Abstract
BackgroundWe reported that the production of BAFF (B cell-activating factor) and IL-6, both of which are involved in survival and differentiation of B cells, is dysregulated in monocytes of patients with primary Sjögren’s syndrome (pSS). In this study, we investigate the relationship between possible aberrations of pSS monocytes and clinical features of pSS patients and the contribution of monocytes to B cell activation, a mechanism involved in the pathogenesis of pSS.MethodsExpression of BAFF-receptor (BR3) on peripheral monocytes from patients with pSS (n = 67) and healthy controls (HC: n = 37) was analyzed by FACS. Peripheral monocytes were stimulated with BAFF, and IL-6 production by the cells was measured by ELISA. Peripheral B cells were cultured with BAFF-stimulated monocytes in the presence or absence of anti-IL-6 receptor antibody, and IgG production by the cells was measured by ELISA. Patients’ serological data were collected from their clinical records. Patients’ disease activity was quantified based on their EULAR Sjögren’s syndrome disease activity index (ESSDAI) scores.ResultsThe proportion of peripheral BR3-positive monocytes (BR3+/CD14+) was significantly increased in pSS patients compared to HC. Moreover, IL-6 production by BAFF-stimulated monocytes was remarkably higher than HC and was significantly correlated with BR3+/CD14+ ratios of patients. In addition, BR3 expression on pSS monocytes was elevated in anti-Ro/SSA and/or anti-La/SSB positive compared to negative patients. Remarkably, BR3 expression on peripheral monocytes was positively and significantly correlated with patients’ serum IgG and IgM levels and ESSDAI scores. Moreover, the amount of IgG produced by B cells was markedly higher in pSS patients compared to HC when the cells were co-cultured with BAFF-stimulated autologous monocytes in vitro. Notably, addition of anti-IL-6 receptor antibody into the co-culture system led to inhibition of IgG production by B cells.ConclusionsOur data suggest that elevated BR3 expression in monocytes is associated with clinical features in pSS patients and that enhanced production of IL-6 by BAFF-stimulated monocytes plays a part in the overproduction of IgG by B cells in pSS. These results suggest that BAFF signaling pathways through BR3 in monocytes are possible therapeutic targets for pSS.
Highlights
Primary Sjögren’s syndrome is an idiopathic autoimmune disease with major clinical manifestations comprising xerostomia and keratoconjunctive sicca and is often accompanied with hypergammaglobulinemia (HγG)
Our data suggest that elevated BAFF receptor (BR3) expression in monocytes is associated with clinical features in primary Sjögren’s syndrome (pSS) patients and that enhanced production of IL-6 by B cell activating factor (BAFF)-stimulated monocytes plays a part in the overproduction of IgG by B cells in pSS. These results suggest that BAFF signaling pathways through BR3 in monocytes are possible therapeutic targets for pSS
We reported that BR3 expression in peripheral monocytes was elevated in pSS patients compared to healthy controls (HC) and that pSS monocytes showed robust increases in IL-6 production following BAFF stimulation [28]
Summary
Primary Sjögren’s syndrome (pSS) is an idiopathic autoimmune disease with major clinical manifestations comprising xerostomia (dry mouth) and keratoconjunctive sicca (dry eyes) and is often accompanied with hypergammaglobulinemia (HγG). Many studies have shown that abnormal B cell functions, such as those that lead to conditions like appearance of rheumatoid factor, HγG, and anti-Ro/SSA and anti-La/SSB antibodies, are a hallmark of pSS [2]. The proportion of peripheral B cell subsets, such as CD27+IgM+IgD+ and CD27+IgM−IgD− memory B cells, are reduced in pSS compared to healthy controls (HC) and patients with rheumatoid arthritis and systemic lupus erythematosus [3, 4], suggesting that these memory B cell subsets may be recruited to glandular tissues, where they differentiate into plasmablasts and plasma cells and produce IgG [5]. We reported that the production of BAFF (B cell-activating factor) and IL-6, both of which are involved in survival and differentiation of B cells, is dysregulated in monocytes of patients with primary Sjögren’s syndrome (pSS). We investigate the relationship between possible aberrations of pSS monocytes and clinical features of pSS patients and the contribution of monocytes to B cell activation, a mechanism involved in the pathogenesis of pSS
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