Altered X-chromosome inactivation predisposes to autoimmunity - Université Paris Cité
Article Dans Une Revue Science Advances Année : 2024

Altered X-chromosome inactivation predisposes to autoimmunity

Nicolas Valentin
Frédéric Charlotte
Claire Rougeulle
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Résumé

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 Xist , 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.
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hal-04581817 , version 1 (21-05-2024)

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Christophe Huret, Léa Ferrayé, Antoine David, Myriame Mohamed, Nicolas Valentin, et al.. Altered X-chromosome inactivation predisposes to autoimmunity. Science Advances , 2024, 10 (18), ⟨10.1126/sciadv.adn6537⟩. ⟨hal-04581817⟩
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