Abstract Text: While systemic lupus erythematosus (SLE) disproportionally affects women versus men, estradiol (E2) elevation alone is not sufficient to promote development of autoantibody producing B cells. The objective of this study is to determine if B-cell intrinsic mechanisms contribute to increased TLR7 response to E2 stimulation. We identified elevated circulating levels of E2 in young African American (AA) SLE patients (24-41yr-old), compared to older AA (42-56yr-old) and European American SLE patients (24-66yr-old). Circulating E2 levels positively correlated with levels of anti-Smith (Sm) and expression of IFN-beta in naïve B cells of SLE patients (n=39). Mouse studies were used to determine if E2 stimulates expression of IFN-beta in B cells, and if sex plays a role to influence B cell responses to E2. Serum levels of Sm/RNP and RNP autoAbs positively correlated with levels of E2 in female lupus prone BXD2 mice post-puberty (12wk-old) but not pre-puberty (4-6wk-old). At the post-puberty stage (>12wk-old), there were significantly elevated levels of anti-DNA and anti-Sm in female BXD2 mice, compared to males. This was associated with increased TLR7-induced expression of IFN-beta and CD69 in transitional stage 1 (T1: CD23-IgM+ CD93+) B cells in female BXD2 mice, compared to males. E2 stimulation promoted intracellular levels of IFN-beta and TLR7 in T1 B cells from female but not male BXD2 mice. Our results suggest that elevation of E2 in combination with increased B-cell susceptibility to E2 induction of IFN-beta may play a role in increased B cell responses to TLR7 stimulation in individuals predisposed to developing SLE.
