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LSO-002 The transcriptional factor Pbx1 adjusts peripheral B cell homeostasis to constrain lupus autoimmunity
  1. Dai Dai1,
  2. Shuangshuang Gu1 and
  3. Nan Shen1,2
  1. 1Shanghai Institute of Rheumatology, Shanghai Renji Hospital, Shanghai Jiaotong University School of Medicine, China
  2. 2Center of Autoimmune Genomics and Etiology, Cincinnati Children’s Hospital Medical Center, USA


Background 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 aims to uncover the regulatory role of the transcription factor Pbx1 in B-cell homeostasis and to provide new targets for SLE treatment.

Methods We constructed mice with B-cell-specific deletion of Pbx1. T-cell-dependent and independent humoral responses were induced by intraperitoneal injection of NP-KLH or NP-Ficoll. The regulatory effects of Pbx1 on autoimmunity were observed in a Bm12-induced lupus model. Mechanisms were investigated by combined analysis of RNA-sequencing, Cut&Tag, and Chip-qPCR assay. B-cells from SLE patients were transduced with Pbx1 overexpression plasmids to explore the in vitro therapeutic efficacy.

Results Pbx1 was specifically downregulated 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 a Bm12-induced lupus model, mice with B-cell-specific Pbx1 deficiency displayed enhancements in germinal center responses, plasma cell differentiation, and autoantibody production. Pbx1-deficient B-cells gained a survival advantage upon activation. Pbx1 regulated genetic programs by directly targeting critical components of the proliferation and apoptosis pathways. In SLE patients, PBX1 expression was negatively correlated with effector B-cell expansion and enforced PBX1 expression attenuated the survival capacity of SLE B-cells.

Conclusions Our study reveals the regulatory function and mechanism of Pbx1 in adjusting B-cell homeostasis and highlights Pbx1 as a therapeutic target in SLE.

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