Altered X-chromosome inactivation predisposes to autoimmunity

• Published in: Science advances Vol. 10; no. 18; p. eadn6537
• Main Authors: Huret, Christophe, Ferrayé, Léa, David, Antoine, Mohamed, Myriame, Valentin, Nicolas, Charlotte, Frédéric, Savignac, Magali, Goodhardt, Michele, Guéry, Jean-Charles, Rougeulle, Claire, Morey, Céline
• Format: Journal Article
• Language: English
• Published: United States American Association for the Advancement of Science (AAAS) 03.05.2024
• Subjects: Animals; Autoimmunity - genetics; B-Lymphocytes - immunology; B-Lymphocytes - metabolism; Dendritic Cells - immunology; Dendritic Cells - metabolism; Female; Life Sciences; Lupus Erythematosus, Systemic - genetics; Lupus Erythematosus, Systemic - immunology; Lupus Erythematosus, Systemic - pathology; Macrophages - immunology; Macrophages - metabolism; Male; Membrane Glycoproteins - genetics; Membrane Glycoproteins - metabolism; Mice; RNA, Long Noncoding - genetics; Signal Transduction; Toll-Like Receptor 7 - genetics; Toll-Like Receptor 7 - metabolism; X Chromosome Inactivation
• ISSN: 2375-2548; 2375-2548
• DOI: 10.1126/sciadv.adn6537

In mammals, males and females show marked differences in immune responses. Males are globally more sensitive to infectious diseases, while females are more susceptible to systemic autoimmunity. X-chromosome inactivation (XCI), the epigenetic mechanism ensuring the silencing of one X in females, may participate in these sex biases. We perturbed the expression of the trigger of XCI, the noncoding RNA , in female mice. This resulted in reactivation of genes on the inactive X, including members of the Toll-like receptor 7 (TLR7) signaling pathway, in monocyte/macrophages and dendritic and B cells. Consequently, female mice spontaneously developed inflammatory signs typical of lupus, including anti-nucleic acid autoantibodies, increased frequencies of age-associated and germinal center B cells, and expansion of monocyte/macrophages and dendritic cells. Mechanistically, TLR7 signaling is dysregulated in macrophages, leading to sustained expression of target genes upon stimulation. These findings provide a direct link between maintenance of XCI and female-biased autoimmune manifestations and highlight altered XCI as a cause of autoimmunity.