Sex-dependent regulation of B cell tolerance by the miR-130b-ERα axis

Autoimmune diseases represent a timely health challenge due to their increasing incidence and lack of definitive cures. Autoreactive B cells play essential roles in several autoimmune diseases, including multiple sclerosis, lupus erythematosus and rheumatoid arthritis, which are more prevalent in women than men. However, the molecular mechanisms regulating these cells remain largely unknown. In this study, we identified miR-130b as a critical regulator of B cell tolerance through its suppression of Estrogen Receptor Alpha (ERα). Elevated levels of miR-130b impaired the elimination of autoreactive B cells by clonal deletion via downregulation of ESR1 (which encodes ERα) and PTEN, allowing their escape into peripheral tissues where they can contribute to autoimmunity. Deficiency in ERα expression alone was sufficient to allow the escape of self-reactive B cells to periphery in female, but not male, mice. Furthermore, elevated levels of miR-130b in patients with multiple sclerosis associated with increased disease activity and severity. Our findings reveal a previously unknown miR-130b-ERα axis that regulates B cell tolerance in a sex-specific manner and open new avenues to improve diagnosis and treatment of autoimmune diseases.