LUPUS PREVALENCE IN FEMALES

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 LUPUS  PREVALENCE IN FEMALES




For years, researchers and clinicians have known that lupus, an autoimmune condition, occurs in women at a rate nine times higher than in men. Some of the factors that cause the disease's high prevalence in women have eluded discovery. Still, in a new study investigating the immune system processes in lupus and the X chromosome, Johns Hopkins Medicine researchers have uncovered insights into the disease's prevalence in females.

Several dysregulated genetic and biological pathways contribute to the development of lupus, along with its varied symptoms, including muscle and joint pain, skin rashes, kidney problems, and other complications that can affect the entire body. One such pathway involves a protein in the immune system called toll-like receptor 7 (TLR7), which, in lupus, reacts to the body's own RNA. These molecules act as messengers of genetic information. TLR7's reaction to RNA triggers an immune response that damages healthy tissue.

In the full article, published in the Journal of Clinical Investigation Insight, researchers focused on this TLR7 immune response in lupus, specifically examining how a piece of genetic material unique to women, known as X-inactive specific transcript (XIST), could trigger TLR7's immune system response. XIST is a type of RNA that plays a crucial role in inactivating one of the two X chromosomes found in female cells, thereby preventing imbalanced gene expression in females.

"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., adjunct professor of medicine at Hopkins University School of Medicine. "Our findings show the opposite, that XIST actually plays a role in promoting autoimmunity -- increasing the susceptibility to lupus and its severity in women."

Using cellular experiments, the research team first tested whether XIST could bind to TLR7 and initiate the receptor's immune response. They observed that XIST could strongly bind to TLR7 and trigger the production of interferons, a type of immune system protein that is elevated in high levels in lupus and contributes to tissue damage in this disease. Rather than protecting from TLR7 and interferon's adverse effects on the body, these tests illustrated that XIST drove the process of an overactive immune response and contributed to lupus development.

"XIST has now taken on a different role, an alarm signal related to autoimmunity," says study author Brendan Antiochos, M.D., medicines 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."

To further study XIST's role in lupus, researchers also examined XIST levels in patients from two lupus cohorts. The team tested blood samples from patients at the Johns Hopkins Lupus Center for XIST levels. Additionally, it utilized publicly available data from another study that demonstrated XIST and interferon levels in white blood cells obtained from the kidneys of individuals with lupus. They found that the levels of XIST in the kidney correlate with higher interferon levels, and that individuals with more XIST in their blood cells experienced greater disease severity and worsened lupus symptoms.

Darrah and Antiochos suggest that these findings may implicate XIST in other autoimmune conditions more commonly seen in women. More research should be conducted to investigate this female-specific process.

Researchers also suggest that understanding XIST's role in lupus development may open the door to innovative therapies that target the XIST-TLR7 pathway and provide additional insights for patients who may wonder about the origins of their disease.

Additional study authors include Jonathan Crawford, Hong Wang, Daniela Trejo-Zambrano, Raffaello Cimbro, C. Conover Talbot Jr., Mekha Thomas, Ashley Curran, Alexander Girgis, John Schroeder, Andrea Fava, Daniel Goldman, Michelle Petri, and Antony Rosen, all from Johns Hopkins University School of Medicine.

C. Conover Talbot Jr. reports ownership of Merck & Co. common stock. Erika Darrah is the author of U.S. Patents 14/617,412 (awarded), 10,874,726 (awarded), 62/481,158 (provisional), 048317-642P01US (temporary), and 63/515,854 (temporary) and is a cofounder of Simmbion, LLC. Michell Petri receives research support from Eli Lilly & Co., GlaxoSmithKline, Janssen, and Aurinia. Erika Darrah and Raffaello Cimbro are current employees of AstraZeneca, and Jonathan Crawford is a current employee of Eli Lilly & Co. and may receive stock options.:

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