X-chromosome inactivation (XCI) is a key epigenetic mechanism that silences one X chromosome in females, contributing to sex differences in immune responses. A study shows that disrupting XCI in female mice leads to the reactivation of genes on the inactive X, including those involved in the Toll-like receptor 7 (TLR7) signaling pathway. This results in autoimmune manifestations similar to lupus, such as anti-nucleic acid autoantibodies, increased B cell populations, and expanded monocyte/macrophage and dendritic cells. Mechanistically, TLR7 signaling is dysregulated in macrophages, leading to sustained expression of target genes upon stimulation. These findings establish a direct link between XCI maintenance and female-biased autoimmune manifestations, highlighting altered XCI as a cause of autoimmunity. The study also shows that XCI perturbation in female mice leads to splenomegaly, increased inflammatory markers, and autoantibody production, suggesting that XCI alterations may contribute to autoimmune diseases. The research underscores the role of X-linked genes in immune function and autoimmunity, and highlights the importance of XCI in maintaining immune balance. The study provides insights into the molecular mechanisms underlying XCI and its impact on immune function, and suggests that XCI alterations may be a potential therapeutic target for autoimmune diseases.X-chromosome inactivation (XCI) is a key epigenetic mechanism that silences one X chromosome in females, contributing to sex differences in immune responses. A study shows that disrupting XCI in female mice leads to the reactivation of genes on the inactive X, including those involved in the Toll-like receptor 7 (TLR7) signaling pathway. This results in autoimmune manifestations similar to lupus, such as anti-nucleic acid autoantibodies, increased B cell populations, and expanded monocyte/macrophage and dendritic cells. Mechanistically, TLR7 signaling is dysregulated in macrophages, leading to sustained expression of target genes upon stimulation. These findings establish a direct link between XCI maintenance and female-biased autoimmune manifestations, highlighting altered XCI as a cause of autoimmunity. The study also shows that XCI perturbation in female mice leads to splenomegaly, increased inflammatory markers, and autoantibody production, suggesting that XCI alterations may contribute to autoimmune diseases. The research underscores the role of X-linked genes in immune function and autoimmunity, and highlights the importance of XCI in maintaining immune balance. The study provides insights into the molecular mechanisms underlying XCI and its impact on immune function, and suggests that XCI alterations may be a potential therapeutic target for autoimmune diseases.