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

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 (Brd4(flox/flox)CD19-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 Brd4(flox/flox)CD19-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.

Automated summary

The role of bromodomain-containing protein 4 (Brd4) in regulating B cell differentiation and its potential as a therapeutic target for B cell-mediated autoimmune diseases, including systemic lupus erythematosus (SLE), were investigated. Brd4 inhibitor was found to suppress plasma cell differentiation in human B cells and reduce the secretion of IgG and IgM. The study also found that Brd4 regulates the expression of B lymphocyte-induced maturation protein 1 (BLIMP1), an important transcription factor involved in plasma cell differentiation. Inhibition of Brd4 showed potential in reducing plasma cells and attenuating nephritis in animal models and SLE patients.