Nearly 80% of people who suffer from autoimmune diseases are women, and why that's the case has long been a medical mystery. But new research suggests the answer may have to do with differences between men's and women's genes—a discovery that could pave the way for better diagnostic methods and treatments in the future.
Autoimmune disorders (such as psoriasis, Crohn's disease, and rheumatoid arthritis) occur when the body’s immune system attacks itself, becoming overactive and flooding the body with inflammatory proteins. Short-term, localized inflammation is useful for healing; too much or for too long, however, is harmful to cells and organ systems.
To date, most of the research on why women are so disproportionately affected by these disorders has focused on sex hormones, like estrogen and testosterone. The latest study, published in the journal Nature Immunology, took a fresh approach, which paid off: "We found a completely new angle," said senior author Johann Gudjonsson, MD, assistant professor of dermatology at the University of Michigan, in a press release. Specifically, his team identified hundreds of gender-specific differences in how certain genes expressed themselves.
These differences, they found, were not influenced by changes in sex hormones. Yet, they appeared to make women more susceptible to developing an overactive immune system.
Dr. Gudjonsson’s lab focuses on autoimmune diseases of the skin, including psoriasis and lupus. (While lupus often affects the whole body, four of the 11 criteria for diagnosis relate to the skin.) For this study, however, they analyzed genetic material from skin samples of 82 healthy men and women.
None of the participants had autoimmune diseases. Nevertheless, they did have some “striking differences in gene expression,” said first author Yun Liang, PhD, a dermatology research investigator, in the statement. In total, the researchers discovered 661 genes that were expressed differently in women versus men. Many were already known to be involved in immune function, Liang added, and some have even been linked to autoimmune disease.
“This finding suggested that these sex-biased genes contributed to not only increased disease susceptibility but possibly also heightened disease activity,” the researchers wrote in their paper. “In this context, we note that being female is the strongest risk factor for the development of autoimmunity, and it dwarfs the identified autoimmune genetic risk variants.”
The team was even was able to identify one protein, called VGLL3, as a “master regulator” of inflammation and autoimmunity. In their analysis of healthy skin samples, VGLL3 was only active in women. But when the researchers looked at biopsies from patients with autoimmune diseases, they saw it activated in men with lupus, as well.
The findings provide new insight into how gender contributes to autoimmune disease, the authors wrote, and highlight the importance of studying men and women separately. They also suggest that these genes and proteins may one day be useful as biomarkers for assessing who’s most at risk, or as targets for new medications.
"Learning more about these disease processes in each gender will provide opportunities for therapeutic interventions we did not imagine before,” said Dr. Gudjonsson, “including both prevention and treatment."