University of Alabama-Birmingham Birmingham, AL, United States
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Kathryn Sullivan, Yong Wang, Winn Chatham, John Mountz and Hui-chen Hsu, University of Alabama at Birmingham, Birmingham, AL
Background/Purpose: While systemic lupus erythematosus (SLE) disproportionally affects women versus men, elevation in 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.
Methods: Serum levels of E2 and anti-Smith (Sm), and expression of IFNb in naïve B cells were evaluated in African American (AA) SLE patients (24-41yr-old), compared to older AA (42-56yr-old) and European American SLE patients (24-66-yr-old). Similarly, serum levels of E2, anti-Smith (Sm), anti-DNA, and anti-Sm/RNP were compared between female lupus prone BXD2 mice post-puberty (12-wk-old) versus pre-puberty (4-6-wk-old). TLR7-induced expression of interferon-beta (IFNb) and CD69 in transitional stage 1 (T1: CD23-IgM+ CD93+) B cells after stimulation with E2 with or without TLR7 agonist R848 were evaluated using female BXD2 mice, compared to male mice.
Results: We identified that there were 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 (24-66-yr-old). Circulating E2 levels positively correlated with the levels of anti-Smith (Sm) and the expression of IFNb in naïve B cells of SLE patients (n=39). Mouse studies were used to determine if E2 stimulates the expression of IFNb 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 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 interferon-beta (IFNb) 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 IFNb and TLR7 in T1 B cells from female but not male BXD2 mice.
Conclusion: Together, our results suggest that elevation of E2 in combination with an increased B-cell susceptibility to E2 induction of IFNb may play a role in the increased B cell responses to TLR7 stimulation in individuals predisposed to the development of SLE.
K. Sullivan: None; Y. Wang: None; W. Chatham: None; J. Mountz: None; H. Hsu: None.
