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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