Based on our finding that ERα is required for the female sex bias in Sle1-induced loss of tolerance and immune cell hyperactivation and the observation that the effects of the Sle1 subloci show varying degrees of female sex bias, we hypothesize that ERα signaling synergizes with the pathways controlled by certain Sle1 subloci to preferentially enhance loss of tolerance, immune cell activation, and ultimately the development of lupus in females. Here, ESR1 is linked to systemic lupus erythematosus.