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Why women are at higher risk of autoimmune diseases such as multiple sclerosis, lupus and rheumatoid arthritis is a long-standing medical mystery, and a research team at Stanford University may now be one step closer to solving it.
How the female body handles the extra X chromosome (the male body only has one plus one Y chromosome) may be a factor that could help explain why women are more susceptible to such diseases, a new study has suggested. Predominantly chronic conditions involve an unbalanced immune system that attacks its own cells and tissues.
Dr. is the senior author of the paper published Feb. 1 in the journal Cell. Howard Chang said the research, which included experiments on mice, was in its early stages, but observations from further studies could help inform new treatments and ways to diagnose diseases..
Chang, a professor of dermatology and genetics at Stanford School of Medicine who led the research, became interested in the subject because the symptoms of some autoimmune disorders, such as lupus and scleroderma, appear in the form of rashes on the skin.
“A lot of these diseases that show up in our clinics, especially immune-related diseases, show this really striking female bias. And I’ve always wondered about that from my own clinical practice,” she said.
There are more than 80 autoimmune diseases, affecting approximately 24 million people in the United States. Montserrat Anguera, an associate professor in the department of biomedical sciences at the University of Pennsylvania School of Veterinary Medicine, explained that these disorders occur when a person’s immune system becomes confused and begins to react as if it were attacked by an infection when no infection exists.
“The same types of players that act in response to a virus or bacteria also play a role in immune disease, but in autoimmune disease the ‘infection’ is not cleared but persists and grows persistently, causing damage to tissues associated with autoimmune disease,” explained Anguera, who was not involved in the research. “Some affect the entire body, while others are specific to a particular organ.”
Other researchers have focused on the “female bias” of the disorders by analyzing sex hormones or chromosome counts. Chang instead focused on the role played by a molecule called Xist (pronounced var), which is not found in male cells.
Testing the ‘crucial role’ of Xist
The main function of the Xist molecule is to deactivate the second female X chromosome in embryos and ensure that the body’s cells are not exposed to the potentially toxic double effect of the chromosome’s protein-coding genes.
“Xist is a very long RNA, 17,000 nucleotides or letters long, and is associated with approximately 100 proteins,” Chang said. Xist molecules work with these proteins to turn off gene expression on the second X chromosome.
Chang made the connection when he was studying for exams to renew his medical license less than a decade ago. He realized that many of the proteins that Xist works with to bind to the X chromosome and silence it were linked to skin-related autoimmune disorders: Patients with these conditions had autoantibodies that mistakenly attacked these normal proteins.
Chang wondered whether the clusters of protein molecules that appear when Xist binds to the X chromosome could be a trigger for autoimmune disease.
To investigate, Chang decided to investigate how Xist, which is naturally produced only by female cells, would work if it were in male mice; This is a feat made possible by genetic engineering. This, he said, would be the first step in eliminating possible competing explanations for women’s susceptibility to autoimmune diseases, such as sex hormones or rogue proteins produced by a second X chromosome that is not fully turned off.
When male mice modified to have a gene that produces Xist were injected with a chemical irritant that mimics lupus, the team found that the male mice developed signs of autoimmunity (autoantibodies) at a rate approaching that of female mice. It may trigger an immune response against Xist. The experiments were not designed to show whether Xist or related proteins cause autoimmune disease in animals.
Chang and his co-authors also analyzed blood serum samples from people 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 higher levels of autoantibodies in response to Xist-related proteins.
Altogether, the data pointed to a “pivotal role” for Xist as a driver of autoimmunity, which could explain why autoimmune disease preys on women, according to the study.
One piece of the autoimmune puzzle
Montserrat said the study shows that the mechanism of the inactive X chromosome is important and may play a role in female bias in autoimmune diseases.
However, he added that the latest finding is just one piece of a potentially huge puzzle – a “coral reef” in the great ocean. It’s unclear whether Xist-related proteins actually cause the disease, he said. In addition, environmental factors also play a major role in autoimmune diseases.
“It’s not just the genetics of the individual… there’s another aspect of the interaction with the environment,” Anguera said. “So it’s diet, microbiome, and then behaviors like smoking.”
READ MORE: The overwhelming majority of lab mice are 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 can speed up that process.
“I think (Xist and its potential to track and explore its diagnostic potential, if it exists) could better help someone decide whether they have an autoimmune disease of one type or another,” Chang said. “The second area we are very interested in is therapeutic. “Now that we know Xist appears to be a major factor, how can you stop this process?”
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