INTRODUCTION
The generation of antibodies is one of the most important roles of B
cells and is the basis for autoantibody-mediated autoimmune disorders.
The modulation of antibody production is associated with the generation
and maintenance of terminally differentiated B cells, known as
plasmablasts and plasma cells, from their B cell precursors(Carsetti,
Rosado et al., 2004; Nutt, Hodgkin et al., 2015). Activated B cells have
the ability to proliferate, undergo immunoglobulin class-switch
recombination, and differentiate into plasmablasts that express high
levels of IRF4 and X-box-binding protein 1 (XBP1) and medium levels of B
lymphocyte-induced maturation protein 1 (BLIMP1)(Radbruch, Muehlinghaus
et al., 2006; Shlomchik & Weisel, 2012). BLIMP1 is a critical
transcriptional repressor that promotes the terminal differentiation of
B cells and plays an essential role in the formation of mature plasma
cells (Nutt, Taubenheim et al., 2011; Shapiro-Shelef, Lin et al., 2003).
However, the mechanisms that control B cell terminal differentiation are
complex and remain incompletely understood.
Systemic lupus erythematosus (SLE) is an autoimmune disorder
characterized by increased levels of pathogenic autoantibodies. Multiple
defective checkpoints during B cell development, maturation, and
activation have been demonstrated in SLE patients (Cappione, Anolik et
al., 2005; Yurasov, Tiller et al., 2006; Yurasov, Wardemann et al.,
2005) and mouse lupus models(Grimaldi, Cleary et al., 2002; Grimaldi,
Michael et al., 2001; Santulli-Marotto, Qian et al., 2001). It is well
recognized that B cells are important for both the initiation and
maintenance of autoimmunity in SLE, and B cell-targeting therapies may
be beneficial for patients with SLE(Parodis, Stockfelt et al., 2020;
Reddy, Cambridge et al., 2015).
As a family of epigenetic adaptors, bromodomain and extraterminal domain
(BET) proteins (Brd2, Brd3, Brd4, and Brdt) can bind to acetylated
lysine residues and link acetylated chromatin and gene transcription
(Filippakopoulos, Picaud et al., 2012). BET bromodomain inhibition
modulates the differentiation and activation of T cells(Bandukwala,
Gagnon et al., 2012; Mele, Salmeron et al., 2013) and dendritic cells
(Toniolo, Liu et al., 2015), which suggests that BET proteins may be
involved in adaptive immune responses. A previous finding indicated a
role of Brd2 in promoting the expansion and mitogenesis of murine B
cells (Belkina, Blanton et al., 2014); however, to date, it remains
undefined whether BET bromodomains regulate the differentiation of B
cell subsets and have therapeutic potential in B cell-associated
autoimmune disorders. Because Brd4 is the most studied BET protein, we
herein aimed to determine the involvement of Brd4 in regulating the
differentiation of B cell subsets and to further explore its possible
therapeutic potential for B cell-mediated autoimmune diseases such as
SLE.