Environmental exposure, estrogen and two X chromosomes are required for disease development in an epigenetic model of lupus

► We examined how genes, environment, and hormones influence female lupus susceptibility. ► Environmental agents suppress ERK signaling, epigenetically activating immune genes. ► Transgenic female but not male mice with an inducible ERK defect developed lupus. ► Suppressing ERK epigenetically activated X-chromosome CD40L and kirl1 genes in females. ► Female predisposition required estrogen, two X chromosomes and ERK suppression.