The suppression of Brd4 inhibits peripheral plasma cell differentiation and exhibits therapeutic potential for systemic lupus erythematosus

Abstract

The mechanisms that control B cell terminal differentiation remain undefined. Here, we investigate the role of bromodomain-containing protein 4 (Brd4) in regulating B cell differentiation and its therapeutic potential for B cell-mediated autoimmune diseases including systemic lupus erythematosus (SLE). We showed that Brd4 inhibitor PFI-1 suppressed plasmablast-mediated plasma cell differentiation in healthy human CD19+ B cells. PFI-1 reduced IgG and IgM secretion in costimulation-induced human B cells. We also observed a reduced percentage of plasma cells in mice with B cell-specific deletion of the Brd4 gene (Brd4flox/floxCD19-cre+). Mechanistically, using the luciferase reporter assay and the chromatin immunoprecipitation, we explored that Brd4 regulates the expression of B lymphocyte-induced maturation protein 1 (BLIMP1), an important transcript factor that is involved in modulation of plasma cell differentiation. Interestingly, PFI-1 decreased the percentages of plasmablasts and plasma cells from patients with SLE. PFI-1 administration reduced the percentages of plasma cells, hypergammaglobulinemia, and attenuated nephritis in MRL/lpr lupus mice. Pristane-injected Brd4flox/floxCD19-cre+ mice exhibited improved nephritis and reduced percentages of plasma cells. These findings suggest an essential factor of Brd4 in regulating plasma cell differentiation. Brd4 inhibition may be a potential strategy for the treatment of B cell-associated autoimmune disorders.