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Up-regulation of proBDNF/p75 NTR signaling in antibody-secreting cells drives systemic lupus erythematosus

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2022

Sci Adv. 2022 Jan 21;8(3):eabj2797. doi: 10.1126/sciadv.abj2797. Epub 2022 Jan 19.

Up-regulation of proBDNF/p75 NTR signaling in antibody-secreting cells drives systemic lupus erythematosus

Wei-Yun Shen, Cong Luo, Plinio Reinaldo Hurtado, Xiao-Jing Liu, Ru-Yi Luo, Hui Li, Zhao-Lan Hu, Jun-Mei Xu, Elizabeth J Coulson, Ming Zhao, Xin-Fu Zhou, Ru-Ping Dai

Department of Anesthesiology, The Second Xiangya Hospital, Central South University, 139 Ren-Min Central Road, Changsha City, Hunan 410011, China. Department of Renal Medicine, Royal Adelaide Hospital, Adelaide, SA 5000, Australia. Queensland Brain Institute, The University of Queensland, 4072 Brisbane, Australia. Department of Dermatology, Hunan Key Laboratory of Medical Epigenomics, The Second Xiangya Hospital, Central South University, 139 Ren-Min Central Road, Changsha City, Hunan 410011, China. School of Pharmacy and Medical Sciences, Division of Health Sciences, University of South Australia, Adelaide, SA 5000, Australia.

Service type: Knock-in mice

Abstract

Inappropriate expansion of antibody-secreting cells (ASCs) is typical of systemic lupus erythematosus (SLE), but the regulatory signaling of pathogenic ASCs is unclear. The present study shows that brain-derived neurotrophic factor precursor (proBDNF) and its high-affinity pan-75 neurotrophin receptor (p75NTR) are highly expressed in CD19+CD27hiCD38hi ASCs in patients with SLE and in CD19+CD44hiCD138+ ASCs in lupus-like mice. The increased proBDNF+ ASCs were positively correlated with clinical symptoms and higher titers of autoantibodies in SLE. Administration of monoclonal antibodies against proBDNF or specific knockout of p75NTR in CD19+ B cells exerted a therapeutic effect on lupus mice by limiting the proportion of ASCs, reducing the production of autoantibodies and attenuating kidney injury. Blocking the biological function of proBDNF or p75NTR also inhibits ASC differentiation and antibody production in vitro. Together, these findings suggest that proBDNF-p75NTR signaling plays a critical pathogenic role in SLE through promoting ASC dysfunction.

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