Ahead of World Lupus Day on May 10, new research from the Garvan Institute of Medical Research and UNSW Sydney helps explain why women are significantly more likely to be diagnosed with an autoimmune disease – a condition where the immune system misfires and mistakenly attacks the body's own healthy tissues. While conditions like lupus affect up to nine women for every one man, the underlying genetic reasons for this sex bias have remained unclear. Now, researchers have discovered over 1,000 genetic switches that operate differently in female and male immune cells, driving higher overall activity of inflammatory pathways in females.
The study, published in The American Journal of Human Genetics , adds a critical piece of evidence that diseases present differently in males and females, emphasising the need to include both sexes in medical research, which has historically relied on male cohorts.
"Our findings show that the immune system needs to be studied with sex in mind. 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," says Garvan's Dr Seyhan Yazar, first author of the study.
A new level of cellular resolution
Until recently, technological limitations meant that immune differences between the sexes were studied using bulk blood analysis, which measures the average activity across a whole mixture of cells, masking specific cell behaviours. Advances in single-cell technologies now allow researchers to study individual immune cells in great detail. This study is the first to examine immunity differences between males and females at single-cell resolution on this scale.
The team sequenced over 1.25 million peripheral blood mononuclear cells – immune cells circulating in the blood – from nearly 1,000 healthy individuals. These participants were part of the OneK1K cohort, a major Australian project designed to map how genetics influence individual immune cells at a population scale.
The analysis revealed distinct cellular profiles between the sexes. Males had higher proportions of monocytes, cells that act as first immune responders, and their genetic activity was more concentrated on basic cellular maintenance and protein-building functions. In contrast, females possessed higher levels of immune cells called B cells and regulatory T cells, with genetic activity heavily skewed towards 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. On the other hand, male immune cells are less primed for inflammation, making men generally more susceptible to infections and non-reproductive cancers," says co-senior author Dr Sara Ballouz, Senior Lecturer at UNSW.
An immune system that is highly reactive is always operating on higher alert; while this vigilance is excellent for fighting off genuine threats, it makes the system more prone to the accidental "friendly fire" against the body's own healthy tissues that causes autoimmune disease.
Surprising genetic switches linked to lupus
Because the researchers analysed the data cell by cell, they were able to spot sex-specific genetic variations that previous bulk studies had missed. They investigated genetic switches that are active in one sex but not the other – called 'expression quantitative trait loci', these act like volume dials controlling how strongly a gene is turned on or off. It is often assumed that immune differences between females and males are driven primarily by the X and Y sex chromosomes. Surprisingly, the researchers found that these sex-specific genetic switches were actually far less common on the sex chromosomes than expected. Instead, they discovered that the vast majority of these variations reside on autosomes – the shared non-sex chromosomes – identifying over 1,000 sex-specific genetic switches in these regions.
Importantly, these genetic controls were linked directly to autoimmune conditions. The team found specific variants affecting the female-biased expression of two genes associated with systemic lupus erythematosus , potentially helping to explain why lupus is nine times higher in women compared to men.
While genetics are just one piece of the puzzle alongside other factors like hormones, these underlying genetic variations establish a distinct biological baseline, shifting how we understand disease susceptibility. "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," Dr Ballouz says. "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."
Moving beyond one-size-fits-all medicine
For people living with conditions like lupus, these findings highlight why widely used autoimmune treatments may not be effective for everyone. Identifying these distinct genetic pathways underscores a long-term need for highly targeted therapies, moving away from broad immunosuppressants that dampen the entire immune system and towards treatments that more precisely target a person's disease presentation.
"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," says Dr Yazar.
"If we want to realise the potential of precision medicine, we have to understand these fundamental biological variables," says Professor Joseph Powell, co-senior author and Director of Garvan's Translational Genomics Program. "Treatments need to be tailored not just to the disease, but to how a patient's immune system operates at a baseline genetic level."
