A new study led by a team of Stanford University researchers uncovers key factors involved in why autoimmune diseases disproportionately affect women.
Why do women suffer from autoimmune diseases more than men? A research team from Stanford University thinks it has found the answer.
According to the
Autoimmune Association, over 50 million Americans, or 1 in 5, suffer from one or more autoimmune diseases. These are the third most common diseases, trailing behind cancer and heart disease. Women, in particular, are affected; approximately 75 percent of people with autoimmune diseases are women. In fact, autoimmune diseases are among the top 10 leading causes of death among American women. While there are more than 100 autoimmune diseases, common diagnoses include lupus, rheumatoid arthritis, Type 1 diabetes, multiple sclerosis, Crohn’s disease, ulcerative colitis, Lyme disease, and cardiomyopathy.
In a
paper published in Cell, the Stanford team indicated that a molecule called Xist—found only in women—is why women are more affected by such diseases. The discovery may mark an encouraging turnaround for autoimmune disease treatment, historically plagued by a lack of understanding of how and why autoimmune diseases strike.
“Understanding the risk factors and drivers of autoimmunity has become even more critical in the race to develop effective therapies and sensitive diagnostics specific to each autoimmune disease,” the research team wrote. “However, the high heterogeneity within autoimmune diseases and overlapping traits across diseases have limited our ability to tailor effective therapies and sensitive diagnostics specific to each autoimmune disease.”
According to the study, the Xist molecule only affects women because they have two X chromosomes, while men have one X and one Y chromosome. Chromosomes, which produce proteins, carry the body’s genetic material. The Xist molecule comes into play by inactivating one of the X chromosomes in a woman’s body, preventing the overproduction of proteins. In essence, the Xist molecule silences one of the chromosomes.
Xist Triggers Autoantibodies
“In some female cells, the X inherited from the mother is silenced, while in others, the X from the father is shut off—in a seemingly random fashion,” Sarah C.P. Williams at the University of California–Los Angeles wrote in a press release. Ms. Williams’ work provides a better understanding of the Stanford research team’s discovery.The Stanford researchers discovered that as the Xist molecule silences the X chromosome, it collects proteins. The molecule can attract more than 100 proteins, many of which aid it in inactivating the X chromosome. Additionally, the research team noted that many of the protein structures the Xist molecule builds attract autoantibodies. Unlike T cells or other fighter cells that protect the body, autoantibodies target free molecules associated with autoimmune diseases. However, in defending the body, the autoantibodies can also wreak havoc, causing inflammation in the organs and tissues. This immune response can put a person at greater risk of developing autoimmune diseases because the autoantibodies think the body’s own proteins are the disease rather than a pathogen.
Determined to better understand the role of Xist separate from the X chromosome, the researchers engineered male mice that carried Xist on one of their chromosomes. Additionally, they ensured the Xist molecule wouldn’t silence the X chromosome in the male mouse, as it does with one of the X chromosomes in females, but would cling to it.
The team then introduced an environmental trigger into the mice to see how the Xist molecule would react. They found that the molecule triggered the same type of autoantibodies in females. The study suggests that exposure to inflammation or tissue damage could trigger or increase a woman’s risk of developing autoimmune diseases, as the Xist molecule triggers the production of autoantibodies that attack the body’s proteins rather than the pathogen.
“I don’t think the data is there yet to say that it’s the most important [factor] right now, because it’s sort of the first observation that this is possible,” said Montserrat Anguera, a researcher at the University of Pennsylvania of the Stanford team’s findings, who wasn’t involved in the study. “It just really highlights the fact that it’s not one pathway that involves the inactive X chromosome; there’s different ways that the inactive X can contribute to female bias in autoimmune disease.”
The breakthrough discovery may help physicians and therapeutic companies progress with better-targeted treatments for people suffering from autoimmune diseases, as currently very few exist.
