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The suppression of Brd4 inhibits peripheral plasma cell differentiation and exhibits therapeutic potential for systemic lupus erythematosus
  • +11
  • Shan Zeng,
  • Qian Qiu,
  • Yi Zhou,
  • Youjun Xiao,
  • Jingnan Wang,
  • Ruiru Li,
  • Siqi Xu,
  • Maohua Shi,
  • Cuicui Wang,
  • Yu Kuang,
  • Minxi Lao,
  • Xiaoyan Cai,
  • liuqin liang,
  • Hanshi Xu
Shan Zeng
Sun Yat-Sen University

Corresponding Author:zs760103@126.com

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Qian Qiu
Sun Yat-Sen University
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Yi Zhou
Sun Yat-Sen University
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Youjun Xiao
Sun Yat-Sen University
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Jingnan Wang
Sun Yat-Sen University
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Ruiru Li
Sun Yat-Sen University
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Siqi Xu
Sun Yat-Sen University
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Maohua Shi
Sun Yat-Sen University
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Cuicui Wang
Sun Yat-Sen University
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Yu Kuang
Sun Yat-Sen University
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Minxi Lao
Sun Yat-Sen University
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Xiaoyan Cai
Sun Yat-Sen University
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liuqin liang
Sun Yat-Sen University
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Hanshi Xu
Sun Yat-Sen University
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Abstract

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.
Feb 2022Published in International Immunopharmacology volume 103 on pages 108498. 10.1016/j.intimp.2021.108498