Why are women more likely to get autoimmune diseases like lupus and multiple sclerosis?
A million-cell study points to baseline sex-related genetic differences in the immune system.
- 29 May 2026
- 5 min read
- by Priya Joi
At a glance
- A new study analysed differences in gene activity in men and women in more than 1.25 million immune cells from 982 people.
- The researchers found over 1,000 genetic ‘switches’ that work differently between the sexes, with immune cells from women showing higher baseline activity in inflammatory pathways linked to autoimmune disease.
- The findings could help explain why women face a higher risk of conditions like lupus and potentially inform more tailored treatments.
A new study of more than a million immune cells offers an explanation for one of immunology’s long-standing puzzles: why autoimmune diseases overwhelmingly affect women.
Multiple sclerosis, for instance, affects three times as many women as men. With lupus, the gender split is even more acute – there are nine women to every man with the disease. The reasons have been thought to involve sex chromosomes, sex hormones and immune cell behaviour, but the cellular detail has been hard to pin down.
A more reactive immune profile means women are generally better at fighting off viral infections, and tend to mount stronger responses to vaccines.
In a study published in The American Journal of Human Genetics in May 2026, researchers in Australia found that female imune cells are running their inflammatory machinery at a higher baseline than male immune cells.
What’s more, more than 1,000 genetic ‘dials’ work differently in men and women in ways that influence the volume at which a gene is expressed; and two of those dials sit on genes already linked to lupus.
The study adds a new layer to the explanation, suggesting that on top of the known roles of sex chromosomes and hormones, sex differences are also written into the baseline genetic activity of immune cells themselves.
They also point towards more tailored treatments for autoimmune conditions that are currently managed with one-size-fits-all drugs.
Investigating sex differences
The team at the Garvan Institute of Medical Research and the University of New South Wales in Australia, with collaborators at the University of Tasmania and the University of Queensland, used single-cell RNA sequencing to compare gene activity across more than 1.25 million immune cells from 982 people, 564 of them female and 418 male.
The blood samples came from a cohort recruited as part of an earlier large immune study in Australia.
Rather than averaging gene activity across a mixture of cells, as most previous studies have done, the team looked at each cell individually.
Around 1,200 cells were sequenced per person. The cells were sorted into 30 distinct types, and the researchers compared men and women in three ways: the proportions of different immune cells they carried, the activity of genes inside those cells and the small genetic variations that influence how active those genes are.
“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,” said co-author Sara Ballouz, bioinformatician at the University of New South Wales.
Different cells, different gene activity
The team found that men carried more of the ‘first responder’ cells that act as the immune system’s front line, detecting invaders and raising the alarm (monocytes, dendritic cells and natural killer cells).
Women carried more of the cells that produce antibodies and more of the precursor cells that get activated into targeted responses against specific threats (B cells and naive CD4 T cells). The authors note these are the same cell populations most often involved in autoimmune disease.
The team also looked at what was happening inside the cells. They found 78 genes that were behaving differently in men and women across 24 cell types. Most of those genes were more active in women.
When the researchers looked at what those genes do, a pattern emerged. Many of the genes that were more active in women play a role in inflammation, and have previously been linked to autoimmune disease.
The genes that were more active in men were mostly involved in routine cell maintenance.
In other words, female immune cells appear to be more ready to mount an inflammatory response, even before they encounter a threat.
Immune trade-off
The picture that emerges, say the researchers, is one of biological trade-off.
A more reactive immune profile means women are generally better at fighting off viral infections, and tend to mount stronger responses to vaccines, a pattern the authors note has been documented across multiple vaccine types.
But the same heightened reactivity increases the risk that healthy tissue gets caught in the crossfire.
“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,” said Ballouz.
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“On the other hand, male immune cells are less primed for inflammation, making men generally more susceptible to infections and non-reproductive cancers.”
The researchers also identified more than 1,000 sex-specific ‘genetic dials’ that influence how genes behave in immune cells. Two of these dials were found on the FCGR3A gene and the ITGB2 gene, both showing female-biased expression, and both genes have previously been linked to systemic lupus erythematosus, which is much more common in women.
Why it matters for treatment
For now, treatments for autoimmune conditions such as lupus are largely one-size-fits-all, aimed at dampening inflammation across the board. The team argues that as understanding of these underlying differences grows, treatments could be designed more precisely.
“If we want to realise the potential of precision medicine, we have to understand these fundamental biological variables,” said co-author Joseph Powell, statistical geneticist at the Garvan Institute. “Treatments need to be tailored not just to the disease, but to how a patient’s immune system operates at a baseline genetic level.”
The researchers note some limitations. The immune cells in the study were not stimulated by an active infection, so the differences captured reflect a resting baseline rather than what happens during illness.
Hormonal fluctuations were not measured directly, and the cohort was sampled at a single point in time. Future work, the authors suggest, will need to explore how these baseline differences shift under stress, infection or hormonal change.
“Our findings show that the immune system needs to be studied with sex in mind,” said co-author Seyhan Yazar of the Garvan Institute of Medical Research.
“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.”
