17?-estradiol and B-cell intrinsic type I interferon amplify toll-like receptor 7 signaling loop in B cells of female lupus prone BXD2 mice

Abstract While systemic lupus erythematosus (SLE) disproportionally affects women versus men, elevation in 17β -estradiol (E2) alone is not sufficient to promote the development of autoantibody producing B cells. The objective of the present study is to determine if B-cell intrinsic mechanisms contribute to the increased TLR7 response to E2 stimulation. We identified that there were elevated circulating levels of E2 in young African American (AA) SLE patients (24–41 yr-old), compared to older AA (42–56 yr-old) and European American SLE patients (24–66 yr-old). Circulating E2 levels positively correlated with the levels of anti-Smith (Sm) and the expression of interferon-beta (IFNβ) in naïve B cells of SLE patients (n=39). Mouse studies were used to determine if E2 stimulates the expression of IFNβ in B cells and if sex plays a role to influence B cell responses to E2. Serum levels of Sm/RNP and RNP autoantibodies positively correlated with the levels of E2 in female lupus prone BXD2 mice post-puberty (12-wk-old) but not pre-puberty (4–6-wk-old). At the post-puberty stage (>12 wk-old), there were significantly elevated levels of anti-DNA and anti-Sm in female BXD2 mice, compared to male mice. This was associated with an increased TLR7-induced expression of IFNβ and CD69 in transitional stage 1 (T1: CD23 −IgM +CD93 +) B cells in female BXD2 mice, compared to male mice. Interestingly, E2 stimulation promoted intracellular levels of IFNβ and TLR7 in T1 B cells from female but not male BXD2 mice. Together, our results suggest that elevation of E2 in combination with an increased B-cell susceptibility to E2 induction of IFNβ may play a role in the increased B cell responses to TLR7 stimulation in individuals predisposed to the development of SLE. This study was supported by grants from VA Merit Review grant (I01BX004049), NIH grants R01-AI-071110, R01 AI134023, and Lupus Research Alliance Distinguished Innovator Award to J.D.M, the LRA Target Identification in Lupus Award to H-C.H., and the P30-AR-048311