Two hands viewed in X-ray format showing red areas of inflammation around the joints to indicate arthritis or rheumatic disease
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Female mammals are more susceptible to autoimmune diseases because of how their X-chromosome is inactivated, new research from France suggests. Scientists “turned back on” the inactive X gene in a mouse model, which led to signs of autoimmune disease. It’s likely the findings will relate to people as well.

The study was published in Science Advances and the lead author is Céline Morey, PhD, Université Paris Cité, CNRS.

“There are several indications that the same kind of regulation also occurs in humans. The X-chromosome inactivation process is conserved amongst all female eutherian mammals,” Morey said.

Males and female mammals show marked differences in immune responses. Males tend to be more sensitive to infectious diseases, while females are more susceptible to systemic autoimmunity. Worldwide, autoimmune diseases affect women versus men at a rate of 2 to 1. 

X-chromosome inactivation (XCI), the epigenetic mechanism ensuring the silencing of one X in females, may play a role in these sex biases. Other work has linked autoimmune diseases in females with the XIST ribonucleoprotein (RNP) complex, which comprises a lncRNA, bound RNA binding proteins, and tethered to pieces of genomic DNA and has qualities resembling nucleic acid autoantigen immune complexes.

The team perturbed the expression of the trigger of XCI, the noncoding RNA Xist, in female mice. This reactivated genes on the inactive X, including members of the Toll-like receptor 7 (TLR7) signaling pathway, in monocyte/macrophages and dendritic and B cells.  

The female mice eventually 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. 

In these studies, TLR7 signaling was dysregulated in macrophages, leading to sustained expression of target genes upon stimulation. “These findings,” the researchers wrote, “provide a direct link between maintenance of XCI and female-biased autoimmune manifestations and highlight altered XCI as a cause of autoimmunity.”

This perturbation did not lead to a complete X-inactivation, which would be lethal, but provided a way to alter X-inactivation significantly, while still allowing the animals to survive, live an almost normal life, and reproduce almost normally. 

“We did not see any phenotype at first,” said Morey. “We had to wait for the females to grow old and only in 1- to 2-year-old females we observed that they had a very big spleen. In immune cells of these animals, some genes with immune function like Tlr7 are expressed from the inactive X chromosome at higher levels than in unmutated female mice.”

Although her team is not pursuing this work further, their collaborators in Toulouse (Jean-Charles Guéry’s team) plan to investigate other types of autoimmune manifestations using the Ftx knockout mice.

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