Why Women Face a Much Higher Risk of Autoimmune Disease

A recent study has identified biological abnormalities that make the female immune system more likely to mistakenly attack the body's own healthy tissues, offering new insight into why women are significantly more likely than men to experience autoimmune diseases.

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It has long remained unclear why there is a significantly higher prevalence of autoimmune diseases in women, such as multiple sclerosis and lupus, and the underlying mechanisms of such higher prevalence.

Researchers from UNSW Sydney and the Garvan Institute of Medical Research have now identified more than 1,000 genetic switches that function differently in male and female immune cells, leaving inflammatory pathways more active in females overall.

The study, published in The American Journal of Human Genetics, also highlights the importance of including both sexes in medical research, which has traditionally relied heavily on male cohorts, adding to growing evidence that diseases can develop and present differently in men and women.

“Our findings show that the immune system needs to be studied with sex in mind,” said study author Dr. Seyhan Yazar.

Even though we know men’s and women’s immune systems differ, many studies still overlook these differences, which can limit how well we understand disease, and in turn bias treatment options.

Dr. Seyhan Yazar, School of Clinical Medicine, University of New South Wales

 A New Level of Cellular Resolution

Until recently, researchers studying sex differences in immunity relied on bulk blood analysis, which measures average activity across a mixed population of cells and can mask the behavior of individual cell types, largely due to technological limitations.

Advances in single-cell technologies now allow scientists to examine individual immune cells in far greater detail. According to the researchers, sex-based immune differences have never before been explored at this scale using single-cell resolution.

The team sequenced more than 1.25 million peripheral blood mononuclear cells: immune cells that circulate in the bloodstream, collected from around 1,000 healthy individuals. The participants were part of the OneK1K cohort, a major Australian initiative focused on mapping how genetics shapes immune cell behavior across the population.

The analysis revealed distinct cellular profiles between males and females. Males were more likely to have monocytes, which act as first responders in the immune system, and their genetic activity was more heavily linked to basic cellular maintenance and protein production. Females, on the other hand, showed higher levels of B cells and regulatory T cells, with genetic activity strongly skewed toward inflammatory pathways.

While this highly reactive immune profile gives females an advantage in fighting viral infections, it comes with a biological trade-off: a greater predisposition to autoimmune diseases.

Dr. Sara Ballouz, Study Co-Senior Author, School of Computer Science and Engineering, University of New South Wales

“On the other hand, male immune cells are less primed for inflammation, making men generally more susceptible to infections and non-reproductive cancers,” she added.

A highly reactive immune system remains in a near-constant state of alert. While this heightened vigilance can be beneficial when confronting genuine threats, it also increases the risk of so-called "friendly fire," where the immune system mistakenly attacks the body’s own healthy tissues, leading to autoimmune disease.

Surprising Genetic Switches Linked to Lupus

By analyzing the data cell by cell, the researchers identified sex-specific genetic variants that previous bulk studies had missed. The team focused on genetic switches known as 'expression quantitative trait loci', which act like volume controls that regulate how strongly genes are turned on or off.

The X and Y chromosomes are often assumed to drive most immune differences between males and females. However, the researchers found far fewer sex-specific genetic switches on the sex chromosomes than expected. Instead, more than 1,000 of these variants were located on autosomes, the non-sex chromosomes shared by both sexes.

Importantly, these genetic control mechanisms were directly linked to autoimmune disease. The researchers identified variants that influence the female-biased expression of two genes associated with systemic lupus erythematosus, which may help explain why lupus occurs around nine times more often in women than men.

Although genetics represents only one part of the picture alongside factors such as hormones, the findings suggest these inherited differences establish a distinct biological baseline that shapes susceptibility to disease.

This is the first time we have shown that these differences occur at the genetic control level, providing a new layer of insight into human immunity. Having shown that female-biased genes are heavily enriched in inflammatory pathways, we now have another biological rationale for why the immune system can more easily mistakenly attack the body’s own tissues in women.

Dr. Sara Ballouz

Moving Beyond One-Size-Fits-All Medicine

These findings may help explain why widely used autoimmune treatments do not work equally well for all patients with conditions such as lupus. The discovery of these distinct genetic pathways also reinforces the long-term push toward more targeted therapies, moving away from broad immunosuppressive drugs that dampen the entire immune system and toward treatments tailored to an individual’s specific disease biology.

Dr. Yazar said: “Our findings add strong evidence that female and male autoimmune diseases may not be the same, and the way we should treat them may not necessarily be the same. Currently, clinicians rely on a one-size-fits-all management approach for most autoimmune diseases – a more inclusive approach is needed.”

According to author Professor Joseph Powell, the findings could also help pave the way for more precisely targeted treatments.

“If we want to realize the potential of precision medicine, we have to understand these fundamental biological variables. Treatments need to be tailored not just to the disease, but to how a patient’s immune system operates at a baseline genetic level,” concluded Professor Joseph Powell.