Why Do Women Get More Autoimmune Diseases? Study of Mice Hints at Answers

Four in five people with an autoimmune disease are women. New research points to an RNA molecule involved in silencing one of their X chromosomes as a potential culprit

An image of the 23 pairs of human chromosomes, with both the XX and XY sex chromosomes
The 23 pairs of human chromosomes. People who inherit two tall X chromosomes (bottom right) are much more susceptible to autoimmune diseases than people with one X and one short Y chromosome. BSIP / Universal Images Group via Getty Images

Compared to men, women are at a much higher risk of developing autoimmune diseases—or conditions in which the immune system attacks healthy cells in the body. While researchers have offered numerous explanations for this discrepancy, its cause remains unclear.

Now, a study published last week in the journal Cell proposes a new theory: A molecule that plays a role in shutting down one of the two X chromosomes in women could be linked to an autoimmune response.

“This transforms the way we think about this whole process of autoimmunity, especially the male-female bias,” E. John Wherry, an immunologist at the University of Pennsylvania who did not contribute to the findings, tells Lauran Neergaard of the Associated Press (AP).

More than 24 million people in the United States have an autoimmune disease, making it the third most common disease type, behind only cancer and heart disease. Scientists have discovered more than 80 autoimmune conditions, including multiple sclerosis, lupus, rheumatoid arthritis and type 1 diabetes.

But these ailments don’t affect men and women equally: Four out of five people with an autoimmune disease are female. Theories as to why have pointed at sex hormones, environmental factors, the microbiome and other possible triggers, but scientists haven’t arrived at a definitive answer.

“It’s a question that’s been irking immunologists and rheumatologists for the past 60 or 70 years,” Robert Lahita, a rheumatologist at the Hackensack Meridian School of Medicine who was not involved in the research, tells Nature News’ Elie Dolgin.

Meanwhile, others have hypothesized that chromosomes could be part of the explanation. Females have two X sex chromosomes, while males have one X and one Y chromosome. X chromosomes are thought to play a role in autoimmune diseases—people with Klinefelter syndrome, who have two X chromosomes and one Y chromosome, have male hormone patterns but face an elevated risk of autoimmune diseases similar to females, the study authors write.

Chromosomes make proteins that perform tasks inside of cells. To prevent the body from making too many of these proteins, one of the two X chromosomes in females is silenced in a process called X-chromosome inactivation.

An RNA molecule called Xist—which functions only in women—randomly inactivates one of the two X chromosomes by attracting clumps of proteins that silence it, the study authors write. Howard Chang, a co-author of the new study and physician-scientist at Stanford University, found that many of the proteins that work with Xist to shut down the X chromosome are related to autoimmune disorders, per the AP. So, in the new study, the team looked for a link between the diseases and Xist.

To do so, they genetically modified male mice to produce Xist that would not silence their X chromosomes but would still attract the mounds of proteins.

“Once the male mice express Xist, they get much worse levels of immune disease,” Chang tells the New York Times’ Carl Zimmer.

The researchers also found that the so-called autoantibodies produced by the mice to attack the Xist-related proteins were also present in the blood of people with the autoimmune diseases lupus, scleroderma and dermatomyositis, per Nature News.

“This is like a completely different and novel explanation for female bias in immune disease,” Chang tells Stat News’ Jonathan Wosen. “What our study really showed was that it’s not just the second X chromosome, it’s actually a very special RNA that comes from that second X chromosome, and just that RNA perhaps plays a major role.”

Notably, this finding doesn’t tell the whole story. If Xist alone caused autoimmune diseases, then all women producing the form of RNA would have these conditions, per the AP. Perhaps it takes a trigger, such as an injury or infection, to kickstart an autoimmune response.

Melissa Lechner, an endocrinologist at the University of California, Los Angeles, who did not contribute to the findings, tells the New York Times that Xist might only increase autoimmunity, as opposed to directly causing autoimmune diseases.

“I don’t think the data is there yet to say that it’s the most important [factor] right now, because it’s sort of the first observation that this is possible,” Montserrat Anguera, a geneticist at the University of Pennsylvania who was not involved in the research, tells Stat News. “It just really highlights the fact that it’s not one pathway that involves the inactive X chromosome; there’s different ways that the inactive X can contribute to female bias in autoimmune disease.”

In the future, scientists could target these newly identified autoantibodies to improve disease detection, scientists say. While more research is needed, the findings “might give us a shorter path to diagnosing patients that look clinically and immunologically quite different,” Wherry tells the AP.

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