As a young girl, I’d always reach into my grandmother’s purse in search of a treat: lipstick, powder, hand cream, and I’d be met with loads and loads of throat lozenges. I’d pop some of the adult candy in my mouth and wonder why she enjoyed the sharp, herbal taste. As I got older, I came to understand that my grandma wasn’t just fond of throat lozenges; she relied on them.

Her dry mouth was a symptom of Sjogren’s Disease, a chronic autoimmune disorder that breaks down the glands responsible for producing and regulating moisture in the body. Years later, my mother was also diagnosed with Sjogren’s, though her symptoms differed from her mother’s. Little did I know that my mother’s and grandmother’s experiences are emblematic of a much larger phenomenon: About 80 percent – or four in five – people with autoimmune diseases are female.

First of all, what is an autoimmune disease? Normally, our bodies produce proteins called antibodies that recognize and attack harmful substances in our bodies, like certain bacteria or cancer cells. When someone has an autoimmune disease, though, the antibodies recognize parts of their own bodies as foreign, causing the breakdown of healthy tissue. In Sjogren’s Disease, for example, the body attacks its own moisture-producing glands, leading to symptoms like dry mouth or dry eyes.

Many diseases you have heard of, such as lupus, multiple sclerosis, Crohn’s, and type 1 diabetes, are actually caused by autoimmune dysfunction. There are roughly 100 distinct diseases, impacting up to 50 million people, each with a unique set of symptoms. This varied landscape underscores a unique challenge facing physicians: autoimmune diseases are notoriously difficult to diagnose. Symptoms can appear and disappear unpredictably, and there’s rarely a single test that can confirm a diagnosis. Adding to the challenge, the same disease can cause a vastly wide range of symptoms; for example, it’s difficult to diagnose Sjogren’s Disease when symptoms range all the way from dry mouth in my grandmother to joint pain in my mother.

Autoimmune diseases can misleadingly present as more familiar diseases, further complicating the diagnosis process. Dr. Sharon Karp, a member of the Women’s Health Research at Yale Advisory Council and Connecticut-based rheumatologist with 30 years of experience treating autoimmune disorders, points out, “A lot of primary care doctors aren’t that familiar with rheumatologic diseases. They’re not comfortable with them, so it’s not at the forefront of their minds.” This diagnostic challenge adds to the skepticism that women often already face in medical settings.

“I think the biggest problem – and it’s a complaint that a lot of my patients will have – is that ‘I look well, so my spouse doesn’t believe me, my friends don’t believe me,’” Dr. Karp continues. “You can have a lot of joint pain and be amazingly fatigued by autoimmune diseases, and not have any joint swelling, not have any deformities, and have cognitive dysfunction from them, and you’re not taken seriously – because you ‘look well.’”

Why is it, then, that approximately four in five people with autoimmune disease are women? Recent research suggests this disproportionality stems from a combination of genetic susceptibility and a cellular process unique to females: X-chromosome inactivation. The X-chromosome contains over a thousand genes which are vital for immune function and various biological processes. Interestingly, females have two X-chromosomes (XX) while males have only one (XY). As a result, the “dosage” from these important genes would be uneven – unless dosage compensation occurs.

Early in female embryonic development, therefore, cells randomly select and inactivate one of the two X-chromosomes. This inactivation process relies on a specialized non-coding RNA called Xist (pronounced “exist”). Xist works by recruiting several unique proteins, forming a complex that wraps itself around the chosen X-chromosome to silence it. And, intriguingly, many of these same silencing proteins that Xist recruits may also be involved in the body’s autoimmune response.

To test this hypothesis, Stanford researchers investigated the following question: If males expressed this Xist complex, as females do, would they become similarly susceptible to developing an autoimmune disease? In a February 2024 study, researchers induced Xist expression in male mice from two strains: one genetically prone to autoimmunity, and one resistant to it. Among the males from a strain that are more likely to have an autoimmune response,, those with Xist expression developed symptoms of lupus – with a severity comparable to that seen in female mice.

Importantly, however, in the strain of mice not genetically prone to autoimmunity, inducing Xist expression did not trigger the development of autoimmune symptoms. This finding aligns with what we observe in humans: despite the increased prevalence of autoimmune disorders in females compared to males, most females do not have an autoimmune disorder. This study supports the original hypothesis: Xist X-chromosome inactivation contributes to females’ higher rates of autoimmune diseases, but typically only in combination with genetic predisposition.

When I asked rheumatologist Dr. Karp about the contribution of this recent research, she responded, “It’s probably one piece of the puzzle.” Dr. Karp emphasized that while X-chromosome inactivation certainly plays a role, other biological factors are important to consider. Specifically, estrogen can trigger the immune system, often causing women to produce more antibodies than necessary. Interestingly, pregnancy can also influence a woman’s autoimmune response, either by improving or aggravating it – a reminder of the unpredictability of these diseases. Environmental factors like stress, toxic chemicals, smoking, or diet can set off an autoimmune response too – and rates are only rising. As the global prevalence rises by 12.5% each year, it’s never been more pressing to understand the triggers.

But Dr. Karp is optimistic. “We’re getting there,” she reflected. “We know so much more than we did 30 years ago, and people know more about autoimmune disorders – and that’s the most important thing. As long as people know more about it then they look for help, and if they look for help, the outcomes are much, much better.”

Moving forward, it is crucial that researchers continue investigating autoimmune mechanisms – and how biological diversity in these processes shapes a patient’s unique experience. But as Dr. Karp’s message illustrates, better diagnosis and treatment rely on the conjunction of two necessary pieces: scientific discovery and education among patients and physicians. While research into mechanisms like Xist advances our understanding of why women face higher autoimmune risk, awareness and recognition of these diseases in medical settings must advance alongside it. Only then can we truly improve outcomes for the millions of people – like my mother and grandmother – living with autoimmune disorders.

Kira Berman (Yale College ‘25) is a Women’s Health Research at Yale Undergraduate Fellow, majoring in English while pursuing a premedical track. Over the course of this semester, she will contribute articles that illuminate critical gaps in healthcare knowledge, aiming to empower women to better understand their bodies. By combining her writing experience with her dedication to women’s health, on this blog, Kira strives to bridge the gap between medical research and public awareness, making complex topics more accessible and relatable to readers.

If you have suggestions for topics that make you ask “Why Didn’t I Know This?” please email Kira at kira.berman@yale.edu.