Why the immune system turns on women more often than men

As many as 50 million Americans live with an autoimmune disease, a broad category of disorders in which the immune system mistakenly attacks the body’s own tissues. Many of these conditions are chronic, debilitating and cannot be cured.

Roughly 80% of people living with an autoimmune disease are women. Women are roughly nine times more likely than men to develop lupus, where the immune system attacks organs throughout the body. Sjögren’s syndrome — which damages moisture-producing glands such as those that make tears and saliva — may be nearly 19 times more common in women. Women are also about three times more likely to develop Multiple Sclerosis, a disease in which the immune system attacks the protective covering surrounding nerve fibers in the brain and spinal cord.

While scientists have long recognized this pattern, emerging research is beginning to converge on a complex underlying explanation: Women appear to have evolved more robust and flexible immune systems.

“It’s kind of well understood now that females tend to have a more robust adaptive immune system,” said Shannon Dunn, an immunology professor at the University of Toronto. “That same biology also applies to when the immune system starts to attack itself.”

Researchers say the imbalance appears to be driven by a complicated mix of hormones, immune-related genes carried on the X chromosome and the unique demands pregnancy places on the female immune system.

An epidemic

Autoimmune diseases have steadily risen both in the U.S. and globally over the past three decades, in what some researchers and advocates have described as an emerging epidemic.

While greater awareness and improved detection may explain some of the increase, many researchers argue the true prevalence of autoimmune disease is rising. Scientists suspect the increase is driven by a combination of environmental and lifestyle changes — including shifts in diet, exposure to pollution and altered gut microbiomes — interacting with genetic susceptibility.

One leading theory is that modern life may be changing the immune system’s development. The so-called “hygiene hypothesis,” first proposed in the 1980s, suggests that reduced exposure to microbes, parasites and infections early in life may leave the immune system improperly trained, making it more likely to overreact later.

A growing body of research has linked exposure to environmental pollutants and endocrine-disrupting chemicals — including substances found in plastics, pesticides, industrial chemicals and air pollution — to immune dysregulation and increased risk of autoimmune disease, though scientists are investigating which exposures may be most harmful and how they alter immune function over time. Smoking, for example, remains one of the clearest established environmental risk factors for diseases like rheumatoid arthritis and lupus.

Scientists are also investigating whether viral infections may trigger disease in genetically susceptible people. A landmark study found strong evidence linking Epstein-Barr virus infection to the later development of multiple sclerosis.

Researchers have also linked highly processed Western diets to rising obesity rates, which can contribute to chronic inflammation, immune dysfunction and less diverse gut microbiomes. Fat tissue itself produces inflammatory signaling molecules that may help drive autoimmune activity. Studies have found that people with autoimmune diseases often have altered microbiomes, and animal research has shown gut bacteria can directly influence autoimmune risk and even sex differences in disease prevalence.

While some of these theories may help explain the overall rise in autoimmune diseases, they do not fully explain why women appear to be far more susceptible.

A stronger immune system

Researchers are moving toward a consensus on why women appear to be far more vulnerable to many of them.

For one, women generally mount stronger adaptive immune responses than men. The adaptive immune system is the branch responsible for learning and memory, creating specialized T cells and antibodies that remember previous infections and respond rapidly when the body encounters them again. Following an infection or vaccination, women produce higher levels of antibodies and generate more vigorous inflammatory responses. Women also tend to clear some infections more efficiently.

The reason for this might be evolutionary. Females across many species appear biologically “hard-wired” to invest more energy into immunity and long-term health maintenance, Dunn said, perhaps because reproductive success historically depended on surviving pregnancy and protecting offspring. (Males, on the other hand, tend to invest more energy in growing bigger.)

Some evolutionary biologists have proposed that autoimmunity may be an unintended consequence of the female immune system’s unusual flexibility: Pregnancy requires the body to tolerate a fetus that is genetically half foreign — something that would normally trigger an immune attack. During pregnancy, however, extremely high hormone levels shift the immune system into a more suppressive and tightly regulated state to prevent rejecting the fetus.

In 2019, researchers outlined the “pregnancy compensation hypothesis,” arguing that the female immune system evolved this remarkable adaptability to support pregnancy, but that the same flexibility may also increase susceptibility to autoimmune disease later in life.

Hormones appear to be at play as well. Testosterone — which is present at much higher levels in men — generally acts to tone down the immune system. Dunn said it reduces the activity of several types of immune cells, lowers antibody production and dampens inflammatory signals that help drive immune responses.

Outside of pregnancy, estrogen generally has the opposite effect, boosting immune activity by increasing antibody production, activating immune cells and amplifying inflammatory responses.

Researchers have long noticed that autoimmune diseases often emerge during periods of hormonal transition. Diseases like lupus and multiple sclerosis commonly appear during women’s childbearing years, while symptoms of some autoimmune disorders improve during pregnancy before flaring again after delivery.

Several physicians have published case reports documenting transgender women developing autoimmune diseases such as lupus after beginning estrogen therapy, while others reported that transgender men receiving testosterone experienced reductions in certain inflammatory immune markers. Other small, observational studies have reported broader immune-system changes during gender-affirming hormone therapy, including shifts in T cells, antibody production and inflammatory signaling that appear to move toward patterns more typically associated with the hormone-associated sex.

The X chromosome

But hormones alone do not appear to fully explain differences in male and female immune systems.

Scientists are also increasingly focused on the X chromosome. Women carry two X chromosomes, while men typically carry one X and one Y. For years, researchers believed one of the female X chromosomes was largely switched off early in development. Now, newer research shows many immune-related genes on the supposedly “inactive” X chromosome remain partially active. Some of those genes are directly involved in regulating immune responses and inflammation.

Researchers have found that women with autoimmune diseases like lupus often show increased activity of these X-linked immune genes. Another group of researchers found that men with Klinefelter syndrome — a condition in which males carry an extra X chromosome — also face substantially elevated autoimmune risk.

In 2024, researchers at Stanford Medicine identified another possible explanation. They reported that a molecule called Xist, which helps switch off one of the two X chromosomes in female cells, may also attract attacks from the immune system. When male mice were genetically engineered to produce Xist, they developed lupus-like autoimmune disease at rates similar to female mice.

Toward targeted treatment

The growing understanding of how hormones, chromosomes and evolutionary forces shape susceptibility to autoimmune disease could eventually lead to more personalized treatment and earlier detection.

While directly treating autoimmune diseases with hormone therapies is unlikely in most cases, Dunn said researchers are increasingly exploring the downstream effects of hormones on the immune system to identify pathways where drugs or other therapies could intervene with fewer major side effects.

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Ella Rae Greene, Editor In Chief

Ella Greene

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