The study investigates the role of X-chromosome inactivation (XCI) in the development of autoimmune diseases, particularly in females. XCI is an epigenetic mechanism that ensures the silencing of one X chromosome in females, but it can be perturbed by changes in the expression of the noncoding RNA Xist. The researchers used female mice with a deletion of the Ftx gene, which impairs XCI, to examine the impact on immune function. They found that this impairment led to the reactivation of genes on the inactive X chromosome, including those involved in the Toll-like receptor 7 (TLR7) signaling pathway, in various immune cells such as monocytes/macrophages, dendritic cells, and B cells. This resulted in the spontaneous development of inflammatory signs typical of lupus, including increased levels of autoantibodies, expanded populations of age-associated and germinal center B cells, and increased monocyte/macrophage and dendritic cell counts. Mechanistically, TLR7 signaling was dysregulated in macrophages, leading to sustained expression of target genes upon stimulation. These findings provide a direct link between altered XCI and female-biased autoimmune manifestations, highlighting the potential role of XCI maintenance in the regulation of immune responses.The study investigates the role of X-chromosome inactivation (XCI) in the development of autoimmune diseases, particularly in females. XCI is an epigenetic mechanism that ensures the silencing of one X chromosome in females, but it can be perturbed by changes in the expression of the noncoding RNA Xist. The researchers used female mice with a deletion of the Ftx gene, which impairs XCI, to examine the impact on immune function. They found that this impairment led to the reactivation of genes on the inactive X chromosome, including those involved in the Toll-like receptor 7 (TLR7) signaling pathway, in various immune cells such as monocytes/macrophages, dendritic cells, and B cells. This resulted in the spontaneous development of inflammatory signs typical of lupus, including increased levels of autoantibodies, expanded populations of age-associated and germinal center B cells, and increased monocyte/macrophage and dendritic cell counts. Mechanistically, TLR7 signaling was dysregulated in macrophages, leading to sustained expression of target genes upon stimulation. These findings provide a direct link between altered XCI and female-biased autoimmune manifestations, highlighting the potential role of XCI maintenance in the regulation of immune responses.