‘A major clue has been discovered’: Data illuminate autoimmunity gap between women and men
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A possible genetic rationale for why women acquire more autoimmune diseases than men has been discovered, according to findings published recently in Cell.
In their study, Howard Y. Chang MD, PhD, Virginia and D.K. Ludwig professor of cancer research, as well as a professor of dermatology and genetics, at the Stanford University School of Medicine, and colleagues unearthed data that suggest the XX sex chromosome complement carries a strong association 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,” Chang and colleagues wrote.
According to the researchers, the Xist ribonucleoprotein (RNP) includes several autoantigenic components that may be driving this autoimmunity in women.
In the first part of the study, the researchers induced a non-silencing form of Xist expression in male mice. They found that expression of Xist RNP was sufficient to produce autoantibodies. In addition, the male mice in which Xist RNP had been induced also developed severe multi-organ pathology in a pristane-induced lupus model. Such an effect was not observed male mice without this altered genetic expression.
Moreover, T and B cell populations were altered in the male mice with Xist expression.
“Human patients with autoimmune diseases displayed significant autoantibodies to multiple components of XIST RNP,” the researchers wrote. “Thus, a sex-specific lncRNA scaffolds ubiquitous RNP components to drive sex-biased immunity.”
Chang sat down with Healio to discuss the rationale behind the study and what the findings might mean for autoimmunity.
Healio: Why did you decide to investigate the Xist ribonucleoprotein in the first place?
Chang: In 2015, my laboratory identified the set of proteins that are associated with Xist RNA. This set of proteins gave a parts list for how Xist RNA shuts down gene expression on one of two X chromosomes in female cells, a critical process that makes gene output from female cells with two X chromosomes equivalent to that of male cells with one X and one Y chromosome.
Around the same time, I was studying to renew my board certification in dermatology and memorizing autoantibodies used to diagnose diseases. Quite serendipitously, I realized that quite a few of the proteins in the Xist associated proteins are also autoantigens. This raised the hypothesis that the Xist ribonucleoprotein could be a female-specific source of autoantigens.
Healio: What can your findings in mice tell us about autoimmunity in humans?
Chang: Human autoimmune diseases also show a strong female bias — four out of five patients with autoimmune disease are women.
In fact, we found patients with autoantibodies to the Xist RNP in systemic lupus erythematosus, scleroderma and dermatomyositis, which suggest a conserved process in humans.
Healio: How did you make the observation that inducible transgenic expression of a non-silencing form of Xist in male mice introduced Xist RNP complexes and sufficed to produce autoantibodies?
Chang: We engineered a male mouse to express Xist and ask if this can confer female level autoimmunity. If the results were positive, this would mean that female sex hormones and even the second X chromosome was not required. Just Xist RNP could be sufficient. Xist silences the chromosome from which it is expressed, so normal male cells would not tolerate Xist expression.
We engineered male mice to express a non-silencing form of Xist to test our hypothesis and found that Xist indeed conferred female level disease in a mouse model of lupus.
Healio: In the study, you observed that male SJL/J mice expressing transgenic Xist developed more severe multi-organ pathology in a pristane-induced lupus model than wild-type males. Can you explain this?
Chang: The pristane induced model of lupus in mice requires a specific genetic background called SJL/J. We found that Xist expression in males of this background conferred female level disease severity for the pristane-induced lupus. The need for a specific genetic background speaks to the genetic risk for autoimmune diseases.
Not all women get lupus or other autoimmune diseases despite every women having Xist expression in their cells. The effect of Xist is manifested only if someone has an autoimmune tendency based on their genetics.
Healio: What is the impact of Xist expression on T and B cells?
Chang: We found that Xist expression made more T cells transition to a memory state and B cells become atypical B cells. Atypical B cells are a type of B cells that have been found to be expanded in human autoimmune diseases and importantly accumulated in aged female animals.
Healio: What diseases are most likely to be induced or associated with this Xist expression?
Chang: Our study examined a mouse model of lupus. We suspect that Xist may also impact other female-biased autoimmune diseases.
Healio: Our readers are primarily practicing rheumatologists. What is the overall take-home message of your study for them?
Chang: A major clue has been discovered that ties a female-specific RNA to why women get more autoimmune diseases.
For more information:
Howard Y. Chang, MD, PhD, can be reached at 450 Broadway St. Pavilion B MC 5338 Redwood City, CA 94063; email: howchang@stanford.edu.
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Dou DR, et al. Cell. 2024;doi:10.1016/j.cell.2023.12.037.
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