A new explanation has been suggested for why women are so much more susceptible to autoimmune diseases than men: a molecular coating typically found on half of a woman’s X chromosomes, but not in males’ cells, that might be provoking unwanted immune responses, say scientists.
The coating, a mix of RNA and proteins, is central to a developmental process called X-chromosome inactivation. Researchers had previously implicated sex hormones and flawed gene regulation on the X chromosome as drivers of the autoimmune disparity, Nature reports.
But the discovery, led by Stanford University in the US, that proteins central to X-chromosome inactivation can themselves set off immunological alarm bells, adds yet another layer of complexity, and could point to new diagnostic and therapeutic opportunities.
“This really adds a new mechanistic twist,” says Laura Carrel, a geneticist at Pennsylvania State College of Medicine.
The study was published in Cell.
Medical mystery
Women account for around 80% of all cases of autoimmune disease, a category that includes conditions such as lupus and rheumatoid arthritis. What explains this sex bias has long been a mystery, however.
“It’s a question that’s been irking immunologists and rheumatologists for 60 or 70 years,” said Robert Lahita, a rheumatologist at the Hackensack Meridian School of Medicine in New Jersey.
A prime suspect is the X chromosome: in most mammals, including humans, a male’s cells typically include only one copy, whereas a female’s cells typically carry two.
X-chromosome inactivation muffles the activity of one X chromosome in most XX cells, making their ‘dose’ of X-linked genes equal to that of the XY cells typical in males. The process is highly physical: long strands of RNA known as XIST (pronounced ‘exist’) coil around the chromosome, attracting dozens of proteins to form complexes that effectively muzzle the genes inside.
Not all genes stay mum, however, and those that escape X inactivation are thought to underpin some autoimmune conditions. Additionally, the XIST molecule itself can initiate inflammatory immune responses, researchers reported in 2023. But that is not the whole story.
XISTential questions
Almost a decade ago, Howard Chang, a dermatologist and molecular geneticist at Stanford University School of Medicine in California and a co-author of the current study, noticed that many of the proteins that interact with XIST were targets of misguided immune molecules called autoantibodies.
These rogue actors can attack tissues and organs, leading to the chronic inflammation and damage characteristic of autoimmune diseases. Because XIST is normally expressed only in XX cells, it seemed logical to think that the autoantibodies that attack XIST-associated proteins might be a bigger problem for women than for men.
To test this idea, Chang and his colleagues turned to male mice, which don’t usually express XIST. The team bioengineered the mice to produce a form of XIST that did not silence gene expression but did form the characteristic RNA–protein complexes.
The team induced a lupus-like disease in the mice and found that animals that expressed XIST had higher autoantibody levels than those that didn’t. Their immune cells were also on higher alert, a sign of predisposition to autoimmune attacks, and they showed more extensive tissue damage.
Immune-system overdrive
Notably, the same autoantibodies were also identified in blood samples from people with lupus, scleroderma and dermatomyositis – evidence that XIST and its associated proteins are “something that our immune systems have trouble ignoring”, said Allison Billi, a dermatologist at the University of Michigan Medical School.
Montserrat Anguera, a geneticist at the University of Pennsylvania, points to the human data as validation that the XIST-related mechanisms observed in mice have direct relevance to human autoimmune conditions, with implications for disease management.
For example, diagnostics targeting these autoantibodies could assist clinicians in detecting and monitoring various autoimmune disorders.
“This is a cool start,” she says. “If we could use this information to expedite the diagnosis, it would be amazing.”
Study details
Xist ribonucleoproteins promote female sex-biased autoimmunity
Diana Dou, Yanding Zhao, Howard Chang, et al.
Published in Cell on 1 February 2024
Summary
Autoimmune diseases disproportionately affect females more than males. The XX sex chromosome complement is strongly associated with susceptibility to autoimmunity. Xist long non-coding RNA (lncRNA) is expressed only in females to randomly inactivate one of the two X chromosomes to achieve gene dosage compensation. Here, we show that the Xist ribonucleoprotein (RNP) complex comprising numerous auto-antigenic components is an important driver of sex-biased autoimmunity. Inducible transgenic expression of a non-silencing form of Xist in male mice introduced Xist RNP complexes and sufficed to produce autoantibodies. Male SJL/J mice expressing transgenic Xist developed more severe multi-organ pathology in a pristane-induced lupus model than wild-type males. Xist expression in males reprogrammed T and B cell populations and chromatin states to more resemble wild-type females. Human patients with autoimmune diseases displayed significant autoantibodies to multiple components of XIST RNP. Thus, a sex-specific lncRNA scaffolds ubiquitous RNP components to drive sex-biased immunity.
Cell article – Xist ribonucleoproteins promote female sex-biased autoimmunity (Open access)
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