Biology Reference
In-Depth Information
mablasts. Within GC, FDC seems to be the principal producer of IL-6, but also
of the IL-8 that modulates IgE production ( Kimata et al., 1995; Krzysiek et al.,
1999).
CHEMOKINE/CHEMOKINE RECEPTORS CONTROL B-CELL
TRAFFICKING
The mechanisms governing the organogenesis of lymphoid organs and the
tra½cking of B cells from the periphery to follicles and within follicles are not
fully understood. Nevertheless, several chemokine/chemokine receptor pairs
have been identi®ed as key molecules controlling B-cell tra½cking. The essen-
tial role of CXCR4 and its ligand, stromal cell-derived factor (SDF )-1a,inB
lineage maturation in vivo has been established in sdf-1ÿ=ÿ and cxcr4ÿ=ÿ
mice, which have highly impaired B lymphopoiesis and abnormally small
numbers of B-lymphoid precursors in fetal liver and bone marrow (Ma et al.,
1998). In the periphery, CXCR4 is expressed on most B cells and orchestrates
the basal tra½cking of resting B cells from the periphery to follicles. GC B cells
have similar amounts of CXCR4 to naive and memory B cells, but are un-
responsive to SDF-1a. After BCR triggering, the responsiveness of naive and
memory B cells to SDF-1a decreases and this e¨ect is enhanced by their con-
comitant stimulation by CD40 (Bleul et al., 1998). CD40 triggering alone is
ine½cient at regulating SDF-1a responsiveness, whereas IL-4 alone increases
SDF-1a responsiveness (Jourdan et al., 1998). In the absence of CXCR5 or its
ligand, BCA-1, the migration of SIgM
, SIgD
naive B cells from blood into
lymphoid tissue is severely impaired. Cxcr5ÿ=ÿ mice have no inguinal lymph
nodes, few Peyer's patches, and B cells that accumulate along the sinuses of the
marginal zone of the spleen rather than being organized in primary follicles
(Forster et al., 1996; Voigt et al., 2000). These ectopic B cells, in close contact
with FDC, nevertheless support hypermutation and antigenic selection ( Voigt
et al., 2000). Lymph node-like structures are induced in pancreatic islets in
transgenic mice expressing BCA-1 under the control of the insulin promotor.
These ectopic lymphoid structures are strictly dependent on B cells and LTa1b2
expression, con®rming the essential cooperation of BCA-1 and LTa1b2 in the
lymphoid neogenesis pathway (Luther et al., 2000). In normal mice and hu-
mans, CXCR5 is highly expressed on all naive and memory B cells from blood
or tonsils. GC B cells also express CXCR5, but migrate poorly in response to
BCA-1 (Forster et al., 1996; Kaiser et al., 1993). Short-term BCR triggering of
naive B cells is su½cient to decrease CXCR5 expression. In contrast, activation
of B cells by CD40 monoclonal antibodies (mAb) and IL-4 progressively de-
creases CXCR5 expression and responsiveness to BCA-1, neither of which are
detectable after 9 days of stimulation ( Bowman et al., 2000). Con¯icting results
have been obtained concerning the role of the CCR7/secondary lymphoid-
tissue chemokine (SLC), and CCR7/EBI-1 ligand chemokine (ELC) pairs in
