biostudies-literatureDou DRNational Institute of Arthritis and Musculoskeletal and Skin DiseasesHoward Hughes Medical InstituteScleroderma Research FoundationNIAMS NIH HHSNIHKao Corporation733-749.e16https://www.ebi.ac.uk/biostudies/studies/S-EPMC10949934biostudies-literatureUnknown187(3)Autoimmune diseases disproportionately affect females more than males. The XX sex chromosome complement is strongly associated 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. Here, we show that the Xist ribonucleoprotein (RNP) complex comprising numerous autoantigenic components is an important driver of sex-biased autoimmunity. Inducible transgenic expression of a non-silencing form of Xist in male mice introduced Xist RNP complexes and sufficed to produce autoantibodies. Male SJL/J mice expressing transgenic Xist developed more severe multi-organ pathology in a pristane-induced lupus model than wild-type males. Xist expression in males reprogrammed CellXist ribonucleoproteins promote female sex-biased autoimmunity.PMC10949934R01 AR069572K99 AR080218T32 AR007422R01-AR069572K99/R00T32 AR050942Belk JAChung LSChang HYShah AAPetri MChen DCLi RChang SLundberg EKFiorentino DFZhao YFeng AAbe BTKraft KYu BCasey KMHellstrom CSrinivasan SWutz AUtz PJGoldman DWSjoberg RDou DRfalseXist ribonucleoproteins promote female sex-biased autoimmunity.Autoimmune diseases disproportionately affect females more than males. The XX sex chromosome complement is strongly associated 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. Here, we show that the Xist ribonucleoprotein (RNP) complex comprising numerous autoantigenic components is an important driver of sex-biased autoimmunity. Inducible transgenic expression of a non-silencing form of Xist in male mice introduced Xist RNP complexes and sufficed to produce autoantibodies. Male SJL/J mice expressing transgenic Xist developed more severe multi-organ pathology in a pristane-induced lupus model than wild-type males. Xist expression in males reprogrammed 2024-01-01T00:00:00Z2024 Feb2026-06-01T14:39:56.513Z2025-04-03T23:22:35.937ZS-EPMC109499343830698410.1016/j.cell.2023.12.037