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.