Discussion
The current study revealed that
CD27+IgD+B cells displayed reduced
amounts and functional impairment regarding the production of natural
antibody-like IgM in patients with SLE compared with healthy
controls. In addition, CD27+IgD+B
cell amounts were associated with clinical characteristics in SLE
patients, and were restored by effective treatment.
In SLE, the number of apoptotic cells increases while phagocytosis is
impaired(14, 15). Concurrent occurrence of increased apoptotic cell
death and deficient phagocytosis represents a major factor in SLE
pathogenesis, promoting autoantigen accumulation and subsequent
autoantibody production and autoimmune disorders(16). Apoptotic cells
undergo phagocytosis by professional phagocytic cells (e.g.,
macrophages) under normal conditions. However, apoptotic cell clearance
depends not only on functional phagocytes, but also on soluble proteins
acting as opsonins and/or bridging materials. Phagocytosis of apoptotic
cells can be increased 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 macrophages are
three- to four-fold less phagocytic in the absence of IgM(17). Decreased
amounts of natural IgM in SLE patients might reduce apoptotic cell
clearance, with dead cells accumulating in blood(18). Individuals with
SLE show anti-PC natural IgM level reduction, which correlates with
disease duration. In addition, decreased anti-PC natural IgM amounts are
associated with a higher frequency of cardiovascular events in human SLE
(19). However, the causes of natural IgM defects in SLE patients remain
largely unknown.
In
a previous study, we demonstrated that
CD27+IgD+B
cells can readily secrete
IgM with poly-reactivity and low affinity. These
CD27+IgD+B cell-associated IgM were
coined natural antibody-like IgM. In this study,
CD27+IgD+B cell amounts in SLE
patients were remarkably reduced and negatively associated with SLEDAI
and anti-dsDNA autoantibodies. The above findings corroborate previously
reported data(20, 21), jointly indicating that B cell-subsets are
disordered in SLE patients. Since distinct B cell subsets have different
functional characteristics, the imbalance of their proportions would
lead to altered immune homeostasis and promote pathological events to
some extent. Cytokines including IFN-γ, BAFF, TNF-α, IL-6 and IL-21 in
the serum of SLE patients affect the B cell signaling pathway, thereby
increasing B cell activation and differentiation(22-24). Therefore, we
speculated that the inflammatory environment in SLE patients is one of
the factors explaining the reduced
CD27+IgD+B cell amounts, which
deserves further investigation.
In addition, qRT-PCR and ELISPOT analyses showed that the ability of
CD27+IgD+B cells to secrete IgM in
human SLE was markedly reduced, indicating that in SLE patients,
CD27+IgD+B cells have defects not
only in quantity, but also in function. Therefore, this may also account
for apoptotic cell accumulation and autoimmunity development in human
SLE. Reduced TCR and/or BCR diversities have been reported in cancer and
autoimmune disorders, as potential etiologic factors(25). Our previous
research revealed that BCR profile in
CD27+IgD+B cells is abnormal in RA.
Therefore, we speculated that BCR profile in
CD27+IgD+B cells might also be
changed in SLE, and a follow-up study is underway to score
CD27+IgD+B cells’ BCR repertoire in
SLE patients.
Overall, CD27+IgD+B cell amounts and
function are altered in SLE. Therefore,
CD27+IgD+B cells could help reliably
detect active SLE, although their precise role in SLE development
deserves further investigation.