The X chromosome provides clues.
Why are women more susceptible to autoimmune diseases than men?For this difference, a new explanation emerges: the molecular coatings typically found on half of a woman's X chromosome may cause an unnecessary immune response.On February 1, the results were published in Cell.
This coating of RNA and protein is at the heart of the X chromosome inactivation process.Researchers previously believed that defective gene regulation of sex hormones and the X chromosome was the driver of autoimmune differences.Now, the discovery that the core protein of inactivation of the X chromosome itself can trigger immune alarms adds complexity to the problem and may provide new opportunities for diagnosis and treatment.
"This really introduces a new mechanism.Laura Carrel, a geneticist at Pennsylvania State Medical School, said.
Women account for about 80% of all autoimmune disease cases, including diseases such as lupus and rheumatoid arthritis.However, how to explain this gender difference has remained a mystery.For the past 60 or 70 years, this problem has plagued scientists.
One major suspect is the X chromosome, because in most mammals, including humans, male cells typically have only one copy, while female cells typically carry two copies.
Inactivation of the X chromosome inhibits the activity of an X chromosome in most XX cells, making the "dose" of its X-linked gene equal to that of male XY cells.The process is highly physical: long strands of RNA called XIST wrap around chromosomes, attracting dozens of proteins to form complexes that effectively seal genes in chromosomes.
However, not all genes are "silent," and those that escape the inactivation of the X chromosome are thought to underlie some autoimmune diseases.In addition, the researchers reported in 20232 that the XIST molecule itself can trigger an inflammatory immune response.But that's not all.
About a decade ago, Howard Chang, a molecular geneticist at Stanford University School of Medicine, noticed that many proteins that interact with XIST are targeted by misguided immune molecules called autoantibodies.
They are capable of attacking tissues and organs, leading to chronic inflammation and damage characteristic of autoimmune diseases.Since XIST is usually only expressed in XX cells, it seems logical to think that autoantibodies attacking XIST-related proteins may have a greater impact on women than on men.
To test this idea, Chang and colleagues studied male mice that typically do not express XIST.The researchers bioengineered the mice to produce an XIST that doesn't silence gene expression, but does form a specific RNA-protein complex.
The team induced a lupus-like disease in mice and found that animals that expressed XIST had higher levels of autoantibodies than animals that did not.Their immune cells are also on higher alert, a sign of vulnerability to autoimmune attacks, and their tissue damage is widespread.
Notably, the same autoantibodies were found in blood samples from patients with lupus, scleroderma and dermatomyositis, said Allison Billi, a dermatologist at the University of Michigan School of Medicine, suggesting that XIST and its associated proteins are "hard for the immune system to ignore."
Montserrat Anguera, a geneticist at the University of Pennsylvania in the United States, pointed out that human data show that the mechanisms associated with XIST observed in mice are directly related to human autoimmune status.Diagnosis of these autoantibodies, for example, can help clinicians detect and monitor various autoimmune diseases.