Scientists have discovered that women are up to four times more likely than men to be affected by autoimmune disease, in which the immune system mistakenly attacks the body’s own cells. They believe that the reason for this increased risk in women may be related to the way the body controls its X chromosomes. Humans have two types of sex chromosomes: X and Y. Most females have two X chromosomes in each cell, while most males have one X and one Y. The X chromosome contains more genes that code for proteins, but in people with two X chromosomes, only one needs to participate in protein production to prevent an overload of proteins in cells. To achieve this, one X chromosome in each cell is “silenced” in females during embryonic development through a long molecule of RNA called Xist, which attaches to one X chromosome. However, it turns out that many proteins are prone to binding to Xist, and these complexes of RNA and proteins may make females more susceptible to autoimmune disease.According to a recent study in mice and humans published in the journal Cell on Thursday (Feb. 1), the complexes could trigger an immune reaction in which the body produces antibodies against the proteins within it. Dr. Howard Chang, co-senior study author and a professor of cancer research and genetics at Stanford University, explained that, “Besides its job in controlling gene activity, there’s really a major immunological imprint that maybe hadn’t previously been recognized.” These new findings could pave the way for further research into treatments for autoimmune diseases.According to the research, autoimmune diseases, which affect more than 23.5 million Americans, result from a combination of genetic and environmental triggers. While scientists have proposed various theories to explain why women are more likely to develop these conditions, such as their hormones and the microbes inside and on them, none of these ideas have been conclusively confirmed. Previous research by Chang and colleagues suggested that the Xist complex may drive sex-biased autoimmunity, as many proteins associated with autoimmune diseases could bind to it. But they needed to study Xist in isolation, without other factors that could potentially mask its influence. To accomplish this, the team genetically engineered two strains of male mice to produce Xist: one that was genetically susceptible to autoimmune symptoms similar to those of lupus and another that was resistant — for comparison. In the lupus-prone strain, female mice were more prone to symptoms than male mice were, so the team theorized that Xist would bring the males’ levels of disease up to that of females. In their experiments, the team inserted a special version of the Xist gene into the genomes of male mice that could be switched on but wouldn’t silence their only X chromosome. To induce autoimmune disease, they exposed the lupus-prone mice to a specific chemical. The researchers found that when Xist was activated and lupus was induced, male mice that expressed Xist developed disease at a similar rate to females and had more severe disease than mice without Xist. However, Chang noted that it was important to require both the environmental chemical trigger and a genetic predisposition to lupus, making the mouse experiments more relevant to humans. “It is important to understand that carrying Xist doesn’t guarantee a person will have an autoimmune condition,” Chang said, as the Xist complex may just account for the difference in case numbers between the sexes.To support their findings from the mouse experiments, the team analyzed blood samples from over 100 patients with autoimmune diseases, including lupus, and 20 without autoimmune disease. They discovered that the patients with autoimmunity had more Xist autoantibodies in their blood than those without autoimmunity. The types and quantities of autoantibodies varied among individuals, which may assist in the future diagnosis and treatment of these conditions. Chang explained that, “Someday, taking these autoantibody profiles could help doctors determine which disease a patient has or predict the trajectory of their condition.” This article is for informational purposes only and is not meant to offer medical advice. If you have any questions about how the human body works or wonder about topics such as why some people build muscle more easily than others or why freckles appear in the sun, feel free to send your questions to community@livescience.com with the subject line “Health Desk Q,” and your question may be featured on the website!
