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.