Noncoding Self-RNA Implicated in Lupus Development

Kathrin Plath, PhD, a professor of biological chemistry, the University of California, Los Angeles, who has studied the role of XIST in initiating and maintaining X chromosome inactivation, says she’s intrigued by the new study. She cautions, however, that more in vivo data will be needed to confirm the role of XIST fragments as important TLR7 ligands. “Overall, [this is] an exciting avenue and it would be amazing if XIST enables female development, but then also causes autoimmunity in females,” Dr. Plath says.

Separate studies are providing independent support for the emerging hypothesis. One recent study in a mouse model of lupus showed that male mice engineered to produce XIST churned out autoantibodies and developed a more severe multi-organ pathology than mice lacking XIST. The finding, the authors report, suggests that complexes formed by XIST and bound proteins act as “antigenic triggers underlying the greater prevalence of autoimmune diseases in females.”⁶

As part of his own lab’s next steps, Dr. Antiochos hopes to understand more about how XIST travels from its initial attachment site on an X chromosome within the cell nucleus to extracellular vesicles in a way that activates TLR7.

“The other big question in my mind that is a direct result of this work is ‘Why is XIST up-regulated in these patients with lupus compared to healthy women?’” Dr. Antiochos says. If interferon doesn’t impact XIST expression in adults, what does? “That’s an area where there’s not a lot that’s understood,” he says.

Bryn Nelson, PhD, is a medical journalist based in Seattle.

References

1. Brown GJ, Cañete PF, Wang H, et al. TLR7 gain-of-function genetic variation causes human lupus. Nature. 2022 May; 605(7909):349–356.
2. Weckerle, CE and Niewold, TM. The unexplained female predominance of systemic lupus erythematosus: clues from genetic and cytokine studies. Clin Rev Allergy Immmunol. 2011 Feb; 40(1):42–49.
3. Crawford JD, Wang H, Trejo-Zambrano D, et al. The XIST lncRNA is a sex-specific reservoir of TLR7 ligands in SLE. JCI Insight. 2023 Oct 23; 8(20):e169344.
4. Souyris M, Cenac C, Azar P, et al. TLR7 escapes X chromosome inactivation in immune cells. Sci Immunol. 2018 Jan 26;3(19):eaap8855.
5. Yu B, Qi Y, Li R, et al. B cell-specific XIST complex enforces X-inactivation and restrains atypical B cells. Cell. 2021 Apr 1;184(7):1790–1803.e17.
6. Dou DR, Zhao Y, Belk JA, et al. Xist ribonucleoproteins promote female sex-biased autoimmunity. Cell. 2024 Feb 1;187(3):733–749.