Uncovering the female bias in lupus

6 April 2019

The autoimmune disease lupus, which can cause fatigue, a facial rash, and joint pain, occurs much more commonly in females than males, representing 85% of cases. It is thought that their second X chromosome is the reason for this discrepancy. According to researchers from Penn, females with lupus don't fully 'silence' their second X chromosome in the immune system's T cells, resulting in abnormal expression of genes linked to that chromosome.

The work, led by Montserrat Anguera of the School of Veterinary Medicine and published in the journal JCI Insight, is the first to connect disruptions in maintaining X chromosome inactivation in T cells to lupus. It also suggests that changes to the nuclear structure in the inactive X chromosome of T cells may play a part in the genetic missteps that can arise in lupus - the first time that nuclear organisation has been noted as a feature of this disease.

"In normal circumstances, the inactive X should be silenced, and what we show is, in lupus, it's not," says Anguera, a biologist at Penn Vet. "And it's ultimately affecting gene expression."

In the researchers’ earlier work, it was found that both T cells and B cells have incomplete inactivation of the second X chromosome due to changes in the patterns of Xist, an RNA molecule necessary for X inactivation.

In the recent study, Anguera and colleagues wanted to more closely examine this process in T cells in the context of an autoimmune disease, which in in this case was lupus. The researchers used a mouse model that spontaneously develops lupus in a female-biased manner, similar to how the disease occurs in humans. Examining the animals' T cells, the researchers discovered that those at early stages of disease resembled healthy controls in their patterns of Xist localisation. But those in the later stages of disease had a dramatically different pattern.

"The only differences we detected happened at late stages of disease," Anguera says. "What this means is that abnormal X inactivation is a consequence of the disease; it's not predisposing the animal to develop the disease."

No one has yet attributed changes in nuclear structure to lupus or other autoimmune diseases. Anguera and her team hope to dig further into the causes and consequences of the altered nuclear DNA organisation in their future work. "This is taking our research and the field into a whole new direction for understanding the female bias with lupus disease," she says.

 



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