Researchers are homing in on a long noncoding RNA fragment called Xist, essential to X chromosome inactivation, as the culprit in sex-biased autoimmune diseases like lupus.
Female bias in autoimmune disease can be profound, with nine females developing lupus for every male affected, and nearly twice that ratio seen in Sjögren disease.
The inactivation process, which scientists liken to wrapping the extra X with a fluffy cloud of proteins, occurs early in embryonic development. After its initial work silencing the X, Xist is produced throughout the female's life, allowing X inactivation to be maintained. By using a male model, the scientists could determine whether Xist could cause an increased vulnerability for autoimmunity absent the influence of female hormones and development. "Everything else about the animal is male," Dr. Dou commented. "You just add the formation of the Xist ribonucleoprotein particles — Xist RNA plus the associating proteins — to male cells that would not ordinarily have these particles.
Dr. Anguera pointed out that autoimmune diseases are complex and can result from a combination of factors. "You also have a host of hormonal and environmental contributors, such as previous viral infections," she said. And of course men can also develop lupus, meaning that the X chromosome cannot explain everything.
"Within rheumatology, the diseases that tend to be most female biased are the ones that are antibody positive and have this presence of upregulated interferon," explained. "Lupus is an example of that. Sjögren's syndrome is another. So there's always been this quest to want to understand the mechanisms that explain why women would have more autoimmunity.
The different hypotheses surrounding Xist's role in sex-biased autoimmunity aren't mutually exclusive, Dr. Plath said. "There's a tremendous enrichment of proteins occurring" during X inactivation, she said, supporting the Stanford team's hypothesis that proteins are triggering autoimmunity. As for the Johns Hopkins researchers' understanding that Xist RNA itself is the trigger, "I'm totally open to that," she said.
SLE - Systemic Lupus Erythematosus Systemic Lupus Erythaematosus SLE Rheumatic Disease Sjogren' S Syndrome Sjogren Syndrome Lupus Autoimmune Disease Genomics Genomic Medicine California Genetics Lymphocytes Pathogenesis Receptors Biologic Therapy Biologics
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