The X factor: why more women get lupus and other autoimmune diseases than men, and how recent research could aid detection

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 last week. This could improve detection 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 John Wherry, who wasn’t involved in the study. More than 24 million Americans (possibly up to 50 million) have an autoimmune disorder; these include lupus – a common sign of which is a red, butterfly-shaped rash across the nose and cheeks, – rheumatoid arthritis and multiple sclerosis. About 80 per cent of those affected are women, a mystery that has baffled scientists for decades. One theory is that the X chromosome might be a culprit. Females have two X chromosomes while males have one X and one Y. Selena Gomez gets kidney transplant to treat lupus The research, published in the medical 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 genes. Performing that X-chromosome inactivation is a special type of RNA called Xist, which parks itself in spots along a cell’s extra X chromosome, attracting proteins and silencing the chromosome. Stanford dermatologist Dr Howard Chang was investigating Xist when his lab identified nearly 100 of those stuck-on proteins. Chang recognised 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 organise 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 suspected a combination of genetic susceptibility and an environmental trigger, such as an infection or injury, causes the immune system to run amok. For example, the Epstein-Barr virus is linked to multiple sclerosis. Blood test by Hong Kong researchers can detect nasopharyngeal cancer risk Chang’s team engineered male lab mice to artificially make Xist – without silencing their only X chromosome. Researchers also bred mice susceptible to a lupus-like condition that can be triggered by a chemical irritant. The mice that produced Xist formed protein clumps and, when triggered, developed lupus-like autoimmunity at levels similar to females. “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,” said Chang. Nobel laureate ‘cautiously optimistic’ on lupus treatment Researchers also examined blood samples from 100 patients – and uncovered autoantibodies targeting Xist-associated proteins that hadn’t previously been linked to autoimmune disorders. A potential reason, Chang suggested, is that standard tests for autoimmunity were made using male cells. Lots more research is necessary, but the findings “might give us a shorter path to diagnosing patients that look clinically and immunologically quite different”, said Wherry. “You may have autoantibodies to protein A and another patient may have autoantibodies to proteins C and D,” but knowing they’re all part of the larger Xist complex allows doctors to better hunt disease patterns, he said. “Now we have at least one big part of the puzzle of biological context.” Chang wonders if it may even be possible to one day interrupt the process. “How does that go from RNA to abnormal cells, this will be a next step of the investigation.” Like what you read? Follow SCMP Lifestyle on Facebook, Twitter and Instagram. You can also sign up for our eNewsletter here.

The X factor: why more women get lupus and other autoimmune diseases than men, and how recent research could aid detection

Women are much more susceptible than men to autoimmune diseases such as rheumatoid arthritis, lupus and multiple sclerosis, and scientists may have learned why Women have two X chromosomes, while men have an X and a Y, and the problem may lie in the RNA that switches off duplicate genes

Women are much more susceptible than men to autoimmune diseases such as rheumatoid arthritis, lupus and multiple sclerosis, and scientists may have learned why

Women have two X chromosomes, while men have an X and a Y, and the problem may lie in the RNA that switches off duplicate genes