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Autoimmune diseases

Implicating XIST in sex-biased autoimmunity

Nature Genetics volume 56, page 357 (2024)Cite this article

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Autoimmune diseases exhibit a strong female sex bias in incidence, but the mechanistic basis for this differential susceptibility is poorly understood. Given previous evidence that X chromosome dosage, and specifically the long non-coding RNA XIST produced from the inactive X chromosome and its associated proteins, could be key factors underlying the increased autoimmune disease risk in females and phenotypic males with an extra X chromosome (XXY males), Dou et al. engineered a transgenic mouse model expressing a truncated version of Xist lacking gene-silencing activity but retaining the ability to coat chromosomes in cis and form ribonucleoprotein (RNP) complexes. They observed that most pristane-treated male mice expressing this truncated Xist transgene on a permissive genetic background developed a severe, multi-organ autoimmune disease pathology, similar to pristane-treated female mice, accompanied by the presence of Xist RNP autoantibodies in serum. They also tested sera collected from human patients with various autoimmune diseases and identified several XIST RNP complex proteins as novel autoantigens. Collectively, these findings provide a compelling model to explain the strong female sex bias in the incidence of autoimmune diseases across human populations.

Original reference: Cell 187, 733–749 (2024)

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  1. Nature Genetics https://www.nature.com/ng

    Kyle Vogan

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  1. Kyle Vogan
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Correspondence to Kyle Vogan.

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Vogan, K. Implicating XIST in sex-biased autoimmunity. Nat Genet 56, 357 (2024). https://doi.org/10.1038/s41588-024-01699-6

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