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Xist ribonucleoproteins promote female sex-biased autoimmunity.
Dou, Diana R; Zhao, Yanding; Belk, Julia A; Zhao, Yang; Casey, Kerriann M; Chen, Derek C; Li, Rui; Yu, Bingfei; Srinivasan, Suhas; Abe, Brian T; Kraft, Katerina; Hellström, Ceke; Sjöberg, Ronald; Chang, Sarah; Feng, Allan; Goldman, Daniel W; Shah, Ami A; Petri, Michelle; Chung, Lorinda S; Fiorentino, David F; Lundberg, Emma K; Wutz, Anton; Utz, Paul J; Chang, Howard Y.
Affiliation
  • Dou DR; Center for Personal Dynamic Regulomes, Program in Epithelial Biology, Department of Dermatology, Stanford University School of Medicine, Stanford, CA, USA.
  • Zhao Y; Center for Personal Dynamic Regulomes, Program in Epithelial Biology, Department of Dermatology, Stanford University School of Medicine, Stanford, CA, USA.
  • Belk JA; Center for Personal Dynamic Regulomes, Program in Epithelial Biology, Department of Dermatology, Stanford University School of Medicine, Stanford, CA, USA.
  • Zhao Y; Center for Personal Dynamic Regulomes, Program in Epithelial Biology, Department of Dermatology, Stanford University School of Medicine, Stanford, CA, USA.
  • Casey KM; Department of Comparative Medicine, Stanford University, Stanford, CA, USA.
  • Chen DC; Center for Personal Dynamic Regulomes, Program in Epithelial Biology, Department of Dermatology, Stanford University School of Medicine, Stanford, CA, USA.
  • Li R; Center for Personal Dynamic Regulomes, Program in Epithelial Biology, Department of Dermatology, Stanford University School of Medicine, Stanford, CA, USA.
  • Yu B; Center for Personal Dynamic Regulomes, Program in Epithelial Biology, Department of Dermatology, Stanford University School of Medicine, Stanford, CA, USA.
  • Srinivasan S; Center for Personal Dynamic Regulomes, Program in Epithelial Biology, Department of Dermatology, Stanford University School of Medicine, Stanford, CA, USA.
  • Abe BT; Center for Personal Dynamic Regulomes, Program in Epithelial Biology, Department of Dermatology, Stanford University School of Medicine, Stanford, CA, USA.
  • Kraft K; Center for Personal Dynamic Regulomes, Program in Epithelial Biology, Department of Dermatology, Stanford University School of Medicine, Stanford, CA, USA.
  • Hellström C; Autoimmunity and Serology Profiling, Division of Affinity Proteomics, Department of Protein Science, KTH Royal Institute of Technology, SciLifeLab, Stockholm, Sweden.
  • Sjöberg R; Autoimmunity and Serology Profiling, Division of Affinity Proteomics, Department of Protein Science, KTH Royal Institute of Technology, SciLifeLab, Stockholm, Sweden.
  • Chang S; Department of Medicine, Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, CA, USA.
  • Feng A; Department of Medicine, Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, CA, USA.
  • Goldman DW; Department of Medicine, Division of Rheumatology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Shah AA; Department of Medicine, Division of Rheumatology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Petri M; Department of Medicine, Division of Rheumatology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • Chung LS; Department of Medicine, Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, CA, USA.
  • Fiorentino DF; Department of Dermatology, Stanford University School of Medicine, Redwood City, CA, USA.
  • Lundberg EK; School of Engineering Sciences in Chemistry, Biotechnology and Health, KTH Royal Institute of Technology, SciLifeLab, Stockholm, Sweden; Departments of Bioengineering and Pathology, Stanford University, Stanford, CA, USA.
  • Wutz A; Department of Biology, Institute of Molecular Health Sciences, Swiss Federal Institute of Technology, ETH Hönggerberg, Zurich, Switzerland.
  • Utz PJ; Department of Medicine, Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, CA, USA; Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, CA, USA.
  • Chang HY; Center for Personal Dynamic Regulomes, Program in Epithelial Biology, Department of Dermatology, Stanford University School of Medicine, Stanford, CA, USA; Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305, USA. Electronic address: howchang@stanford.edu.
Cell ; 187(3): 733-749.e16, 2024 Feb 01.
Article in En | MEDLINE | ID: mdl-38306984
ABSTRACT
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 T and B cell populations and chromatin states to more resemble wild-type females. Human patients with autoimmune diseases displayed significant autoantibodies to multiple components of XIST RNP. Thus, a sex-specific lncRNA scaffolds ubiquitous RNP components to drive sex-biased immunity.
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Full text: 1 Database: MEDLINE Main subject: Autoantibodies / Autoimmune Diseases / RNA, Long Noncoding Type of study: Prognostic_studies Limits: Animals / Female / Humans / Male Language: En Journal: Cell Year: 2024 Type: Article Affiliation country: United States
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Full text: 1 Database: MEDLINE Main subject: Autoantibodies / Autoimmune Diseases / RNA, Long Noncoding Type of study: Prognostic_studies Limits: Animals / Female / Humans / Male Language: En Journal: Cell Year: 2024 Type: Article Affiliation country: United States