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

• DOI: 10.1126/sciadv.abj2797
• Publication Date: 2022-01-19T18:59:26Z
• Authors: Wei-Yun Shen; Cong Luo; Plinio Reinaldo H...; 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
• Keywords: B-Lymphocytes; pathogenesis; Brain-Derived Neurotrophic Factor; Antigens, CD19; Receptors, Nerve Growth Factor; Up-Regulation; 3. Good health; Mice, Inbred C57BL; proBDNF; Mice; systemic lupus erythematosus; Animals; Humans; Lupus Erythematosus, Systemic; Biomedicine and Life Sciences; Autoantibodies

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 (p75 NTR ) are highly expressed in CD19 + CD27 hi CD38 hi ASCs in patients with SLE and in CD19 + CD44 hi CD138 + 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 p75 NTR 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 p75 NTR also inhibits ASC differentiation and antibody production in vitro. Together, these findings suggest that proBDNF-p75 NTR signaling plays a critical pathogenic role in SLE through promoting ASC dysfunction.