Elevated expression of BAFF receptor, BR3, on monocytes correlates with B cell activation and clinical features of patients with primary Sjögren's syndrome

Abstract

Background: 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). 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. Methods: Expression 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. Results: The 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. Conclusions: Our 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.