Women are diagnosed with autoimmune diseases far more often than men — lupus alone affects up to nine women for every one man — and new research from the Garvan Institute of Medical Research in Sydney may help explain why. Scientists have identified more than 1,000 genetic switches that operate differently in male and female immune cells, providing the first large-scale single-cell resolution view of sex-based immune differences.

The study, published in The American Journal of Human Genetics, sequenced more than 1.25 million peripheral blood immune cells from nearly 1,000 healthy participants in Australia's OneK1K cohort. Comparing cellular profiles between sexes, the researchers found that males had larger proportions of monocytes focused on basic cell maintenance, while females had more B cells and regulatory T cells with much higher genetic activity in 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 Dr. Sara Ballouz, co-senior author at UNSW Sydney. "On the other hand, male immune cells are less primed for inflammation, making men generally more susceptible to infections."

Crucially, the researchers found that most of the 1,000+ sex-specific genetic switches were not on the X and Y chromosomes, as long assumed, but on autosomes — the non-sex chromosomes shared by both sexes. Some of these switches were directly associated with autoimmune disease risk, including variants that influence the expression of two genes linked to systemic lupus.

The findings could have significant implications for treatment. Current autoimmune therapies broadly suppress immune activity, but the study suggests that male and female autoimmune diseases may operate through different biological mechanisms and could benefit from sex-specific treatment approaches.

"If we want to realize the potential of precision medicine, we have to understand these fundamental biological variables," said Professor Joseph Powell, co-senior author and Director of Garvan's Translational Genomics Program.

Sources