Women are much more likely than men to have their immune systems turn against them, resulting in a range of so-called autoimmune diseases, such as lupus and multiple sclerosis. A study published Thursday offers an X-chromosome-based explanation.
The research, published in the journal Cell, suggests that a special set of molecules that act on the extra X chromosome that women carry can sometimes confuse the immune system.
Independent experts said the molecules are unlikely to be the only reason the autoimmune disease disfigures women. But if the results hold up in further experiments, it may be possible to base new treatments on these molecules, rather than current drugs that dampen the entire immune system.
“Maybe this is 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 one X and one Y, which lead to the development of male genitalia.
Each chromosome contains genes that, when “turned on,” make proteins to work inside cells. You might expect that women, with two copies of X, would produce twice as many X proteins as men. Instead, they produce roughly the same level. This is because one of the two X chromosomes is silenced.
A molecule called Xist attaches to the second X chromosome “like Velcro,” Dr. Chang said. As hundreds of Xist molecules wrap around the X chromosome, they completely shut it down.
The silence of one X is vital for women’s health. If a gene on the second X chromosome escapes the control of Xist, it will lead to an oversupply of proteins, some of which could be toxic.
In 2015, Dr. Chang thought that gagging itself might have a downside. His epiphanies 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 examine autoimmune diseases by memorizing the names of human proteins that may be targeted by a misguided immune system. When he looked at the list, he was surprised to see some familiar names.
When Dr. Chang is not 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.
Perhaps, thought Dr. Chang, this was no accident.
The new study grew out of years of research testing his belief that Xist molecules could cause autoimmune disease. He and his colleagues studied a strain of mice in which females are at high risk of the autoimmune disease lupus, while males never develop severe cases.
The researchers genetically engineered the male mice so that, like the females, they produced Xist. “Once male mice express Xist, they show 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.
