Monday, May 20, 2024

Lupus and other autoimmune diseases strike far more women than men. Now there’s a clue why

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image Mayra Santos-Febres

Mayra Santos-Febres is a Puerto Rican journalist renowned for her incisive reporting and captivating storytelling. With a keen eye for detail, she illuminates societal issues through her insightful journalism, captivating audiences with her compelling narratives.

Women are far more likely than men to get autoimmune diseases, when an out-of-whack immune system attacks their own bodies — and new research may finally explain why.

It’s all about how the body handles females’ extra X chromosome, Stanford University researchers reported Thursday — a finding that could lead to better ways to detect a long list of diseases that are hard to diagnose and treat.

“This transforms the way we think about this whole process of autoimmunity, especially the male-female bias,” said University of Pennsylvania immunologist E. John Wherry, who wasn’t involved in the study.

More than 24 million Americans, by some estimates up to 50 million, have an autoimmune disorder — diseases such as lupus, rheumatoid arthritis, multiple sclerosis and dozens more. About 4 of every 5 patients are women, a mystery that has baffled scientists for decades.

One theory is that the X chromosome might be a culprit. After all, females have two X chromosomes while males have one X and one Y.

The new research, published in the journal Cell, shows that extra X is involved — but in an unexpected way.

Our DNA is carried inside each cell in 23 pairs of chromosomes, including that final pair that determines biological sex. The X chromosome is packed with hundreds of genes, far more than males’ much smaller Y chromosome. Every female cell must switch off one of its X chromosome copies, to avoid getting a toxic double dose of all those genes.

Performing that so-called X-chromosome inactivation is a special type of RNA called Xist, pronounced like “exist.” This long stretch of RNA parks itself in spots along a cell’s extra X chromosome, attracts proteins that bind to it in weird clumps, and silences the chromosome.

Stanford dermatologist Dr. Howard Chang was exploring how Xist does its job when his lab identified nearly 100 of those stuck-on proteins. Chang recognized many as related to skin-related autoimmune disorders — patients can have “autoantibodies” that mistakenly attack those normal proteins.

“That got us thinking: These are the known ones. What about the other proteins in Xist?” Chang said. Maybe this molecule, found only in women, “could somehow organize proteins in such a way as to activate the immune system.”

If true, Xist by itself couldn’t cause autoimmune disease or all women would be affected. Scientists have long thought it takes a combination of genetic susceptibility and an environmental trigger, such as an infection or injury, for the immune system to run amok. For example, the Epstein-Barr virus is linked to multiple sclerosis.

Chang’s team decided to engineer male lab mice to artificially make Xist — without silencing their only X chromosome — and see what happened.Researchers also specially bred mice susceptible to a lupus-like condition that can be triggered by a chemical irritant.