Biology Reference
In-Depth Information
immediately following ASCT in all patients, but fall to near normal levels in
patients who do not develop cGVHD such that BAFF levels are significantly
higher in patients with cGVHD
[8,88]
. This decline in BAFF levels in patients
who do not develop cGVHD is coincident with a rise in B-cell numbers so
that these patients have significantly higher B-cell numbers by 6-12 months
following ASCT compared with patients who do have cGVHD. The end result
is a significantly higher BAFF/B-cell ratio in patients with cGVHD. Further
phenotypic analysis revealed that patients without cGVHD had greater pro-
portions of naïve CD27
−
B cells, whereas patients who developed cGVHD
had greater proportions of activated CD27
+
B cells
[8]
. CD27
−
B cells were
further classified as naïve or transitional based on low or high cell surface
expression of CD38, respectively. CD27
+
B cells were further classified as
IgD
+
memory (IgD
+
CD38
Lo
), pre-germinal center (IgD
+
CD38
Hi
), post-ger-
minal center memory (IgD
−/Lo
CD38
Lo
), or plasmablast/plasma cell (IgD
−/
Lo
CD38
Hi
) B cells. Overall, the proportion of IgD
+
B cells that coexpressed
CD27 (IgD
+
memory B cells) and pre-germinal center B cells was higher
in patients with cGVHD compared to patients without cGVHD or healthy
controls. Among patients with active cGVHD, high BAFF levels were signifi-
cantly associated with increased numbers of plasmablast/plasma cells and
pre-germinal center B cells. These findings suggest that persistent elevation
of BAFF levels in the setting of delayed B-cell reconstitution can support the
survival of activated, potentially alloreactive B cells and therefore promote
the development of cGVHD.
307
Studies from other laboratories have also demonstrated an increase in
immature transitional B cells in patients with active cGVHD, using lack of
CD21 cell surface expression as a marker of these cells
[89]
. Interestingly, low
B-cell numbers and high BAFF/B-cell ratios associated with cGVHD were
predominantly seen in patients with hypogammaglobulinemia. Patients
with cGVHD and hypogammaglobulinemia have a higher proportion of
immature and transitional B cells and a lower proportion of naïve CD27
−
B cells compared with cGVHD patients who have normal or high levels of
gammaglobulin
[90]
. Naïve CD27
−
B cells were increased, however, in all
cGVHD patients compared to healthy controls. Contrary to the finding that
IgD
+
memory B cells appear to be increased in patients with cGVHD, these
cells are decreased in this specific population of patients with cGVHD and
hypogammaglobulinemia and in patients with severe compared with mild
or moderate cGVHD. In contrast, cGVHD patients with hypergammaglobu-
linemia had higher proportions of CD27
−
naïve B cells and IgD
+
memory
B cells and had an increased frequency of autoantibody production com-
pared with cGVHD patients with normo- or hypogammaglobulinemia;
sclerodermatous cGVHD manifestations were also significantly associated
with hypergammaglobulinemia. These data suggest that B cells may be
pathologic in cGVHD by different mechanisms and that these mechanisms
can be classified by distinct aberrancies in B-cell profiles.
Whether BAFF is driving these alterations in B-cell homeostasis or is a
bystander molecule is unclear, but single-nucleotide polymorphisms
(SNPs) in the BAFF gene have been found to correlate with the lack of
development of cGVHD
[91]
. How these SNPs correlate with BAFF expres-
sion and function has not been investigated but this provides a poten-
tial mechanism whereby altered BAFF expression or receptor binding
Search WWH ::
Custom Search