Back to Search Start Over

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

Authors :
Gu, Shuangshuang
Zhang, Jinsong
Han, Xiaxia
Ding, Huihua
Yao, Chao
Ye, Zhizhong
Yin, Zhihua
Hou, Guojun
Jiang, Yang
Qian, Jie
Zhou, Haibo
Guo, Qiang
Chen, Sheng
Dai, Dai
Shen, Nan
Source :
Arthritis & Rheumatology; Aug2023, Vol. 75 Issue 8, p1381-1394, 14p
Publication Year :
2023

Abstract

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 production. Pbx1‐deficient B cells had increased survival and proliferative advantages after 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; when PBX1 expression was enforced, the survival and proliferative capacity of SLE B cells were attenuated. Conclusion: Our study reveals the regulatory function and mechanism of Pbx1 in adjusting B cell homeostasis and highlights Pbx1 as a therapeutic target in SLE. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
23265191
Volume :
75
Issue :
8
Database :
Complementary Index
Journal :
Arthritis & Rheumatology
Publication Type :
Academic Journal
Accession number :
168591135
Full Text :
https://doi.org/10.1002/art.42487