Figure 1: The long non-coding RNA molecule Xist (in pink) promotes the production of proteins that inactivate the X chromosome. Image courtesy of Wikimedia Commons.
Around the globe, a universal statistic dominates: women are more likely than men to experience autoimmune diseases including lupus, Sjögren syndrome, celiac disease, and over eighty others. Autoimmune diseases occur when the immune system attacks the healthy cells of the body, destroying healthy tissues. In terms of numbers, autoimmune diseases are the third most prevalent category of diseases, following heart disease and cancer. While most are not fatal, these diseases impose limitations on an individual’s health and lifestyle, requiring constant treatment and certain lifestyle changes. Women make up an overwhelming eighty percent of those affected and are thus the primary population subjected to the limitations brought by autoimmune disease.
The female and male genotypes are almost identical, with twenty-two out of twenty-three pairs of chromosomes being indistinguishable between the two sexes. The twenty-third pair, however, is different: females carry two X chromosomes, while males carry one X and one Y chromosome. A recent study, published in the scientific journal Cell, suggests that the extra X chromosome females bear may explain the higher rates of autoimmune diseases observed in women.
The molecule Xist, a long non-coding RNA, encodes proteins that “silence” the second X chromosome. A long non-coding RNA molecule is a ribonucleic acid that is not translated into a protein—instead, the RNA itself plays a role in regulating gene expression. Hundreds of Xist molecules wrap themselves around the second X chromosome to completely “turn off” the functionality of the chromosome, inducing the inactivation of gene expression of the second X chromosome. In some cases, if the second X chromosome is not fully inactivated, genes can “leak out” and cause an excess protein production, which can be toxic.
Scientists have been studying this phenomenon to explain the increased rates of autoimmune diseases in women. However, Howard Chang, a dermatologist and geneticist at Stanford University and the study’s lead author, noticed that many of the proteins that assist Xist in inactivating the second X chromosome are also key proteins present in the development of autoimmune diseases. Chang’s team has been investigating the Xist molecule to explain the emergence of autoimmune diseases in women rather than investigating the leakage of proteins. In their paper, Chang and his team hypothesize that chromosome inactivation, facilitated by Xist, plays a substantial role in the development of autoimmune disease among women in addition to environmental factors.
To investigate the effect of Xist molecules on the development of autoimmune diseases, Chang and his team studied a strain of female mice, the control group, that were at a high risk of experiencing lupus, an autoimmune disorder. Next, they genetically engineered male mice, which had a limited risk of experiencing lupus, to produce levels of Xist comparable to females. As deduced in their hypothesis, the male mice showed higher levels of autoimmune disease once they produced Xist.
In previous studies, scientists had observed that immune cells known as autoantibodies tended to attack large nucleic acid-protein complexes. Chang and his team believe that Xist is a component of a large nucleic acid-protein complex that triggers immune responses. They explained that when a cell dies during tissue injury, it splits open and releases the Xist complex into the bloodstream. These freely moving Xist molecules, with multiple proteins attached to them, come into contact with immune cells that produce antibodies against these proteins. With sufficient genetic predisposition and multiple tissue injuries, Xist becomes a key player in the development of autoimmune diseases among women.
While the Xist molecule, unique to females, is not the sole determining factor in the development of autoimmune disorders, this new study carries clinical and societal implications as it sheds light on the importance of sex differences in health. Many modern-day treatments of autoimmune diseases directly attack the entire immune system. Physicians and scientists can now focus their research on the second X chromosome and the Xist molecule to create targeted and improved treatments for women with autoimmune diseases. Chang’s unconventional study, which hypothesized chromosome inactivation as the problem, emphasizes the importance of further medical research to understand sex-biased health in depth.