Session Information
Session Type: Poster Session A
Session Time: 9:00AM-11:00AM
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.
To cite this abstract in AMA style:
Dou D, Zhao Y, Belk J, Zhao Y, Casey K, Chen D, Li R, Yu B, Srinivasan S, Abe B, Kraft K, Hellström C, Sjöberg R, Chang S, Feng A, Goldman D, Shah A, Petri M, Chung L, Fiorentino D, Lundberg E, Wutz A, Utz P, Chang H. Xist Ribonucleoproteins Promote Female Sex-biased Autoimmunity [abstract]. Arthritis Rheumatol. 2023; 75 (suppl 9). https://acrabstracts.org/abstract/xist-ribonucleoproteins-promote-female-sex-biased-autoimmunity/. Accessed .« Back to ACR Convergence 2023
ACR Meeting Abstracts - https://acrabstracts.org/abstract/xist-ribonucleoproteins-promote-female-sex-biased-autoimmunity/