BALTIMORE — Doctors have known for years that lupus, an autoimmune disease causing the immune system to mistakenly attack healthy tissues, is much more common among women than men. Estimates show that lupus affects women at a rate nine times higher than males. Now, a new study focusing on the immune system processes in lupus and the X chromosome is revealing why women are disproportionately affected by lupus.
Researchers at Johns Hopkins Medicine say numerous dysregulated genetic and biological pathways contribute to the development of lupus and its various symptoms (muscle and joint pain, skin rashes, kidney problems). One of those pathways features an immune protein called toll-like receptor 7 (TLR7). In lupus, this protein reacts to the body’s own RNA, or molecules that serve as messengers of genetic information. This reaction by TLR7 to RNA sparks an immune response that damages healthy tissue.
The research team behind these findings focused on this TLR7 immune response in lupus. More specifically, they assessed how a piece of genetic material only found in women, known as X-inactive specific transcript (XIST), triggers TLR7’s immune system response. XIST is a variety of RNA that plays a crucial role in deactivating one of the two X chromosomes present in female cells, which ensures that women do not have imbalanced gene expression.
“XIST has previously been implicated in autoimmunity, but more as something that could prevent autoimmune conditions like lupus, rather than drive the disease’s development,” says study author Erika Darrah, Ph.D., a former adjunct professor of medicine at the Johns Hopkins University School of Medicine, in a media release. “Our findings show the opposite, that XIST actually plays a role in promoting autoimmunity — increasing the susceptibility to lupus and its severity in women.”
Study authors gauged whether XIST could bind to TLR7 and initiate the receptor’s immune response through a series of cellular experiments. This led them to observe that XIST is capable of strongly binding to TLR7 and triggering the production of molecules called interferons, which are immune system proteins observed at high levels in lupus thought to contribute to tissue damage in this disease. Instead of protecting against TLR7 and interferon’s negative effects on the body, these tests showed that XIST drives the phenomenon of an overactive immune response, ultimately contributing to lupus development.
“XIST has now taken on a different role, an alarm signal related to autoimmunity,” adds study author Brendan Antiochos, M.D., assistant professor of medicine at the Johns Hopkins University School of Medicine. “The immune system activation through XIST and TLR7 is female-specific, helping explain the observation that lupus is so much more common in women compared to men.”
In order to further examine XIST’s role in lupus, researchers also analyzed XIST levels among patients from two lupus cohorts. They tested blood samples from patients at the Johns Hopkins Lupus Center for XIST levels. Meanwhile, researchers also utilized publicly available data from another study that displayed XIST and interferon levels in white blood cells taken from the kidneys of lupus patients. The research team determined that not only did the levels of XIST in the kidney correlate with higher interferon levels, but people with more XIST in their blood cells also reported greater disease severity and worsened lupus symptoms.
Study authors believe this work may implicate XIST in additional autoimmune conditions also seen more often in women. They add that future research should investigate this female-specific process.
The research team concludes that understanding XIST’s role in lupus development may open new possibilities for creative therapies to treat the condition that target the XIST-TLR7 pathway. Such research may also offer another explanation for patients curious about the origins of their disease.
The study is published in the Journal of Clinical Investigation.
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I’m sure it’s all men’s fault.