Altered X-chromosome inactivation predisposes to autoimmunity

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.

XistDeletion in B Cells Results in Systemic Lupus Erythematosus Phenotypes

“…Our results are in agreement with a recent publication demonstrating that global reduction of Xist expression following whole-body deletion of X-linked Ftx , a positive activator of Xist expression 66 , results in development of lupus-like disease. Although Xist RNA levels are only reduced by female Ftx KO mice by ∼50%, these mice exhibit upregulation of X-linked immunity genes including Tlr7 in splenic B cells, dendritic cells, and monocyte/macrophages and Tasl in dendritic cells and monocyte/macrophages.…”