Altered X-chromosome inactivation predisposes to autoimmunity.
Sci Adv
; 10(18): eadn6537, 2024 May 03.
Article
en En
| MEDLINE
| ID: mdl-38701219
ABSTRACT
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.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Autoinmunidad
/
Receptor Toll-Like 7
/
Inactivación del Cromosoma X
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Macrófagos
Límite:
Animals
Idioma:
En
Revista:
Sci Adv
/
Sci. Adv
/
Science advances
Año:
2024
Tipo del documento:
Article
País de afiliación:
Francia
Pais de publicación:
Estados Unidos