Discussion
In this study, we observed that the rate of
CD27+IgD+B cells were decreased and
functionally impaired in producing natural antibody-like IgM in patients
with SLE when compared with healthy controls. The number of
CD27+IgD+B cells is correlated with
the clinical characteristics of SLE patients. After effective therapy,
these CD27+IgD+B cells could get
recovered.
In SLE, the number of apoptotic cells increases while the phagocytosis
function is impaired (14, 15). The contemporaneous occurrence of
enhanced apoptosis and impaired phagocytosis is considered to be a key
process in the pathogenesis of SLE and can lead to the cumulative
exposure to the autoantigens which resulted in autoantibody production
and autoimmunity(16). Apoptotic cells are normally phagocytosed by
professional phagocytes such as macrophages, but the clearance of
apoptotic cells depends not only on functioning phagocytes but also on
soluble proteins that act as opsonins and/or bridging molecules.
Phagocytosis of apoptotic cells can be enhanced by C-reactive protein
(CRP), serum amyloid P component (SAP), C1q, IgM, MBL and other
proteins, forming a redundant backup mechanism. Previous studies have
found that phagocytic activity of macrophages is reduced three-fold to
four-fold in the absence of IgM (17). Decreased natural IgM level in SLE
patients may lead to inefficient clearance of apoptotic cells, leading
to the accumulation of dead cells in peripheral blood(18). SLE patients
were reported to demonstrate lower levels of anti-PC natural IgM,
reductions of which correlated with duration of the disease. Lower
levels of anti-PC natural IgM were also reported to be associated with
more frequent cardiovascular events in patients with SLE (19). However,
till now little is known about the causes of natural IgM defects in SLE
patients.
In
our previous study, we proved that
CD27+IgD+B
cells can spontaneously secrete
IgM that were polyreactive and low affinitive. We termed these
CD27+IgD+B cells-derived IgM as
natural antibody-like IgM. In this study, we found that
CD27+IgD+B cells in SLE patients
were significantly reduced and negatively correlated with SLEDAI and
anti-dsDNA autoantibodies. These data are consistent with previous
reports (20, 21) and, taken together, indicate that the B cell-subsets
are disordered in SLE patients. Since different B cell subsets have
different functional characteristics, the imbalance of their proportions
will lead to the imbalance of immune homeostasis and promote the
development of the disease to some extent. Cytokines such as IFN-gamma,
BAFF, TNF-alpha, il-6, il-21 in the serum of SLE patients will affect
the B cell signaling pathway and thus increase its activation and
differentiation(22-24). Therefore, we speculated that the inflammatory
environment in SLE patients is one of the reasons for the reduction of
CD27+IgD+B cells, but this
speculation need to be further studied.
In addition, QPCR and ELISPOT analyses showed that the ability of
CD27+IgD+B cells to secrete IgM in
SLE patients was significantly lower than that in healthy control,
indicating that in SLE patients,
CD27+IgD+B cells has defects not
only in quantity, but also in function. Therefore, this is also a reason
for the accumulation of apoptotic cells and the generation of
autoimmunity in SLE patients. The decreased TCR or BCR diversity has
been observed in cancers and autoimmune diseases, which may contribute
to the development of the diseases(25). Our previous research has shown
that the BCR repertoire of
CD27+IgD+B cells was altered in RA.
Compared with healthy controls, the variable region of the
CD27+IgD+B cells-derived IgM μ chain
showed much narrower spectrum. Therefore, we speculated that the BCR
repertoire of CD27+IgD+B cells was
also changed in SLE, and the following study will be conducted to score
the BCR repertoire of CD27+IgD+B
cells in SLE patients.
In summary, we demonstrated that
CD27+IgD+B cells were numerically
and functionally impaired in SLE.
CD27+IgD+B cells are a reliable
biomarker for active SLE and that the role of these cells in the
pathogenesis of SLE deserve to further investigation.