For decades, scientists have known that men and women can experience diseases differently. Now, a large-scale genetic study is providing a deeper explanation for one important reason why: the immune systems of males and females are controlled differently at the genetic level.
Researchers found more than 1,000 sex-specific genetic switches that influence immune activity. The findings, published in The American Journal of Human Genetics, offer fresh insight into why women tend to have stronger immune responses, but also face a much higher risk of autoimmune diseases.
Looking at Immune Cells One by One
Traditional studies often analyze blood as a whole. While useful, this approach can hide differences between individual types of immune cells.
Researchers used advanced single-cell technology to look at more than 1.25 million immune cells collected from nearly 1,000 healthy people in the OneK1K cohort. This allowed them to examine how individual cells behave in males and females.
The differences were striking. Men tended to have higher proportions of monocytes, which act as early responders when the body encounters a threat. Their immune cells also showed stronger activity related to basic cell maintenance and protein production.
Women, meanwhile, had greater numbers of B cells and regulatory T cells. Their immune cells also displayed stronger activity in inflammatory pathways.
That heightened immune response can be beneficial. It may help women fight viral infections more effectively. However, there is a downside: an immune system that is highly ready to react may also be more likely to mistakenly attack healthy tissues.
This phenomenon, sometimes described as immune “friendly fire,” is one reason autoimmune diseases are much more common in women.
A Genetic Pattern Hidden in Plain Sight
Perhaps the most surprising discovery was where these differences were found.
Scientists have often assumed that sex-related differences in immunity would mainly come from the X and Y chromosomes. Instead, researchers found that most of the more than 1,000 sex-specific genetic switches were located on autosomes—the chromosomes shared by both sexes.
These switches act somewhat like volume controls for genes, influencing how strongly certain genes are turned on or off. Finding sex-specific controls on ordinary chromosomes suggests that differences between male and female immunity are more complex than previously understood.
A Possible Clue to Lupus
The research also uncovered genetic clues connected to systemic lupus erythematosus, an autoimmune disease that affects women far more often than men.
Some of the genetic variants identified by the researchers influenced the female-biased activity of two genes associated with lupus. Genetics is only one part of the story, since hormones and environmental factors also influence autoimmune disease. Still, these findings suggest that women may begin with a different genetic immune “setting” that can affect their vulnerability to disease.
What This Could Mean for Future Treatments
The study could eventually influence how autoimmune diseases are treated.
Many current therapies work by broadly suppressing the immune system. While this can reduce harmful inflammation, it can also weaken useful immune responses.
Understanding the genetic differences between male and female immune systems could help researchers develop more targeted treatments. Instead of relying on a one-size-fits-all approach, future therapies might consider a person's sex-specific biology and individual genetic profile.
The researchers say these findings reinforce an important message: medical research needs to study both sexes carefully. If biological differences are overlooked, treatments may not work equally well for everyone.
As precision medicine continues to evolve, understanding how the immune system operates at its genetic baseline could be an important step toward treatments designed not only for a disease, but for the individual experiencing it.