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The dramatic female sex bias observed in human lupus is thought to be due, at least in part, to estrogens. Using mouse models, we have shown that estrogens, acting through estrogen receptor alpha (ERα) promote lupus development and contribute significantly to the female sex bias observed in this disease. C57Bl/6 (B6) mice carrying the lupus susceptibility locus  Sle1  locus exhibit immune cell hyperactivation and loss of tolerance, and the action of  Sle1  displays a strong female sex bias. Previously, we showed that disruption of ERα completely eliminates the female sex bias in the effects of  Sle1 . Here we report that ERα signaling selectively modulates the action of  Sle1b , one of the three subloci that together constitute  Sle1 . We observed that disruption of ERα signaling attenuated T cell hyperactivation, formation of spontaneous germinal centers, loss of tolerance, and the development of anti-chromatin autoantibodies in B6. Sle1b  female mice, but had no impact on these phenotypes in B6. Sle1b  male mice. In fact, disruption of ERα completely abolished the female sex bias that is seen in each of these phenotypes in B6. Sle1b  mice. Strikingly,  Sle1b -induced B cell hyperactivation, a female sex-specific manifestation of  Sle1b , was completely abrogated by disruption of ERα in B6. Sle1b  females. Altogether, these results demonstrate that ERα signaling is responsible for the female sex bias in the actions of  Sle1b , and is absolutely required for the female-specific B cell hyperactivation phenotype associated with this lupus susceptibility locus. By contrast, we found that ERα signaling had no impact on  Sle1a , the other  Sle1  sublocus that exerts effects that show a female sex bias.

frontiers in immunology

Estrogen Receptor Alpha Signaling Is Responsible for the Female Sex Bias in the Loss of Tolerance and Immune Cell Activation Induced by the Lupus Susceptibility Locus Sle1b