80% of autoimmune patients are women, and a study may reveal the reason

Dubai, United Arab Emirates - Why women are at greater risk of developing autoimmune diseases such as multiple sclerosis, lupus and rheumatoid arthritis has been a long-standing medical mystery, and a team of researchers at Stanford University may be one step closer to solving it. A new study suggests that the way the female body handles the extra

Chronic conditions often involve a dysregulated immune system that attacks its own cells and tissues. Although the research involving experiments on mice is preliminary, according to Dr. Howard Chang, lead author of the study published in the journal Cell on February 1, observation after further study may help provide new treatments and ways to diagnose diseases.

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 on the skin as a rash. “The types of players that respond to a virus or bacteria (are the ones) that respond in immune diseases, but in autoimmune diseases, the infection is not eliminated, it persists, it magnifies with persistence, and it causes tissue damage, depending on the autoimmune disease,” said Montserrat Angera, associate professor in the Department of Biomedical Sciences at the University of Pennsylvania College of Veterinary Medicine.

Other researchers have focused on the "female bias" of disorders by analyzing sex hormones or chromosome numbers. Instead, Zhang focused on the role played by a molecule called Xist that is not found in male cells.

Testing the molecule's 'critical role' 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,” Zhang said.

Xist molecules work with these proteins to stop gene expression on the second X chromosome. While studying for his medical license renewal exams less than a decade ago, Zhang made a connection.

He noted that many of the proteins that the Xist molecule works with to bind and silence the X chromosome are linked to skin-related autoimmune disorders. Patients with these conditions have autoantibodies that mistakenly attack these normal proteins.

Zhang wondered whether clumps of protein molecules that arise when the Xist molecule attaches to the X chromosome act as a trigger for autoimmune diseases. To investigate, Zhang decided to study how the Xist molecule, which is naturally produced only in female cells, works and whether it is present in male mice, a feat made possible by genetic engineering.

He explained that 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 switched off. When male mice that had been modified to have a gene that produces the Xist molecule were injected with a chemical irritant that mimicked lupus, the team found that the male mice developed hallmarks of autoimmunity, autoantibodies, at a rate close to that of female mice, demonstrating that proteins that bind to Xist can trigger 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 pointed to an “important role” for Xist as a driver of autoimmunity.

A piece of the autoimmune puzzle Angera said the study showed that the mechanism of an inactive X chromosome was important and may play a role in the female bias for autoimmune diseases. But she added that the latest discovery may be just one piece of a very large puzzle.

She explained that it is not clear whether the proteins associated with “Xist” actually cause the disease. In addition, environmental factors play a large role in the development of autoimmune diseases.