Why do women have more autoimmune diseases? Study points to X chromosome

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 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 the molecules are unlikely to be the sole reason why autoimmune diseases skew women. But if the results hold up in further experiments, it could be possible to base new treatments on these molecules, rather than on current drugs that blunt the entire immune system.

“Maybe that's a better strategy,” says 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, leading to the development of male sexual organs.

Each chromosome contains genes that, when 'on', produce proteins that do their work in the cells. You would expect that women, with two copies of X, would make twice as many X proteins as men. Instead, they produce about the same level. That's because one of the two X chromosomes has been silenced.

A molecule called Xist attaches “like Velcro” to the second X chromosome, said Dr. Chang. As hundreds of Xist molecules wrap around the X chromosome, they seal it off completely.

Keep one X still crucial for 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 can be toxic.

In 2015, it occurred to Dr. Chang that the shutdown itself might have a downside. His epiphany occurred as he was preparing to take the medical exams to renew his license as a dermatologist.

As part of his studies, Dr. Chang delved into autoimmune diseases, requiring him to remember the names of human proteins that could be targeted by a misdirected immune system. When he looked at the list, he was surprised to see some familiar names.

If Dr. Chang does not work as a dermatologist, he examines the X chromosome in his laboratory. He noticed that many of the proteins involved in autoimmune diseases also helped Xist shut down the X chromosome.

Maybe, Dr. Chang thought, that wasn't a coincidence.

The new study emerged from years of research testing his suspicion that Xist molecules could cause autoimmune diseases. He and his colleagues studied a strain of mice in which the females are at high risk for the autoimmune disease lupus, while the males never develop severe cases.

The researchers genetically engineered the male mice so that they produced Xist, just like the females. “Once the male mice express Xist, they get much worse immune diseases,” said Dr. Chang.

The researchers also found that people with lupus or two other autoimmune diseases had high levels of antibodies against Xist-related proteins in their blood.