Background and purpose: To investigate the role of
bromodomain-containing protein 4 (Brd4) in regulating B cell
differentiation and its therapeutic potential for B cell-mediated
autoimmune diseases such as systemic lupus erythematosus (SLE).
Experimental Approach: Human and murine B cells were purified and
cultured with different stimuli. B cell surface markers, proliferation
and apoptosis were estimated by flow cytometry. Gene expression was
measured by quantitative real-time PCR. Brd4 binding sites were analysed
by the luciferase reporter assay and the chromatin immunoprecipitation
(ChIP) assay. PFI-1 or JQ1 was used to inhibit Brd4. Mice with B
cell-specific deletion of the Brd4 gene (Brd4flox/floxCD19-Cre+/-) and
MRL/lpr mice were used to perform the in vivo experiments. Key Results:
Brd4 inhibition suppressed plasmablast-mediated plasma cell
differentiation but did not influence proliferation or apoptosis in
healthy human and murine CD19+ B cells. PFI-1 treatment reduced the
secretion of IgG and IgM in the supernatants of costimulation-induced B
cells. Mechanistically, Brd4 regulates the terminal differentiation of B
cells into plasma cells by targeting BLIMP1 by directly binding and
activating the endogenous BLIMP1 promoter. Interestingly, PFI-1
treatment 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
mice. Pristane-injected Brd4flox/floxCD19-Cre+/- mice exhibited improved
nephritis and reduced percentages of plasma cells. Conclusions and
Implications: Brd4 is an essential factor in regulating plasma cell
differentiation. Brd4 inhibition may be a potential new strategy for the
treatment of B cell-associated autoimmune disorders, including SLE.
IL-21 acts as a promising therapeutic target in systemic lupus erythematosus by regulating plasma cell differentiation