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Why women are at greater risk of autoimmune diseases such as multiple sclerosis, lupus and rheumatoid arthritis has long been a medical mystery, and a team of researchers at Stanford University may now be one step closer to solving it. .
The way the female body handles its extra X chromosome (the male body has only one and a Y chromosome) may be a factor that helps explain why women are more susceptible to the types these disorders, it is suggested by a new study. The chronic conditions mainly involve an extra-hepatic immune system attacking its own cells and tissues.
Although the research involving experiments on mice is preliminary, the observation, after further study, could help inform new treatments and ways to diagnose the diseases, said Dr. Howard Chang, senior author of the papers published in the journal Cell on 1 February.
Chang, a professor of dermatology and genetics at the Stanford School of Medicine who led the research, was interested in the subject because symptoms of some autoimmune disorders such as lupus and scleroderma appear in the skin as a rash.
“A lot of these diseases that come up in our clinics, especially the immune-related diseases, show this amazing female bias. And so I was always thinking about that from my own clinical practice,” he said.
There are more than 80 autoimmune diseases, affecting approximately 24 million people in the United States. The disorders occur when a person’s immune system becomes confused and begins to react as if it is being attacked by an infection when there is none, explained Montserrat Anguera, associate professor in the Department of Biomedical Sciences at the School of Veterinary Medicine University of Pennsylvania.
“The same type of players that are acting in response to a virus or bacteria (those are the ones) are at work in an immune disease but in an autoimmune disease the ‘infection’ is not being cleared, it is persistent and persistent, it is getting bigger and it is causing tissue damage, depending on the autoimmune disease,” explained Anguera, who was not involved in the research. “Some affect the whole body and others are localized to a specific organ.”
Other researchers focused on the “female bias” of the disorder by analyzing sex hormones or chromosome counts. Chang instead zeroed in on the role played by a molecule called Xist (pronounced there) that is not present in male cells.
Testing the ‘significant role’ of Xist
The main job of the Xist molecule is to inactivate the second female X chromosome in embryos, ensuring that the body’s cells do not receive a potentially toxic double whammy of the chromosome’s protein-coding genes.
“Xist is a very long RNA, 17,000 nucleotides long, or letters, and it binds to nearly 100 proteins,” Chang said. Xist molecules work with those proteins to shut down gene expression in the second X chromosome.
While studying for exams to renew his medical license just under a decade ago, Chang made a connection. He noted that many of the proteins that Xist works with to bind and silence the X chromosome were involved in autoimmune disorders involving the skin: Patients with these conditions had autoantibodies that attack those normal proteins by mistake.
Chang wondered if the clumps of protein molecules that form when Xist binds to the X chromosome were the trigger for autoimmune disease.
To investigate, Chang decided to study how Xist, which is produced naturally only by female cells, would function in male mice – something that genetic engineering could do. This, he said, was the first step in eliminating possible competing explanations for women’s susceptibility to autoimmune disease such as sex hormones or rogue proteins made by a second X chromosome that did not completely turned off.
When male mice were injected with a chemical irritant that had been altered to have a Xist-producing gene that mimicked lupus, the team found that male mice developed auto-immune traits – auto-antibodies – at a rate approaching that of female mice , which showed that the proteins were binding. Xist can stimulate an immune response. The experiments were not designed to show whether Xist or related proteins cause autoimmune disease in the animals.
Chang and his co-authors also analyzed blood serum samples from people with lupus, dermatomyositis and systemic sclerosis and compared them to samples from people without autoimmune disease. The samples from patients with autoimmune disease produced higher levels of autoantibodies as a reaction to proteins related to Xist, the researchers found.
Overall, the data showed that Xist played a “significant role” as a driver of autoimmunity that may explain why autoimmune disease is overwhelming females, according to the study.
A piece of the autoimmune puzzle
The study showed that the machinery of the inactive X chromosome was important and could play a role in the female bias in autoimmune diseases, said Montserrat.
However, she said the latest finding was just one piece in a very large puzzle – a “coral reef” in a vast ocean. It’s not clear, she said, whether the Xist-related proteins are actually causing disease. In addition, environmental factors play a major role in autoimmune diseases.
“It’s not just human genetics… there’s a whole other aspect, which is interaction with the environment,” Anguera said. “So these are diet, microbiome, and then behaviors like smoking.”
READ MORE: Lab rats are overwhelmingly male, and that’s a problem
Autoimmune diseases are difficult to detect and often take years to diagnose. Ultimately, Chang said he hopes the findings could speed up that process.
“I think the potential is there to pursue and explore the diagnostic potential (of Xist and if it is) to better help someone determine if they have this or that type of autoimmune disease,” said Chang. ” The second area we’re really interested in is therapeutics. Now that we know Xist appears to be an important driver, how can you stop this process?”
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