Exist Molecule: Why autoimmune diseases are more common in women than men

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Why are women at higher risk for autoimmune diseases such as multiple sclerosis? lupus Rheumatoid arthritis is a long-standing medical mystery, and a team of researchers at Stanford University may now be one step closer to solving it.

How women's bodies handle extra X chromosomes (men's bodies only have one Y chromosome) helps explain why women are more susceptible to these types of diseases. A new study suggests that it may be possible. Chronic symptoms mainly involve abnormalities in the immune system, which attack the patient's own cells and tissues.

Although the study, which included experiments on mice, is preliminary, observations after further research could help inform new treatments and ways to diagnose the disease, said senior doctor Dr. Howard Chan. Authors of papers published in journal cell February 1.

Chan, a professor of dermatology and genetics at Stanford School of Medicine who led the study, was interested in the topic because the symptoms of some autoimmune diseases, such as lupus and scleroderma, appear on the skin as rashes. .

“A lot of these diseases that show up in our clinics, especially immune-related diseases, show this really pronounced female bias. So I've always wondered about that from my own clinical practice. '' he said.

There are more than 80 autoimmune diseases that affect approximately 24 million people in the United States. The disorder occurs when a person's immune system becomes confused and begins to react as if it were being attacked by an infection when it isn't, said Montserrat Angela, associate professor in the Department of Biomedical Sciences at the University of Pennsylvania College of Veterinary Medicine. explains.

“The same kind of players that act in response to viruses and bacteria… “It works for immune diseases, but in autoimmune diseases, the 'infection' does not go away, but persists and spreads as it persists, and in some autoimmune diseases it damages tissues,” Angela said. Not involved. I explained the research. “Some of them affect the whole body, while others are localized to specific organs.”

Other researchers focused on the “female bias” of the disease by analyzing sex hormones and chromosome numbers. Instead, Chan focused on the role played by a molecule called Xist (pronounced “exist”), which is not present in men's cells.

The main job of the Xist molecule is to inactivate the embryo's second female X chromosome, so that the body's cells do not receive the potentially toxic double whammy of the chromosome's protein-coding genes. be.

“Xist is a very long RNA, 17,000 nucleotides, or letters, long, and it binds to nearly 100 proteins,” Zhang said. The Xist molecule works with these proteins to shut down gene expression on the second X chromosome.

Less than 10 years ago, when Chan was studying for the exam to renew his medical license, he made a connection. He noticed that many of the proteins that Xist acts to bind to and silence his X chromosome are associated with skin-related autoimmune diseases. Patients with these symptoms had autoantibodies that mistakenly attacked these normal proteins.

Chang suspected that the clumps of protein molecules created when Xist binds to the X chromosome might trigger autoimmune diseases.

To investigate, Professor Chan decided to study how Xist, which is only naturally produced by female cells, works in the case of male mice. This is a feat made possible by genetic engineering. This is a first step toward ruling out possible competing explanations for women's susceptibility to autoimmune diseases, such as sex hormones or rogue proteins made by a second X chromosome that isn't completely turned off. He said:

When male mice engineered to carry the gene that produces Xist were injected with a chemical irritant that mimics lupus, the researchers found that the mice developed autoantibodies, a hallmark of autoimmunity. — shows that proteins that bind to Xist can trigger an immune response at a rate similar to that in female mice. This experiment was not designed to show whether Xist or related proteins cause autoimmune disease in animals.

Chang and his co-authors also analyzed serum samples from humans with lupus, dermatomyositis, and systemic sclerosis and compared them with samples from people without autoimmune diseases. The researchers found that samples from patients with autoimmune diseases produced high levels of autoantibodies in response to proteins associated with Xist.

Overall, the data points to an “important role” for Xist as a promoter of autoimmunity, which may explain why autoimmune diseases disproportionately affect women, according to the study.

This study showed that the inactive X chromosome mechanism is important and may play a role in the female bias in autoimmune diseases, Montserrat said.

But she added that the latest discovery could be just one piece of a potentially very large puzzle – a “coral reef” in a large ocean. It's unclear whether the proteins associated with Xist actually cause the disease, she says. Additionally, environmental factors also play a major role in autoimmune diseases.

“It's not just the individual's genetics…there's a whole other dimension of interaction with the environment,” Angela says. “So these are diets, microbiome, and behaviors such as smoking. ”

read more: Lab rats are overwhelmingly male, which is a problem.

Autoimmune diseases are difficult to detect and can take years to diagnose. Ultimately, Chan said he hopes his findings will speed up that process.

“I think there is potential to pursue and explore the diagnostic potential[of Xist]and potentially be more helpful in determining whether someone has this type of autoimmune disease.” Mr. Chan said. “The second area that we're very interested in is therapeutics. Now that we know that Xist is a key driver, how can we stop this process?”