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Why women have a greater risk of developing 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 solving that mystery.
A new study suggests that the way the female body handles its extra Chronic conditions often involve a dysregulated immune system that attacks its own cells and tissues.
Dr. Howard Chang, lead researcher, said that although the research involving experiments on mice is preliminary, the observation, after further study, may help provide new treatments and ways to diagnose diseases. Author of the paper published in the journal Cell on February 1.
Zhang, a professor of dermatology and genetics at Stanford University School of Medicine who led the research, became interested in the topic because symptoms of some autoimmune disorders such as lupus and scleroderma appear in the skin as a rash.
“A lot of these diseases that appear in our clinics, especially immune-related diseases, show this really amazing female bias. And so I’ve always wondered about that in my clinical practice,” he said.
There are more than 80 autoimmune diseases, affecting about 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 the disorders occur when a person’s immune system becomes confused and begins to respond as if they are being attacked by an infection when there is none.
“The same type of players who act in response to a virus or bacteria (are) doing this They work in immune diseases, but in autoimmune diseases, the “infection” is not eliminated, it persists and, with persistence, amplifies and causes tissue damage, depending on the autoimmune disease,” the research explained. “Some affect the whole body and others are concentrated in an organ specific.”
Other researchers have focused on the “female bias” of these disorders by analyzing sex hormones or chromosome numbers. Instead, Chang focused on the role played by a molecule called Xist (pronounced there), which is not found in male cells.
The main function of the Xist molecule is to inactivate the second female X chromosome in embryos, ensuring that the body’s cells are not exposed to a potentially toxic double hit from the chromosome’s protein-coding genes.
“Xist is a very long RNA, 17,000 nucleotides, or letters, long, and binds to about 100 or so proteins,” Zhang said. Xist molecules work with these proteins to turn off gene expression on the second X chromosome.
While studying for his medical license renewal exams less than a decade ago, Zhang was able to connect. He noted that many of the proteins that Xist acts on to bind and silence the
Zhang wondered whether clumps of protein molecules that arise when Xist attaches to the X chromosome are a trigger for autoimmune diseases.
To investigate, Zhang decided to study how the Xist protein, which is naturally produced only by female cells, would function if it was present in male mice — a feat made possible by genetic engineering. This would be a first step in eliminating potential competing explanations for female susceptibility to autoimmune diseases such as sex hormones or rogue proteins made by a second X chromosome that has not been completely turned off, he said.
When male mice that had been modified to contain a gene producing Xist were injected with a chemical irritant that mimicked lupus, the team found that the male mice developed the hallmarks of autoimmunity — autoantibodies. – at a rate approaching that of female mice, indicating that proteins that bind to Xist can elicit an immune response. The experiments were not designed to show whether Xist or related proteins cause autoimmune diseases in animals.
Zhang and his colleagues also analyzed blood 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 taken from patients with autoimmune diseases produced higher levels of autoantibodies in response to Xist-related proteins.
Overall, the data suggested an “important role” for Xist as a driver of autoimmunity, which may explain why autoimmune diseases are more skewed in females, according to the study.
Montserrat said the study showed that the mechanism of an inactive X chromosome was important and may play a role in female bias in autoimmune diseases.
She added, however, that the latest discovery may have been just one piece in a very large puzzle – a “coral reef” in a large ocean. It’s not clear whether Xist-related proteins actually cause the disease, she said. In addition, environmental factors play a large role in the development of autoimmune diseases.
“It’s not just an individual’s genetics,” Anguera said. “There’s a whole other aspect, which is the interactions with the environment.” “These are diet, microbiome, and then behaviors like smoking.”
Read more: Lab rats are overwhelmingly male, which is a problem
Autoimmune diseases are difficult to detect and often take years to diagnose. Ultimately, Zhang said he hopes the results will speed up this process.
“I think there is potential to pursue and explore the diagnostic potential (of Xist and whether it exists) that could better help someone determine whether they have this or that type of autoimmune disease,” Zhang said. “The second area we’re very interested in is therapeutics. Now that we know that Xist seems to be an important driver, how do you stop this process?
