases.
Therefore, these B cells that are still
able to capture antigen have to have a
high afFnity for the antigen – and only
they will survive. The survival of the
respective B cells involves uptake and
processing of antigen hold on ±DCs, and
its presentation to T cells via MHC class
II molecules (±ig. 9). This event will lead
to T-cell activation – the CD40–CD40L
interaction conveys long-term survival to
the respective centrocyte. The net result
of this selection process is a population
of
B
cells
producing
antibodies
with
signiFcantly higher afFnities for antigen
than
the
antibodies
produced
by
the
same clones of B cells earlier in the
immune response.
Some antigen-activated B cells acquire
the ability to survive for long periods of
time. They are termed
memory B cells
capable of mounting rapid responses to
subsequent infections. It is possible that
memory cells are continually generated
and maintained by antigenic stimulation,
facilitated by the help of ±DCs. Memory B
cells typically bear high-afFnity Ig. The
production of large quantities of high-
afFnity antibodies is strongly accelerated
after
secondary
exposures
to
antigen.
This can be attributed to the activation
of B cells in germinal centers and the
rapid formation of immune complexes
presented by ±DCs and processed by
memory B cells in order to contact cognate
T helper cells.
9.3.2
HLA-DO
HLA-DO is an MHC class II molecule
that is unable to bind peptide but serves
as
a
regulator
of
the
peptide
editor
and
chaperone
HLA-DM.
HLA-DO
is
expressed in B cells, but not in other APCs.
In further contrast to the classical MHC
class II molecules and to HLA-DM, HLA-
DO expression is initiated only after B-cell
development is complete, that is, when B
cells start becoming capable of interacting
successfully with T cells.
HLA-DO is tightly bound to HLA-DM
and is rapidly degraded in the absence of
HLA-DM. HLA-DM–HLA-DO complexes
are poorly active in removal of the CLIP
peptide, especially at moderate pH found
in early and late endosomes, suggest-
ing that HLA-DO is a negative regulator
of antigen presentation. However, at the
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