Clinical relevance of circulating anti‐ENA and anti‐dsDNA secreting cells from SLE patients and their dependence on STAT‐3 activation

Disturbances of plasma cell homeostasis and auto‐antibody production are hallmarks of systemic lupus erythematosus. The aim of this study was to explore the presence of circulating anti‐ENA and anti‐dsDNA antibody‐secreting cells, to determine their dependence on plasma cell‐niche cytokines and to analyze their clinical value. The study was performed in SLE patients with serum anti‐ENA and/or anti‐dsDNA antibodies (n = 57). Enriched B‐cell fractions and sorted antibody‐secreting cells (CD19^lowCD38^high) were obtained from blood. dsDNA‐ and ENA‐specific antibody‐secreting cells were identified as cells capable of active auto‐antibody production in culture. The addition of a combination of IL‐6, IL‐21, BAFF, APRIL, and CXCL12 to the cultures significantly augmented auto‐antibody production and antibody‐secreting cell proliferation, whereas it diminished apoptosis. The effect on auto‐antibody production was dependent on STAT‐3 activation as it was abrogated in the presence of the JAK/STAT‐3 pathway inhibitors ruxolitinib and stattic. Among patients with serum anti‐dsDNA antibodies, the detection of circulating anti‐dsDNA‐antibody‐secreting cells was associated with higher disease activity markers. In conclusion, auto‐antibody production in response to plasma cell‐niche cytokines that are usually at high levels in SLE patients is dependent on JAK/STAT‐3 activation. Thus, patients with circulating anti‐dsDNA antibody‐secreting cells and active disease could potentially benefit from therapies targeting the JAK/STAT3 pathway.