Study Unveils Sex Differences in Immune Genetics

New research from the Garvan Institute of Medical Research and UNSW Sydney reveals why women face higher rates of autoimmune diseases. The immune system in women shows greater activity in inflammatory pathways compared to men, increasing susceptibility to conditions where it attacks healthy tissues. Scientists identified over 1,000 genetic switches—known as expression quantitative trait loci—that function differently in female and male immune cells. 

Published in The American Journal of Human Genetics, the findings stress the importance of studying both sexes in medical research. Past efforts often focused on male cohorts, overlooking key immune variations. “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,” states first author Seyhan Yazar.

Advances in single-cell technologies enabled this detailed analysis. The team examined over 1.25 million peripheral blood mononuclear cells from nearly 1,000 healthy individuals in the OneK1K cohort. This approach uncovered specific cellular differences missed by earlier bulk blood studies.

Men exhibited more monocytes, immune first responders focused on cellular maintenance and protein production. Women had elevated B cells and regulatory T cells, with genetic activity tilted toward inflammation. “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,” explains co-senior author Sara Ballouz.

Most sex-specific genetic switches appeared on autosomes, not sex chromosomes as commonly assumed. These controls linked to autoimmune risks, including variants influencing two genes tied to systemic lupus erythematosus, which affects women nine times more than men.

The study challenges one-size-fits-all treatments like broad immunosuppressants. “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,” Dr. Yazar notes.