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.

Abnormal Changes of Monocyte Subsets in Patients With Sjögren’s Syndrome

“…Recent studies have proven the existence of distinct monocyte subsets and they have critical roles in the development of some rheumatic diseases such as SLE and rheumatoid arthritis (RA), and targeting monocytes is a potential treatment for those diseases (17,33). There are also some studies focusing on the roles of monocytes in SjS, and some have shown that aberrant changes in immunophenotypes, intracellular functional pathways and epigenetics exist in SjS patients (20)(21)(22)(23)(24). Those outcomes suggest the key roles of monocytes in the development and progression of SjS, though the underlying mechanisms are largely elusive.…”

“…For instance, monocytes can participate in the pathogenesis of SLE by immune mechanisms such as secreting pro-inflammatory cytokines and assisting in the activation of B cells and T cells (16)(17)(18)(19). In recent years, the roles of monocytes in the pathogenesis of SjS have also gained increased attentions, and some studies have proved possible key roles of monocytes in the development and progression of SjS (20)(21)(22)(23)(24). However, the mechanisms of monocytes in SjS have not been fully clarified, and further research is required.…”

Pleiotropic effects of BAFF on the senescence-associated secretome and growth arrest

“…We validated the increase of BAFF mRNA and protein in multiple senescent models ( Figures 1 and Figure 1—figure supplement 1 ) and found that IRF1 transcriptionally elevated BAFF mRNA levels in senescence ( Figures 2 and Figure 2—figure supplement 1 ). Given that BAFF is mainly produced by monocytes (Yoshimoto et al 2011; Yoshimoto et al 2020), we focused on the induction of BAFF in the monocytic cell line THP-1. Transcriptomic and proteomic analyses suggested a role for BAFF in monocyte activation and inflammation in senescence ( Figures 3 and Figure 3— figure supplement 1 ), as BAFF depletion led to a striking reduction in the production of SASP factors in irradiated THP-1 cells, while BAFF overexpression or ectopic addition of BAFF increased the secretion of pro-inflammatory molecules ( Figures 4 and Figure 4—figure supplement 1 ).…”

Longitudinal analysis of symptom-based clustering in patients with primary Sjogren’s syndrome: a prospective cohort study with a 5-year follow-up period

“…Nevertheless, symptom variables might not be objective parameters associated with the pathogenic mechanism of pSS. Subclassification of patients with pSS has focused on molecular signatures that appear to be more associated with pathogenesis of the disease [ 2 , 12 – 15 ]. James et al found that transcriptional modules identified three clusters with differences in interferon, inflammation modules, and molecules, such as CXCL10, CXCL9, and BAFF [ 16 ].…”