Involvement of Transcriptional Factor Pbx1 in Peripheral B Cell Homeostasis to Constrain Lupus Autoimmunity

作者：Shuangshuang Gu, Jinsong Zhang, Xiaxia Han, Huihua Ding, Chao Yao, Zhizhong Ye, Zhihua Yin, Guojun Hou, Yang Jiang, Jie Qian, Haibo Zhou, Qiang Guo, Sheng Chen, Dai Dai, Nan Shen · 发表于：Arthritis & Rheumatology · 年份：2023 · DOI：10.1002/art.42487 · 被引用次数：18 · 研究领域：T-cell and B-cell Immunology、Diabetes and associated disorders、Pancreatic function and diabetes

OBJECTIVE: Disruption of B cell homeostasis and subsequent dominance of effector B cell subsets are critical for the development of systemic lupus erythematosus (SLE). Revealing the key intrinsic regulators involved in the homeostatic control of B cells has important therapeutic value for SLE. This study was undertaken to determine the regulatory role of the transcription factor Pbx1 in B cell homeostasis and lupus pathogenesis. METHODS: We constructed mice with B cell-specific deletion of Pbx1. T cell-dependent and T cell-independent humoral responses were induced by intraperitoneal injection of nitrophenyl-containing hapten (NP) conjugated to keyhole limpet hemocyanin or NP-Ficoll. The regulatory effects of Pbx1 on autoimmunity were observed in a Bm12-induced lupus murine model. We investigated mechanisms of Pbx1 using RNA sequencing, the cleavage under targets and tagmentation assay, and chromatin immunoprecipitation-quantitative polymerase chain reaction assay. We transduced B cells from SLE patients with plasmids that overexpressed PBX1 to explore the in vitro therapeutic efficacy of PBX1. RESULTS: Pbx1 was specifically down-regulated in autoimmune B cells and negatively correlated with disease activity. The deficiency of Pbx1 in B cells resulted in excessive humoral responses following immunization. In the Bm12-induced lupus model, mice with B cell-specific Pbx1 deficiency displayed enhancements in germinal center responses, plasma cell differentiation, and autoantibody...