Women have supercharged immune systems and we now know why

The women in my family are hardy, to put it lightly. They have shaken off countless illnesses and powered through pregnancies. They’ve managed this in spite of questionable lifestyle choices (let’s just say a taste for gin and Virginia Slims didn’t stop my grandmother from hitting her 90s before she slowed down). For at least five generations, the women in my lineage have cruised into old age seemingly unfazed by what life – or their own predilections – threw at them.

As fun and fabulous as my female relatives were and are, my family isn’t unique. It is possible that yours tells a similar story.  Statistically, women don’t just outlive men, but they are also better at fighting off almost every challenge to their health. They even get more benefit from vaccination. And there’s a reason for that. Their immune systems are superior – faster, stronger and more durable than men’s. This advantage is seen across continents, historical periods and illnesses. It is recognised by traditional medical systems such as Ayurveda.

Now, research by immunologists, virologists and geneticists is finally exposing why, illuminating the reasons for women’s long-known yet under-examined immune strength. It reveals the roles that hormones and sex chromosomes play in supercharging women’s immune cells to detect, fight and remember intruders, and in keeping their immune systems more youthful for longer than men’s.

This knowledge can be harnessed to design more precise, sex-specific health interventions. It already informs cancer therapies, and it could result in differing vaccine protocols and treatments for a variety of infections. It’s not only women who stand to benefit. In an age of global pandemics and vaccine uncertainty, understanding the female immune advantage will improve the health of everyone.

The stronger sex

The historical lack of research into female bodies throughout medical science extends to immunology. To date, it has favoured a “one-size-fits-all approach skewed toward male biology”, says Caroline Duncombe at Stanford University in California, whose research explores the ways that sex-based differences influence immune response. The fact that immunology research is still underpinned by foundational knowledge based largely on studies of men is a problem for women. “Biological sex is one of the most important factors affecting health and disease across the lifespan,” she says, “because it affects environment and lifestyle, as well as genetics and hormones – all of which are important when you’re evaluating immune response.”

But the male bias in research is also a problem for men. “[Women] have an immunity advantage that could have offered insights had it not been neglected for so long,” she says.

XX chromosome advantage

What has become apparent from research on immunity in female bodies is that a significant part of this advantage lies in the sex chromosomes. The usual female complement is two X chromosomes, one from each parent, both packed with genes related to immune function. Those who are male usually inherit one X chromosome from their mother and a diminutive Y chromosome with fewer genes on it from their father. “The X chromosome has the greatest number of immune-related genes, so having two copies gives women a genetic advantage,” says immunologist Duygu Ucar at the Jackson Laboratory in Connecticut.

Although one copy is usually inactivated to ensure the correct amount of protein is produced, between about 15 and 25 per cent of genes escape this silencing. And these escapees often have a role in immunity. As a result, female bodies have more options when faced with threats. “This stronger gene expression leads to a more potent immune system,” says immunologist Petter Brodin at the Karolinska Institute in Stockholm, Sweden.

Such strength in diversity is obvious when you look at the first line of defence against intruders, known as innate immunity. It consists of cells bristling with a range of receptors, including killer-activated receptors, pattern-recognition receptors and toll-like receptors, which detect the presence of pathogens, then initiate a response involving a slew of other immune cells to fight off intruders and heal the body.

With greater variability and redundancy in the genes coding for them, female receptors can respond to a wider range of pathogens faster and more reliably. The result? Infections are caught earlier, giving female bodies a head start in eliminating them – often before symptoms even appear.

Escapee genes may also help explain why women are around 20 per cent less likely to develop most types of cancer than men. Cancer cells often contain mutations in genes that help suppress tumours. Some of these genes are on the X chromosome, and when things go awry, escapee genes provide women with a backup copy that can override the error. Not so for men. Indeed, new research by Margaret Gadek at the University of California, San Francisco, and her colleagues indicates that the same system of redundancy provided by two X chromosomes could also help explain why female brains show greater resilience in ageing.

Meanwhile, the Y chromosome, once considered a genetic wasteland that is set to disappear from the human genome with time, is now known to influence immunity too – but not always in a good way. In particular, a lineage of the Y chromosome common in men of European descent leaves them with an elevated risk of coronary artery disease due to increased inflammation and a suppressed immune response. Separately, a gene called UTY seems to underpin an immunity-driven susceptibility to complex diseases in some men.

One way we know that some of the female immune advantage lies in fundamental genetics is that it lasts a lifetime. Research shows that women of all ages are less likely to get hospital-acquired infections than men. “If you trigger a female immune system with a virus, it is more likely to respond more strongly than a male, and it doesn’t matter when in life you do this,” says Brodin.

Precision immune attack

Hormones have an impact too. Oestrogen enhances both arms of the immune system: innate immunity – those first responders – and adaptive immunity, which develops over time. It does this by modulating the activity of immune cells, which helps them to coordinate a faster, more precise attack.

We already saw that having two X chromosomes gives the innate immune system a more diverse range of receptors on its cells. And it turns out that oestrogen can also boost the power of some of these cells, including neutrophils, the white blood cells that engulf and destroy intruders. Immunologists knew that women have more neutrophils than men. More recently, they have found that oestrogen helps activate these cells, making them more sensitive to invaders and increasing the efficiency of their pattern-recognition receptors. Research by Sarthak Gupta at the US National Institutes of Health and his colleagues revealed that this is what makes neutrophils in women better equipped to detect and destroy pathogens, particularly in those aged between 20 and 30.

Oestrogen also influences the development of B-cells, the elite task force of the adaptive immune system that produces antibodies to lock onto and neutralise invaders. In a process called somatic hypermutation, B-cells mutate up to a million times faster than other cells to fine-tune their antibody output, and women’s immune systems run more cycles of this refinement. This means tighter-fitting antibodies and more effective immune responses.

As well as producing antibodies, B-cells create the body’s memory of pathogens encountered in the past. Once formed, memory B-cells can last for decades or even a lifetime. And across a wide range of species, females retain these cells for longer than males, suggesting it evolved as an adaptive advantage, probably so mothers can transfer protective antibodies to their offspring. It may also explain why girls and women tend to have stronger, more durable responses to vaccines. If their bodies already have a memory of a virus, the challenge from a vaccine will provide a bigger uplift in immunity.

The key to differences in lifespan?

Hormones are involved here too, but they can’t be the whole story because postmenopausal women retain their superior B-cell function. What’s more, this seems to be a key factor when it comes to keeping the immune system stronger for longer. Research by Ucar and her colleagues found that both men and women lose immune capacity, starting in their 40s. However, men hit a second decline in their early 60s, whereas this comes about five years later in women – “which could be linked to differences in lifespan”, says Ucar. The biggest difference was after the age of 65, when women’s B-cells (and T-cells, the other major component of the adaptive immune system) were more active than men’s. This, she suggests, might explain why older men are more prone to infectious diseases than older women.

The downside for women of all ages is that a more reactive immune system can sometimes overcorrect and attack the body it is supposed to defend. Women account for between 70 and 80 per cent of people with autoimmune diseases and, although the exact mechanisms aren’t known, there is no doubt that this is underpinned by both genes and hormones. “Women have a greater resistance to infectious diseases and cancer, but greater susceptibility to all kinds of unpleasant autoimmune diseases,” says Mark Davis at Stanford University. “It’s a double-edged sword.”

There is still much to be discovered about the immunological differences between the sexes, but what we know already exposes the inadequacy of the one-size-fits-all approach to the science of immunity. For a start, it means we are missing the nuanced picture when it comes to women. “People have hormones in different amounts throughout life, so understanding and taking into account that impact is really important,” says Duncombe.

It also has big implications for medical research. In trials for new antivirals and vaccines, if data from male and female participants is lumped together, sex-specific reactions get averaged out, potentially leading to men getting too low a dose and women being given too much, or providing the wrong treatment entirely. That’s not to mention how treatments might be tailored for transgender people, where there has been even less research.

Cancer treatment is another area where a person’s sex really matters. “Sex hormones influence your response to different types of cancer therapies, by both influencing tumour growth directly and the immune response trying to fight it off,” says Duncombe. Here, however, researchers are beginning to recognise that they can use this knowledge to their advantage. “Understanding how you can leverage different hormones to maximise or minimise your immune response to different cancer therapies is being actively researched for this reason,” she says. For example, researchers know that oestrogen acts as a catalyst for breast cancer growth, and they are designing therapies that could prevent activation by blocking that hormone’s receptors.

Others who could benefit from this approach are people with long covid or myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). New research by Davis and his colleagues has found that both men and women with these conditions have high levels of reactive oxygen species (ROS), chemically reactive molecules that are a normal by-product of energy production in cells and play a critical role in immunity. “You have to elevate ROS to activate B-cells and T-cells to do their job,” says Davis.

ROS levels in these women are especially high, which may help them fight off infections, but this comes at a cost: an even higher risk of autoimmune diseases than usual. This is useful knowledge because preliminary studies suggest that a common diabetes drug called metformin can lower ROS levels, offering a promising treatment for people with long covid and ME/CFS – especially women.

If medicine had paid closer attention to the ways female bodies fight illness, heal and adapt to health challenges, we might already have better vaccines, fewer autoimmune flare-ups and more targeted treatments for conditions like long covid and cancer. So, it is good news that researchers are finally looking at women’s immune systems on their own terms, not just as quirky deviations from a male baseline. What they are discovering is something those hardy women in our family trees seemed to know intuitively: strength isn’t just about brute force. It is about endurance, adaptability and outsmarting pretty much everything.

Just ask my grandma.

Starre Vartan is the author of  The Stronger Sex: What science tells us about the power of the female body.