Women are diagnosed with autoimmune diseases far more often than men, and new research from the Garvan Institute of Medical Research and UNSW Sydney may help explain why. Autoimmune diseases occur when the immune system mistakenly targets the body’s own healthy tissues. Lupus, for example, can affect as many as nine women for every one man, yet the genetic factors behind this striking difference have remained poorly understood.
Researchers have now identified more than 1,000 genetic switches that behave differently in female and male immune cells. These differences appear to contribute to greater activity in inflammation-related pathways in females, offering a new biological explanation for why women may be more susceptible to autoimmune disease.
The findings, published in The American Journal of Human Genetics, provide further evidence that diseases can develop and appear differently in males and females. They also reinforce the importance of including both sexes in medical research, which has historically depended heavily on male study groups.
“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,” says Garvan’s Dr. Seyhan Yazar, first author of the study.
Studying Immune Cells One at a Time
For years, researchers studying immune differences between the sexes were limited by technology. Traditional bulk blood analysis measures average activity across a mixture of many cells, which can hide important differences in the behavior of specific cell types.
New single-cell technologies have made it possible to examine individual immune cells in much greater detail. According to the researchers, this is the first study to investigate male and female immune differences at single-cell resolution on such a large scale.
The team sequenced more than 1.25 million peripheral blood mononuclear cells, which are immune cells circulating in the bloodstream, from nearly 1,000 healthy people. The participants belonged to the OneK1K cohort, a major Australian research project created to investigate how genetics affects individual immune cells across a large population.
Clear differences emerged when the researchers compared the cellular profiles of males and females. Males had larger proportions of monocytes, immune cells that serve as early responders to threats. Their gene activity was also more strongly focused on fundamental cell maintenance and protein production.
Females, by comparison, had greater numbers of B cells and regulatory T cells. Their immune cells also showed much more genetic activity associated with 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. On the other hand, male immune cells are less primed for inflammation, making men generally more susceptible to infections and non-reproductive cancers,” says co-senior author Dr. Sara Ballouz, Senior Lecturer at UNSW.
A more reactive immune system can provide valuable protection because it remains more prepared to respond to genuine threats. However, maintaining that heightened state of readiness may also increase the chance of immune “friendly fire,” in which the body mistakenly attacks its own healthy tissues and triggers autoimmune disease.
More Than 1,000 Genetic Switches Reveal a Hidden Pattern
Examining individual cells allowed the researchers to detect sex specific genetic differences that earlier studies using bulk blood samples could not see.
The team focused on genetic switches that function in one sex but not the other. Known as ‘expression quantitative trait loci’, these switches can be thought of as volume controls that influence how strongly particular genes are activated or suppressed.
Researchers have often assumed that differences between male and female immune systems are largely driven by the X and Y sex chromosomes. The new findings challenged that expectation.
The sex specific genetic switches were much less concentrated on the sex chromosomes than researchers anticipated. Instead, most were located on autosomes, the non sex chromosomes shared by males and females. In total, the researchers identified more than 1,000 sex specific genetic switches in these regions.
Genetic Clues to Why Lupus Affects More Women
Some of these genetic controls were directly associated with autoimmune disease.
The researchers identified particular variants that influenced the female-biased expression of two genes linked to systemic lupus erythematosus. The finding could help explain why lupus occurs about nine times more often in women than in men.
Genetics alone does not determine autoimmune risk. Other influences, including hormones, also play important roles. Even so, these genetic differences appear to establish a distinct biological starting point that could affect a person’s susceptibility to disease.
“This is the first time we have shown that these differences occur at the genetic control level, providing a new layer of insight into human immunity,” Dr. Ballouz says. “Having shown that female-biased genes are heavily enriched in inflammatory pathways, we now have another biological rationale for why the immune system can more easily mistakenly attack the body’s own tissues in women.”
Toward More Personalized Autoimmune Treatments
The findings could also have implications for people living with autoimmune conditions such as lupus. Current treatments do not work equally well for everyone, and many commonly used therapies broadly suppress immune activity throughout the body.
By identifying distinct genetic pathways involved in male and female immunity, the research points toward a future in which treatments could be more precisely targeted to a patient’s particular form of disease rather than broadly weakening the entire immune system.
“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. Currently, clinicians rely on a one-size-fits-all management approach for most autoimmune diseases — a more inclusive approach is needed,” says Dr. Yazar.
“If we want to realize the potential of precision medicine, we have to understand these fundamental biological variables,” says Professor Joseph Powell, co-senior author and Director of Garvan’s Translational Genomics Program. “Treatments need to be tailored not just to the disease, but to how a patient’s immune system operates at a baseline genetic level.”
Dr. Seyhan Yazar is a Conjoint Lecturer at St Vincent’s Clinical School, Faculty of Medicine and Health, UNSW Sydney. Dr. Sara Ballouz is Senior Lecturer in UNSW’s School of Computer Science and Engineering. Professor Joseph Powell is the Director of UNSW’s Institute of Genomics and Health.