Now, researchers have come up with a potential explanation for that — one that’s rooted in genes that drive a person’s gender.
The female body has a complex means by which it handles the additional X chromosome, and it appears this process also renders some women more susceptible to autoimmune diseases, according to a report published Feb. 1 in the journal Cell.
This finding helps explain why women account for about 80% of all cases of autoimmune disease, in which the immune system turns on the body and attacks its tissues and organs.
More importantly, it could lead to better ways to detect and treat dozens of these disorders, researchers say.
“It’s a question that’s been irking immunologists and rheumatologists for the past 60 or 70 years,” Dr. Robert Lahita, a rheumatologist at the Hackensack Meridian School of Medicine in Nutley, N.J., told the journal Nature. Lahita was not involved in the study.
Biological sex is determined in mammals by the presence of two X chromosomes in every female cell. Males have just one X chromosome, paired with a shorter Y chromosome.
The X chromosome carries hundreds of active genes that support life, while the Y chromosome contains only a handful, researchers explained.
Unfortunately, having two X chromosomes ups risks that the female body will produce a lethal double dose of these proteins, so nature has devised a way to deactivate one of them.
A special type of RNA called Xist — pronounced “exist” — is produced by the extra copy in a XX pair.
Xist attaches to long sections of the extra X chromosome, cutting its genetic output to zero or close to it, while leaving the other X chromosome alone to do its job.
Unfortunately, Xist also attracts odd combinations of proteins that clump together with it, and many of those close to 100 proteins are associated with autoimmune disorders, researchers realized.
That led them to suspect that the protein clumps created by Xist’s X-chromosome deactivation could be triggering autoimmune diseases in women.
To test this, researchers inserted the gene for Xist into male lab mice bred to be susceptible to a lupus-like autoimmune disorder.
Xist could be turned on and off using chemicals, so it would only produce Xist when researchers wanted.
The mere insertion of the Xist gene had no noticeable effect on the male mice, researchers said.
But once the Xist gene was activated, the typical protein clumps began forming in the male mice.
To see whether that made an autoimmune disorder more likely, researchers injected both those mice and non-bioengineered male mice with an irritant known to induce that lupus-like disorder.
It turned out that male mice with an active Xist gene developed the lupus-like condition at rates approaching those of females.
Because not all female or Xist-activated male mice developed the autoimmune disorder, it shows that some kind of trigger is required to activate such a disease, the researchers noted.
“We think that’s really important, for Xist RNA to leak out of the cell to where the immune system gets to see it. You still needed this environmental trigger to cause the whole thing to kick off,” researcher Dr. Howard Chang, a professor of dermatology and genetics at Stanford University, told the Associated Press.
But even the irritant trigger used in the mice didn’t cause all of them to develop the lupus-like disorder. That means that other genetic influences might come to bear on whether a person develops an autoimmune disease, researchers said.
Because these Xist-linked protein clumps are tied to autoimmune disorders, researchers might be able to use them as the basis for a test to determine a person’s susceptibility.
Researchers examined blood samples from about 100 patients with autoimmune problems, looking for autoantibodies — antibodies that target the proteins that clump with Xist.
They found a list of autoantibodies that potentially could be used as a test for autoimmune susceptibility.
Gender bias in medical research could be one reason why it’s taken so long for scientists to figure this out.
“Every cell in a woman’s body produces Xist,” Chang said in a university news release. “But for several decades, we’ve used a male cell line as the standard of reference. That male cell line produced no Xist and no Xist/protein/DNA complexes, nor have other cells used since for the test. So, all of a female patient’s anti-Xist-complex antibodies — a huge source of women’s autoimmune susceptibility — go unseen.”
SOURCE: Stanford University, news release, Feb. 1, 2024; Associated Press
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