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Why Autoimmune Disease Is More Common In Women: X Chromosome Holds Clues
Protein–RNA complexes that shroud some copies of the X chromosome (artificially coloured) contribute to the female bias in prevalence of autoimmune disease.Credit: Lennart Nilsson, TT/Science Photo Library
Why are women so much more susceptible to autoimmune diseases than men? A new explanation for the discrepancy has emerged: a molecular coating typically found on half of a woman's X chromosomes — but not in males' cells — might be provoking unwanted immune responses1.
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. But the discovery 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 the Pennsylvania State College of Medicine in Hershey.
The study was published today in Cell1.
Medical mysteryWomen 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 the past 60 or 70 years," says Robert Lahita, a rheumatologist at the Hackensack Meridian School of Medicine in Nutley, New Jersey.
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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.
(This article uses 'women' and 'female' to describe people with two X chromosomes and no Y chromosome, reflecting the language of the study, while acknowledging that gender identity and chromosomal make-up do not always align.)
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 20232. But that is not the whole story.
XISTential questionsAlmost 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.
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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 overdriveNotably, 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", says Allison Billi, a dermatologist at the University of Michigan Medical School in Ann Arbor.
Montserrat Anguera, a geneticist at the University of Pennsylvania in Philadelphia, 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."
How A Type Of Molecule May Be The Reason Women Have A Higher Risk Of Autoimmune Disease
Scientists say they may have made a breakthrough in uncovering what is behind the higher rates of autoimmune disease in women.
They say the difference may revolve around a type of molecule found only in females.
Research published today in the journal Cell by Stanford University researchers in California report that a molecule known as Xist may be driving female-biased autoimmunity.
"Four out of five patients with autoimmune diseases are women. This study showed that an RNA called Xist that is made only in female cells could be a major driver of autoimmunity. This understanding can help design new ways to diagnose and perhaps treat autoimmune diseases," Howard Chang, PhD, the senior author of the study and a professor of dermatology and genetics at Stanford, told Medical News Today.
About 50 million people in the United States have one or more autoimmune diseases. Up to 80% of these people are women.
Many autoimmune diseases disproportionately impact women more than men. The ratio of females to males is 9 to 1 in lupus and in Sjorgen's syndrome it's as high as 19 to 1.
The Stanford researchers say they have honed in on this disparity and narrowed it down to one of the most fundamental features differentiating the biological sexes.
"Doctors and scientists have wondered for decades about the female prevalence of autoimmune diseases. Sex hormones, different chromosome counts, and other factors like pregnancy were invoked. This research shows that a single female specific RNA is a major driver – a novel explanation to a longstanding mystery," Chang said.
RNA refers to ribonucleic acid, a type of molecule that exists in the majority of living cells and is similar to DNA.
The researchers found a particular RNA may play a role in the high rates of autoimmune diseases in women and it's all because of the X chromosome.
Every biologically female mammal has two X chromosomes. Men have one X and one Y.
A person can live without a Y chromosome, as biological females do, but it's not possible to live without an X chromosome. The X chromosome holds hundreds of important genes that hold the instructions for the creation of proteins.
However, having two X chromosomes can mean there is a risk of an overproduction of proteins, which can have consequences.
X-chromosome inactivation solves that problem. During this process, every single cell in a female shuts down the activity of one of the X chromosomes.
This is made possible by a molecule called Xist. While the gene for Xist is found on all X chromosomes, and therefore in both females and males, it is only actually produced in a matched pair of two X chromosomes. This is only found in females.
Following X-chromosome inactivation, odd combinations of RNA, DNA, and protein are formed. It is the development of these complexes that triggers a strong immune response in the body.
One of the first indications of the development of autoimmunity is the presence of autoantibodies in the blood.
When the researchers examined blood samples of more than 100 people with autoimmune diseases they said they found autoantibodies to many protein complexes that are associated with Xist.
"Every cell in a woman's body produces Xist. 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," Chang said in a press release.
The researchers conducted some experiments on mice with lupus to examine the effect of Xist.
"The results showed that making Xist significantly increased the severity of lupus. We do not yet know about other types of autoimmune diseases, but we detected antibodies to the Xist RNA protein complex in 3 types of human autoimmune diseases," Chang said.
There are more than 100 autoimmune diseases, in which the body's own immune system launches an attack on its own cells, tissues and organs.
Generally, there is no cure for an autoimmune disease and some diseases require lifelong treatment.
Dr. Daniel Arkfeld is a rheumatologist with Keck Medicine of USC in California who was not involved in the new research.
He says the Stanford study is an important step forward in autoimmune disease research.
"It actually is very much I think, a game changer in rheumatology, the way we look at our immune disorders. To kind of unraveling the mystery of autoimmune disorders," Arkfeld told Medical News Today.
He says it could pave the way for potential interventions in the future.
"I think gene manipulation… will be coming in the future as well, which may target the chromosomal expressions a little bit more," Arkfeld added. "We're finding these antibodies present years before they were ever activating to disease, so there's a lot of time, you could probably control things before they would ever lead to any end organ damage."
The Stanford researchers are just one of many teams all over the world trying to gain a better understanding of the mechanisms underpinning autoimmune diseases.
Experts say there is still a lot going unanswered.
"We know a lot about some diseases and we've got very good treatments for some diseases. I think that what we haven't cracked, is this question of, can we prevent them? How do we prevent them? So many researchers, like myself… are looking at people before the onset of disease, and then looking at those populations around the world," Ranjeny Thomas, a researcher in autoimmune disease at The University of Queensland in Australia who was not involved in the new study, told Medical News Today.
"They're monitoring them, looking at their immune system, why it fails, why it turns on itself and whether there are forms of immunotherapy or other forms of interventions that could help to prevent that from occurring," Thomas added. "How can we actually prevent these diseases from occurring? Because they're so life changing. They're chronic diseases and life threatening in many cases."
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