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) are highly expressed in CD19CD27CD38 ASCs in patients with SLE and in CD19CD44CD138 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 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 also inhibits ASC differentiation and antibody production in vitro. Together, these findings suggest that proBDNF-p75 signaling plays a critical pathogenic role in SLE through promoting ASC dysfunction.
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| http://dx.doi.org/10.1126/sciadv.abj2797 | DOI Listing |
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