IL-21 enhances STAT3/Blimp-1 signaling pathway in B cells and contributes to plasma cell differentiation in newly diagnosed patients with myasthenia gravis

Abstract

The transcription factor Blimp-1 is necessary for the B cell differentiation toward immunoglobulin-secreting plasma cells. However, the immunopathological mechanisms of Blimp-1 that regulates B cell differentiation remain unclear in MG. The purpose of this study was to perform a quantitative and functional analysis of Blimp-1 in MG. A total of 34 patients with MG (18 ocular MG (OMG) and 16 generalized MG (GMG) and 20 healthy controls (HC) were recruited in this study. CD19⁺ B cells were isolated by positive selection using CD19 beads. The expression of Blimp-1 and p-STAT3 protein in isolated B cells was assessed by Western blot. Plasma cells were analyzed by flow cytometry. Serum IL-21 levels were detected by ELISA. Our data demonstrated that Blimp-1 in peripheral blood B cell of MG patients was significantly increased compared with HC. The increased expression of Blimp-1 was positively associated with clinical severity score (QMGs), plasma cell frequency, and serum IL-21 levels. Furthermore, glucocorticoid (GC) treatment reduced the expression of Blimp-1 and p-STAT3 in B cells, and this change was accompanied with relieved clinical severity, reduced plasma cell frequency, and decreased serum IL-21 levels. In vitro assay demonstrated that IL-21 stimulation upregulated STAT3 phosphorylation, increased Blimp-1 expression in B cells, and promoted plasma cell differentiation, and these processes could be inhibited by dexamethasone or STAT3 inhibitor stattic. This work indicates for the first time that aberrant expression of Blimp-1 exists on B cells and contributes to the plasma cell differentiation in MG patients. Modulation of IL-21/STAT3/Blimp-1 signaling pathway in B cells may be one of the mechanisms of glucocorticoid in the treatment of MG.

Keywords: B cells; Blimp-1; IL-21; Myasthenia gravis; Plasma cell; STAT-3.