Autoimmune diseases, where the immune system mistakenly targets the body, are significantly more prevalent in women. A recent study involving the analysis of over 1.25 million blood cells sheds light on this phenomenon.
This analysis, conducted by the Garvan Institute of Medical Research in Australia, identified more than 1,000 genetic ‘switches’ in immune cells that operate differently based on sex.
These differences in gene activity suggest that the inflammatory pathways, which are crucial in responding to threats, tend to be more active in women. This increased activity could elevate the risk of autoimmune conditions such as lupus and multiple sclerosis.
“Our findings illustrate the importance of considering sex when studying the immune system,” says Seyhan Yazar, a computational biologist at the Garvan Institute.
“Despite awareness that men’s and women’s immune systems are distinct, many studies still ignore these disparities, potentially hindering disease understanding and treatment options,” Yazar adds.
The study collected blood samples from 982 participants, comprising 564 females and 418 males.
The researchers then employed single-cell RNA sequencing, a precise technique to measure gene activity, to examine peripheral blood mononuclear cells (PBMCs), which include various white blood cells circulating in the bloodstream.
This research marks the first time that immune cell differences have been studied with such detail, profiling individual cells rather than averaging gene activity across multiple cells.
The study found that males and females have different compositions of immune cells. Men have more ‘first responder’ monocyte immune cells, with a genetic focus on maintenance, repair, and construction.
In contrast, women possess higher levels of B and T cells in their immune systems, indicating a more specialized and adaptive defense. These cells are genetically coded to be vigilant and ready for immediate action.
This heightened state of alert in female immune systems may enhance their ability to combat foreign invaders, but it also raises the risk of mistakenly attacking healthy tissue.
This reasoning is consistent with earlier research into sex-specific genetic signals and other factors, including antibodies and hormones. However, the current study highlights fundamental genetic differences influencing immune responses at the single-cell level.
“Our research reveals that genes favoring females are significantly enriched in inflammatory pathways, providing another rationale for why women’s immune systems might mistakenly target their own tissues,” says Sara Ballouz, a bioinformatician from the University of New South Wales in Australia.
“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.
“In contrast, male immune cells are less primed for inflammation, making men generally more susceptible to infections and non-reproductive cancers.”
The genetic ‘switches’ driving this cell activity, known as expression quantitative trait loci, were discovered in unexpected places, including autosomes, which are chromosomes shared between sexes, in addition to the X and Y chromosomes.
To further solidify the autoimmune connection, two specific gene switches that were more active in females were identified for the FCGR3A and ITGB2 genes, which have been previously linked to systemic lupus erythematosus, a condition more prevalent in women.
These findings not only enhance our understanding of why autoimmune diseases disproportionately affect women but also pave the way for developing personalized treatments.
For diseases like lupus, the current standard is one-size-fits-all medications aimed at reducing inflammation. Given the biological differences between men and women, these treatments could be significantly more effective with targeted precision.
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“To fully leverage precision medicine, we must grasp these essential biological variables,” says Joseph Powell, a statistical geneticist at the Garvan Institute.
“Treatments need to be tailored not just to the disease, but to the fundamental genetic operation of a patient’s immune system.”
The research has been published in The American Journal of Human Genetics.
