by Women are much more likely than men to have their immune system turn against them, resulting in a number of so-called autoimmune diseases, such as lupus and multiple sclerosis. TO study published on Thursday offers an explanation based on the X chromosome.
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 autoimmune diseases skew women. But if the results hold up in future experiments, it might be possible to base new treatments on these molecules, rather than current drugs that weaken the entire immune system.
“Maybe that’s a better strategy,” said Dr. Howard Chang, a Stanford geneticist and dermatologist who led the new study.
Male and female embryos carry 22 identical pairs of chromosomes. The 23rd pair is different: women carry two Xs, while men carry an X and a Y, which lead to the development of the male sexual organs.
Each chromosome contains genes that, when “turned on,” make proteins to do jobs inside cells. Women, with two copies of X, might be expected to produce twice as many X proteins as men. Instead, they produce approximately 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 deactivate it.
Keeping an X silent is crucial for women’s health. If a gene on the second X chromosome escapes the control of Xist, an oversupply of proteins will occur, some of which could be toxic.
In 2015, it occurred to Dr. Chang that silencing itself might also have a downside. His revelation occurred as he was preparing to take medical board exams to renew his license as a dermatologist.
As part of his studies, Dr. Chang had to review autoimmune diseases and memorize the names of human proteins that can be attacked 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 laboratory. He realized that many of the proteins implicated in autoimmune diseases also helped Xist silence the X chromosome.
Maybe, Dr. Chang thought, that wasn’t a coincidence.
The new study emerged from years of research that tested his hunch that Xist molecules could cause autoimmune diseases. He and his colleagues studied a strain of mice in which females are at high risk for lupus, an autoimmune disease, while males never develop severe cases.
The researchers genetically modified male mice so that, like females, they produced Xist. “Once male mice express Xist, they exhibit 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 against Xist-related proteins in their blood.
