The New York Times, February 1, 2024
Women are much more likely than men to have their immune system turn against them, resulting in an array of so-called autoimmune diseases, like lupus and multiple sclerosis. A study published on Thursday offers an explanation rooted in the X chromosome.
The research, published in the journal Cell, suggests that a special set of molecules that act on the extra X chromosome carried by women can sometimes confuse the immune system.
Independent experts said that the molecules are unlikely to be the sole reason autoimmune disease skews female. But if the results hold up in further experiments, it might be possible to base new treatments on these molecules, rather than on the current drugs that blunt the entire immune system.
“Maybe that’s a better strategy,” said Dr. Howard Chang, a geneticist and dermatologist at Stanford who led the new study.
Male and female embryos carry 22 identical pairs of chromosomes. The 23rd pair is different: Females carry two Xs, while males carry an X and a Y, which lead to the development of male sex organs.
Each chromosome holds genes that, when “switched on,” produce proteins to do work inside of cells. You might expect that women, with two copies of X, would make twice as many X proteins as men do. Instead, they produce about the same level. That’s because one of the two X chromosomes is silenced.
A molecule called Xist clings to the second X chromosome “like Velcro,” Dr. Chang said. As hundreds of Xist molecules wrap themselves around the X chromosome, they completely shut it down.
Keeping one X silent is crucial to women’s health. If a gene on the second X chromosome escapes Xist’s control, it will result in an excess supply of proteins, some of which could be toxic.
In 2015, it occurred to Dr. Chang that the silencing itself might also have a downside. His epiphany occurred while he was preparing to take his medical board exams to renew his license as a dermatologist.
As part of his studies, Dr. Chang had to brush up on autoimmune diseases, memorizing the names of human proteins that can be targeted by a misdirected immune system. When he looked at the list, he was surprised to see some familiar names.
When Dr. Chang isn’t working as a dermatologist, he researches the X chromosome in his lab. He noticed that many of the proteins involved in autoimmune diseases also helped Xist silence the X chromosome.
Maybe, Dr. Chang thought, that was no coincidence.
The new study emerged from years of research testing his hunch that Xist molecules could cause autoimmune disease. He and his colleagues studied a strain of mice in which the females are at high risk of the autoimmune disease lupus, while the males never develop severe cases.
The researchers genetically engineered the male mice so that they, like the females, produced Xist. “Once the male mice express Xist, they get much worse levels of immune disease,” Dr. Chang said.
The researchers also found that people with lupus or two other autoimmune disorders had high levels of antibodies to Xist-related proteins in their blood.
Dr. Chang suspects that autoimmune diseases may come about during the normal process of cells dying in a woman’s body. The cells spill open, dumping their molecules into the bloodstream. In women, that debris includes a lot of Xist molecules and the proteins attached to them.
When an immune cell encounters an Xist molecule, it also finds a huge number of proteins stuck to it. This unusual experience may confuse immune cells, which then mistakenly start making antibodies to the Xist proteins.
Once the immune system starts treating Xist proteins as the enemy, it may start attacking other parts of the body as well. That’s because every cell sticks fragments of its proteins on its surface, where immune cells can inspect them. If an immune cell encounters an Xist protein fragment, Dr. Chang proposed, it will kill the cell that presents it.
Montserrat Anguera, a geneticist at the University of Pennsylvania who was not involved in the study, said the scenario was plausible. But she also noted that some people make antibodies to these same proteins — including men — without developing autoimmune diseases.
Dr. Melissa Lechner, an endocrinologist at U.C.L.A. who also was not involved in the work, said that while the new study was intriguing, it was possible that the Xist proteins only boost autoimmunity, rather than acting as a causal trigger. “The data doesn’t let me distinguish between the two,” she said.
Some studies suggest that the X chromosome fuels autoimmune diseases in other ways. For instance, it carries a number of genes for proteins that act as signals between immune cells. If one of those genes escapes silencing, it may create extra signals that confuse the immune system.
The challenge the scientists face now is in figuring out how all these factors work collectively to produce the female bias in immune diseases. “This is biology — it’s a beautiful thing but it’s frustrating,” Dr. Anguera said.
Copyright 2024 The New York Times Company. Reprinted with permission.