0017: Xist Ribonucleoproteins Promote Female Sex-biased Autoimmunity

Diana Dou¹, Yanding Zhao¹, Julia Belk¹, Yang Zhao¹, Kerriann Casey², Derek Chen¹, Rui Li¹, Bingfei Yu¹, Suhas Srinivasan¹, Brian Abe¹, Katerina Kraft¹, Ceke Hellström³, Ronald Sjöberg⁴, Sarah Chang⁵, Allan Feng⁵, Daniel Goldman⁶, Ami Shah⁷, Michelle Petri⁶, Lorinda Chung⁸, David Fiorentino⁹, Emma Lundberg¹⁰, Anton Wutz¹¹, Paul Utz⁵ and Howard Chang¹, ¹Center for Personal Dynamic Regulomes and Program in Epithelial Biology, Department of Dermatology, Stanford University School of Medicine, Stanford, CA, ²Department of Comparative Medicine, Stanford University, Stanford, CA, ³Autoimmunity and Serology Profiling, Division of Affinity Proteomics, Department of Protein Science, KTH Royal Institute of Technology, SciLifeLab, Stockholm, Sweden, ⁴Department of Protein Science, SciLifelab, KTH Royal Institute of Technology, Stockholm, Sweden, ⁵Department of Medicine, Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, CA, ⁶Department of Medicine, Division of Rheumatology, Johns Hopkins University School of Medicine, Timonium, MD, ⁷Department of Medicine, Division of Rheumatology, Johns Hopkins University School of Medicine, Ellicott City, MD, ⁸Department of Medicine, Division of Immunology and Rheumatology, Stanford University School of Medicine, Woodside, CA, ⁹Department of Dermatology, Stanford University School of Medicine, Menlo Park, CA, ¹⁰Departments of Bioengineering and Pathology, Stanford University, Stanford, CA, ¹¹Department of Biology, Institute of Molecular Health Sciences, Swiss Federal Institute of Technology, ETH Hönggerberg, Zurich, Switzerland

Background/Purpose: Autoimmune diseases disproportionately affect females more than males. The XX sex chromosome complement is strongly associated with susceptibility to autoimmunity. Xist long noncoding RNA (lncRNA) is expressed only in females to randomly inactivate one of the two X chromosomes to achieve gene dosage compensation. The Xist lncRNA complexes with numerous proteins associated with autoimmune diseases as autoantigens. The goal of our study is to determine whether the Xist ribonucleoprotein (RNP) complex is a driver for female-biased autoimmunity.

Methods: We developed a unique transgenic mouse to confer inducible expression of a non-silencing form of Xist in male animals. We assessed disease severity/progression in Xist-expressing/non-expressing mice in the pristane-induced systemic lupus erythematous (SLE) model using ATAC-seq, RNA-seq and single cell multiomic analyses of splenic immune cells, histopathology of physical disease markers in tissue sections, and serum autoantibody levels. We screened ChIRP-MS datasets to develop an XIST protein antigen array to test autoimmune disease patient serum for reactivity to XIST complex proteins.

Results: Inducible transgenic expression of Xist in male mice introduced Xist RNP complexes and sufficed to produce autoantibodies. Male SJL/J mice expressing transgenic Xist developed more severe multiorgan pathology in pristane-induced model of lupus than wild-type males. Xist expression in males reprogrammed T and B cell population and chromatin states to more resemble wild type females. Human autoimmune disease patients displayed significant levels of autoantibodies to multiple components of the XIST RNP.

Conclusion: Xist is a sex-specific lncRNA that scaffolds ubiquitous RNP components to drive sex-biased immunity.




D. Dou: None; Y. Zhao: None; J. Belk: None; Y. Zhao: Synthego, 3; K. Casey: None; D. Chen: None; R. Li: None; B. Yu: None; S. Srinivasan: None; B. Abe: Eli Lilly, 3; K. Kraft: None; C. Hellström: None; R. Sjöberg: None; S. Chang: Genentech, 3; A. Feng: None; D. Goldman: None; A. Shah: Arena Pharmaceuticals, 5, Eicos Sciences, 5, Kadmon Corporation, 5, Medpace LLC, 5; M. Petri: Alexion, 1, Amgen, 1, AnaptysBio, 1, Annexon Bio, 1, Argenx, 1, Arhros-Focus Med/Ed, 6, AstraZeneca, 1, 5, Aurinia, 1, 5, 6, Axdev, 1, Biogen, 1, Boxer Capital, 2, Cabaletto Bio, 2, Caribou Biosciences, 2, CVS Health, 1, Eli Lilly, 1, 5, Emergent Biosolutions, 1, Exagen, 5, Exo Therapeutics, 2, Gilead Biosciences, 2, GlaxoSmithKlein(GSK), 1, 5, 6, Horizon Therapeutics, 2, Idorsia Pharmaceuticals, 2, IQVIA, 1, Janssen, 1, 5, Kira Pharmaceuticals, 2, MedShr, 6, Merck/EMD Serono, 1, Momenta Pharmaceuticals, 2, Nexstone Immunology, 2, Nimbus Lakshmi, 2, Proviant, 2, Sanofi, 2, Sinomab Biosciences, 2, Thermofisher, 5, UCB, 2; L. Chung: Eicos Science, 1, 2, Eli Lilly, 1, 2, Genentech, 1, 2, IgM biosciences, 1, 2, Janssen, 1, 2, Kyverna, 1, 2, Mitsubishi Tanabe, 1, 2; D. Fiorentino: None; E. Lundberg: None; A. Wutz: None; P. Utz: None; H. Chang: 10x Genomics, 1, Accent Therapeutics, 8, Arsenal Biosciences, 1, Boundless Bio, 8, Cartography Biosciences, 8, Chroma Medicine, 1, Orbital Therapeutics, 8, Spring Discovery, 1.