Over 1,000 Genetic Switches Help Explain Why Female Immunity Differs From Male

Women are diagnosed with autoimmune diseases -- conditions in which the immune system mistakenly attacks the body's own healthy tissue -- far more often than men; lupus, for example, affects as many as nine women for every man. New research from the Garvan Institute of Medical Research and UNSW Sydney, published in The American Journal of Human Genetics, has identified more than 1,000 genetic switches that behave differently in female and male immune cells, offering a biological explanation for the gap.

'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,' said Dr. Seyhan Yazar of Garvan, the study's first author. The team sequenced more than 1.25 million peripheral blood mononuclear cells, the immune cells that circulate in the bloodstream, from nearly 1,000 healthy people in the OneK1K cohort, a major Australian research project -- the first study to examine sex differences in immunity at single-cell resolution on this scale.

Males had larger proportions of monocytes, early-responder immune cells, with gene activity focused mainly on cell maintenance and protein production. Females had more B cells and regulatory T cells, and their immune cells showed far more genetic activity tied to 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. Male immune cells are less primed for inflammation, making men generally more susceptible to infections and non-reproductive cancers,' said co-senior author Dr. Sara Ballouz of UNSW Sydney.

Contrary to researchers' expectations, the sex-specific genetic switches they found were concentrated not on the X and Y sex chromosomes but mainly on the autosomes, the chromosomes shared by both sexes; among them were variants that influence the female-biased expression of two genes linked to systemic lupus erythematosus, offering a possible explanation for why the disease occurs about nine times more often in women.