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LO-007 EZH2 deficiency in B cells impairs plasmablast differentiation and ameliorates lupus-like disease in mice
  1. Xiaoqing Zheng1,
  2. Mikhail Dozmorov2,
  3. Colleen Strohlein1,
  4. Sheldon Bastacky3 and
  5. Amr Sawalha1
  1. 1Division of Rheumatology, Departments of Pediatrics and Medicine, University of Pittsburgh, USA
  2. 2Department of Biostatistics, Virginia Commonwealth University, USA
  3. 3Department of Pathology, University of Pittsburgh, USA


Background Enhancer of zeste homolog 2 (EZH2) is an epigenetic regulator with a role in B cell development. We have previously demonstrated increased EZH2 expression in peripheral blood mononuclear cells isolated from lupus patients, and that pharmacological inhibition of EZH2 alleviates lupus-like disease in mouse models. The goal of this study was to evaluate the role of B cell EZH2 overexpression in lupus pathogenesis.

Methods Using CRISPR/Cas9 technology, we generated an MRL/lpr mouse with floxed Ezh2, which was crossed with CD19-Cre mice. Autoantibody production, proteinuria, and kidney histology were evaluated. Flow cytometry, single cell RNA sequencing, and single cell B cell receptor sequencing were used to investigate compositional and functional changes of B cell subsets. In vitro B cell culture with/without an XBP1 inhibitor was performed. EZH2 and XBP1 mRNA levels in CD19+ B cells isolated from SLE patients and healthy controls were analyzed.

Results Ezh2 deletion in B cells decreased autoantibody production and improved glomerulonephritis in MRL/lpr mice. B cell development and differentiation were altered in the bone marrow and spleen in EZH2-deficient mice. Differentiation of germinal center (GC) B cells and plasmablasts was impaired. XBP1, a key transcription factor in B cell development, was downregulated in the absence of EZH2, and inhibiting XBP1 in vitro impairs plasmablast differentiation similar to EZH2-deficient mice. Single cell B cell receptor RNA sequencing revealed defective immunoglobulin class switch recombination in EZH2-deficient mice. In human lupus B cells, there was a strong correlation between EZH2 and XBP1 mRNA expression levels.

Conclusions Our results suggest that EZH2 overexpression in B cells contributes to disease pathogenesis in lupus. EZH2 enhances GC B cell development and the differentiation of plasmablasts via upregulating XBP1. Inhibiting B cell EZH2 expression impairs B cell development and immunoglobulin class switch recombination, and might provide a novel therapeutic approach in lupus.

  • EZH2
  • B cells
  • Epigenetics

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