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Why women are at greater risk for autoimmune diseases such as multiple sclerosis, lupus and rheumatoid arthritis is a long-standing medical mystery, and a team of researchers at Stanford University may now be one step closer to unraveling it.
How the female body handles its extra X chromosome (the male body has only one plus a Y chromosome) could be a factor that helps explain why women are more susceptible to these types of conditions, a new study suggests. The predominantly chronic conditions involve an abnormal immune system that attacks its own cells and tissues.
Although the research involving experiments on mice is preliminary, with further study, the observation could help inform new treatments and ways to diagnose the diseases, said Dr. Howard Chang, senior author of the paper published Feb. 1 in the journal Cell..
Chang, a professor of dermatology and genetics at the Stanford School of Medicine who led the study, became interested in the topic because the symptoms of some autoimmune diseases such as lupus and scleroderma manifest in the skin as rashes.
“Many of these diseases that come into our clinics, especially the immune-related diseases, have these really striking female biases. And so I’ve always wondered 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 goes haywire and starts reacting as if it were being attacked by an infection when there isn’t one, explains Montserrat Anguera, associate professor in the department of biomedical sciences at the School of Veterinary Medicine of the University of Pennsylvania.
“The same kind of players that act in response to a virus or bacteria (are the ones) that act in immune diseases, but in autoimmune diseases the ‘infection’ is not cleared, it persists and with persistence it is magnified. and it causes damage to tissues depending on the autoimmune disease,” explains Anguera, who was not involved in the study. “Some of them affect the entire body and others are localized to a particular organ.”
Other researchers had focused on the “female bias” of the disorder by analyzing sex hormones or chromosome counts. Chang focused instead on the role played by a molecule called Xist (pronounced as existing) that is not present in male cells.
Testing the ‘important role’ of Xist
The Xist molecule’s main job is to deactivate the second female
“Xist is a very long RNA, 17,000 nucleotides long, or letters, and associates with about almost 100 proteins,” Chang said. Xist molecules work with those proteins to turn off 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 noticed that many of the proteins that Xist works with to bind and silence the X chromosome were linked to skin-related autoimmune diseases: patients with these conditions had autoantibodies that accidentally attacked those normal proteins.
Chang wondered whether the clumps of protein molecules that form when Xist connects to the X chromosome were a trigger for autoimmune diseases.
To investigate this, Chang decided to investigate how Xist, which is only produced naturally by female cells, would function if it were found in male mice – a feat made possible by genetic engineering. This, he said, would be a first step in eliminating possible competing explanations for women’s susceptibility to autoimmune diseases, such as sex hormones or malignant proteins made by a second X chromosome that was not completely disabled.
When male mice modified to have a gene-producing Xist were injected with a chemical irritant that mimicked lupus, the team found that male mice developed the hallmarks of autoimmunity – autoantibodies – at a rate that female mice approached, showing that the proteins that bind against Xist can trigger an immune response. The experiments were not intended to show whether Xist or the related proteins cause autoimmune diseases in the 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 disease. The samples from patients with an autoimmune disease produced higher levels of autoantibodies in response to proteins associated with Xist, the researchers found.
Taken together, the data indicated a “significant role” for Xist as a driver of autoimmunity, which could explain why autoimmune diseases skew female, the study said.
A piece of the autoimmune puzzle
The study showed that the machinery of the inactive X chromosome was important and may play a role in the female bias in autoimmune diseases, Montserrat said.
However, she added that the latest find may have been just one piece of a very large puzzle: a “coral reef” in a vast ocean. It’s not clear, she said, whether the proteins associated with Xist actually cause disease. In addition, environmental factors play a major role in autoimmune diseases.
“It’s not just about an individual’s genetics… there’s a whole other aspect: the interaction with the environment,” Anguera said. “So these are diet, microbiome and behaviors like smoking.”
READ MORE: Lab rats are predominantly 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 there is a potential to pursue and explore the diagnostic potential (of Xist and whether it) can and better help someone decide if they have some autoimmune disease,” Chang said. “The second area we are very interested in is therapy. Now that we know that Xist appears to be a major driver, how can you stop this process?”
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