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

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 (p75^NTR) are highly expressed in CD19⁺CD27^hiCD38^hi ASCs in patients with SLE and in CD19⁺CD44^hiCD138⁺ 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.