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A healthy immune system defends the body against disease and infection. However, for one in 10 people, mostly women, the immune system malfunctions and attacks its own cells. This causes more than 80 types of autoimmune diseases, such as lupus, multiple sclerosis, and rheumatoid arthritis. The reason women may be more affected, according to a couple of recent studies, may be linked to a faulty mechanism that is supposed to shut down one of a woman's two X-chromosomes.
One study from Stanford University shows that a molecule called Xist (pronounced 'exist'), which turns off one copy of the X-chromosome in every cell in the female body, can trigger a rogue immune response. Another study from France, not yet peer-reviewed, shows that when certain genes on the silenced X-chromosome become active again, it can cause lupus-like symptoms in older mice.
Since most autoimmune diseases are diagnosed after puberty, more in girls than in boys, sex hormones were thought to be the primary driver of this difference. For example, four in five patients with autoimmune diseases are women. Ten times more women than men get lupus. And 20 times more women develop Sjögren's syndrome, an illness that mainly causes dry eyes and dry mouth.
"Our study shows that you do not need female sex hormones; you don't even need a second X-chromosome; just this Xist [molecule] could have a major role in developing some autoimmune diseases," says Howard Chang, a dermatologist and molecular geneticist at Stanford University School of Medicine in California, who led the study.
"There is clear evidence now that the sex bias in autoimmune disease is not only linked to hormones but also to the presence of the number of X chromosomes and to the process of X chromosome inactivation," says Claire Rougeulle, an epigeneticist who led the second study at the National Centre for Scientific Research (CNRS) in the Université Paris Cité in France.
That so many antibodies exist that target/destroy the molecules required to silence or shut-off the X-chromosome, "was not known at all," says Jean-Charles Guéry, an immunologist at the Toulouse Institute for Infectious and Inflammatory Diseases (Infinity) in France.
Paradoxically, the increased risk of autoimmune disease in women may even be an evolutionary adaptationto protect the lives of their children. "Women have a better immune system to fight things," says Johann Gudjonsson, a dermatologist at the University of Michigan, Ann Arbor.
Women tend to produce more antibodies than men, which protects both them and their babies through breastmilk, says Vanessa Kronzer, a Rheumatologist at the Mayo Clinic in Rochester, Minnesota.
Hormones are also involved. Female estrogen hormones boost immunity while male hormones not only suppress immunity but also protect against autoimmunity. These differences in sex hormones were thought to explain why women have more robust immunity, making them also more vulnerable to developing autoimmune diseases than men. But that may not be the only reason.
The combination of sex chromosomes inherited during fertilization determines a person's sex. Males inherit an X (left) and a Y (right) chromosome (as seen here); females inherit two copies of the X chromosome. The Y chromosome carries instructions for the development of male characteristics.
Photograph by Biophoto Associates, Science Photo Library
Silencing one X chromosomeEach cell in a woman's body has two X-chromosomes, one from the mother and one from the father. Men have an X-chromosome from their mother and a much smaller Y-chromosome from their father.
The Y-chromosome contains just about a hundred genes, but the X-chromosome contains more than 900.
To make sure the activity of genes located on the X-chromosome is equal in both men and women, one of the two X-chromosomes in every female cell randomly shuts down. This happens early in fetal development when the Xist molecule and its partner proteins coil around one of the X-chromosomes and switch it off. If both X-chromosomes remain equally active, the cell will die.
As a result, the female body contains a mosaic of cells in which either the mother's or the father's X-chromosome is silenced. This X-chromosome inactivation is the reason female Calico cats develop a patchwork of orange and brown fur. While some of their hairs express a black color from one active X-chromosome, others develop an orange color from the other.
However, X-chromosome inactivation is far from perfect, and 15 to 23 percent of genes remain active. One such gene that continues to function, when it should not, has been linked to lupus. More evidence comes from boys and men who are born with an extra X chromosome who also have an increased risk of developing autoimmune diseases, suggesting the critical role of the X chromosome.
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What do long flights do to our bodies? Xist triggers autoantibodiesChang has been studying the Xist molecule for many years and in 2015 he discovered that many proteins working together with Xist were involved in autoimmune disorders and were attacked by rogue antibodies, called autoantibodies. Instead of fighting foreign invaders, such as germs, autoantibodies mistakenly target an individual's own cells.
To test whether faulty X-chromosome inactivation was the reason more women suffer from autoimmune diseases than men, Chang's team engineered male mice that produce the Xist molecule, which is usually only present in female cells.
However, Xist molecule alone did not cause the autoimmune disease in the engineered male mice.
Only when researchers injected an irritant into these genetically modified male mice did the levels of autoantibody rise and trigger a lupus-like disease. With the addition of the irritant, the autoantibody levels in Xist-producing males matched those in females and were higher than in normal males without Xist. These engineered mice also showed more extensive tissue damage and signs of heightened inflammation when exposed to the irritant.
That suggests that even with Xist, either a genetic susceptibility or an environmental trigger is needed to cause the female-biased autoimmune disease. The study hints that only when cells get damaged, either by an environmental trigger or due to genetic susceptibility, Xist molecules and its protein partners leak outside of the cell and cause the immune system to produce autoantibodies against the Xist-protein complex, which then initiates an autoimmune disease.
"So that's one major reason why, of course, most women do not get autoimmune disease," says Chang. "Even though every woman is expressing Xist throughout their body."
X-chromosome ties to lupusRougeulle collaborated with Céline Morey, a fellow epigeneticist in Paris, to understand what happens when the X-chromosome is not completely turned off.
They engineered female mice to display imperfect X-chromosome inactivation—in which most, but not all, the genes on the second X-chromosome were shut off. The researchers resorted to incomplete inactivation because blocking all Xist activity would keep both X-chromosomes fully functional and kill the mice. While French scientists weren't expecting their mice to develop an autoimmune disease, they were surprised when engineered female mice showed symptoms of a lupus-like condition.
"You don't see the symptoms of autoimmune disease in these mice right away, but you begin to see it as they get older," says Morey.
This supports Guéry's 2018 study that showed that when a gene that promotes inflammation escapes inactivation in immune cells, it increases risk of developing lupus.
The common theme between the Stanford and French study is that both link the X-chromosome, and the process of X-chromosome inactivation, to autoimmunity, says Rougeulle.
Mechanisms linked with X-chromosome inactivation do seem to explain the sex differences in some autoimmune diseases such as lupus and Sjögren's, says Guéry. "[But] you cannot have a single mechanism for all autoimmune diseases."
Predicting who might develop an autoimmune diseaseThe Stanford study discovered that autoantibodies against many proteins associated with Xist are found in the blood of patients suffering from auto-immune diseases, such as lupus, scleroderma, or dermatomyositis.
While some autoantibodies were specific to certain autoimmune diseases, others were common among several. So, it might be possible to develop a panel of autoantibodies that could be used to distinguish between different disorders.
Rougeulle warns, however, that the current studies do not show whether the autoantibody levels rise significantly preceding the diseases, so more studies are needed before a diagnostic tool can be developed.
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