An international team led by scientists from Stanford University has uncovered a likely explanation for a longstanding biological puzzle:
the disproportionately higher prevalence of autoimmune diseases among women compared to men, such as lupus and rheumatoid arthritis.
Women make up approximately 80 percent of individuals affected by autoimmune diseases, a group encompassing more than 100 conditions that collectively affect 50 million Americans, according to the nonprofit Autoimmune Association.
These diseases manipulate the body’s immune system to attack healthy tissues.
In a study published Thursday in the journal Cell, researchers present new findings suggesting that a molecule called Xist, present exclusively in women, plays a significant role in these diseases.
Enhanced understanding of this molecule could lead to new diagnostic tests for early detection of autoimmune diseases and, in the longer term, to more effective treatments, researchers noted.
Women typically possess two X chromosomes, while men generally have one X and one Y chromosome.
Xist is crucial in women as it deactivates one of the X chromosomes, preventing an otherwise potentially harmful overproduction of proteins.
However, the research team discovered that in this process, Xist also generates peculiar molecular complexes associated with numerous autoimmune diseases.
Although much of the research was conducted using mice, the team made an intriguing observation involving human patients:
The Xist complexes — lengthy strands of RNA intertwined with DNA and proteins — prompt a chemical response in individuals that is a hallmark of autoimmune diseases.
The identification of Xist’s role does not fully explain how men develop these diseases or why certain autoimmune diseases, like Type 1 diabetes, have a higher prevalence among men.
“Clearly there’s got to be more, because one-tenth of lupus patients are men,” remarked David Karp, chief of the division of rheumatic diseases at UT Southwestern Medical Center in Dallas. “So it’s not the only answer, but it’s a very interesting piece of the puzzle.”
Autoimmune diseases have posed significant challenges for medical intervention.
Treatments are limited, and many of these diseases are chronic, requiring lifelong management without a cure, leaving millions of Americans hopeful for advancements in scientific understanding.
Stephanie Buxhoeveden was 25 years old when she started experiencing vision issues in her left eye and struggled to hold a syringe in her left hand—a critical tool for her nursing career.
The cause was multiple sclerosis, an autoimmune condition where the immune system attacks the protective covering of the brain, spinal cord, and optic nerves.
“I was overwhelmed and scared because I knew there was no cure,” said Buxhoeveden, a resident of Virginia.
“All of these things that I had laid out, planned and worked really hard for all of a sudden were completely up in the air and no longer guaranteed.”
Previous theories speculated that the gender disparity in autoimmune diseases might stem from female hormones like estrogen and progesterone, or merely the presence of a second X chromosome.
A hint came from men with Klinefelter syndrome, a rare condition where they have two X chromosomes and one Y chromosome, who face a significantly higher risk of autoimmune diseases, suggesting the number of X chromosomes plays a pivotal role.
Howard Y. Chang, senior author of the Cell paper and professor of dermatology and genetics at Stanford, began looking for the ideas that led to this new discovery when he identified over 100 proteins that either directly bind to Xist or interact with proteins that bind to Xist.
He noted that many of these collaborating proteins were linked to autoimmune diseases.
Chang and his team engineered male mice to produce Xist to test if males producing the molecule would have increased rates of autoimmune diseases.
While Xist alone isn’t adequate to cause autoimmune diseases, the scientists induced a lupus-like disease in these mice using an environmental trigger.
They observed that male mice then produced Xist at levels similar to those of regular female mice, exceeding those of typical male mice.
In humans, genetics and environmental factors such as viral or bacterial infections can also trigger autoimmune diseases.
Researchers collected serum from human patients with dermatomyositis, a rare autoimmune disease causing muscle weakness and skin rash.
Serum contains antibodies that combat diseases. They discovered that in these patients, Xist complexes generate autoantibodies.
Rather than defending the body from invaders like antibodies, autoantibodies target the body’s own features.
“Inactivation of the second X chromosome remains a critical process that you don’t necessarily want to eliminate or significantly modify,” said Karp of UT Southwestern.
“But this work shifts direction entirely, suggesting that the mechanism required to silence the second X chromosome, that mechanism itself may be responsible for generating autoimmunity,” Karp added.
Understanding these mechanisms could be pivotal if researchers can use them to develop novel diagnostic tools, he noted:
“We still use laboratory tests developed in the 1940s, ’50s and ’60s because they were easy to conduct and detected the most robust autoimmune responses.”
Jeffrey A. Sparks, associate physician and director of immuno-oncology and autoimmunity at Brigham and Women’s Hospital, anticipated examining how current treatment options might fit into this newfound mechanism.
“The possibilities are endless,” said Sparks, who wasn’t part of the study. “Once you understand the fundamental mechanisms, you can think about developing therapies, early detection, and prevention.”
However, major treatment advances may be years away, cautioned Keith B. Elkon, adjunct professor of immunology and associate director at the Center for Innate Immunity and Immune Disease at the University of Washington.
Yet, he said, scientific breakthroughs over the past two decades have extended the lives of many individuals with autoimmune conditions.
“In 1950, a lupus diagnosis was as dire as a cancer diagnosis,” Elkon remarked. “But in the last 15 to 20 years, there have been remarkable breakthroughs in understanding the disease. It’s now on the cusp of being manageable.”
Buxhoeveden, now 36 and pursuing a nursing PhD, uses immunosuppressants to manage her MS. She found solace in knowing that “we’ve made progress, like this study, to better understand what triggers it.”
