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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 greater detail. This study is the first to examine immunity differences between males and females at single-cell resolution on this scale.

The team sequenced more than 1.25 million peripheral blood mononuclear cells – immune cells circulating in the blood – from nearly 1000 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 had 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,” said co-senior author Dr Sara Ballouz, from 91ɫ��Ƭ’s School of Computer Science and Engineering.

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

An immune system that is highly reactive is always operating on high alert. While this vigilance is excellent for fighting off genuine threats, it makes the system much 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 these sex-specific genetic switches were far less common on the sex chromosomes than expected. Instead, they discovered the vast majority of these variations reside on autosomes – the shared non-sex chromosomes – identifying more than 1000 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 , potentially helping to explain why lupus is nine times more common in women compared with men.

While genetics are just one piece of the puzzle alongside 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 said. “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.

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.”

Co-senior author Professor Joseph Powell, Director of Garvan’s Translational Genomics Program and the, said the findings could help pave the way for more precisely targeted treatments.

“If we want to realise 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.”