SRP477191 PRJNA1050815 GSE249828 Xist ribonucleoprotein particles promote female sex-biased autoimmunity [bulk RNA-seq] 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. Here, we show that the Xist ribonucleoprotein (RNP) complex, comprised of 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 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 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. Overall design: C57BL6/J mice WT or heterozygous for the transgene of a non-silencing, doxycycline-inducible mutant of Xist (tgXist) inserted on Chr11 were injected at 12-14 weeks of age with 0.5 mL pristane or PBS (injection control), fed water with or without doxycycline, and spleens harvested at 52 weeks post-injection. Spleens were mechanically dissociated and isolated by FACS for viably CD4+ T-cells (C57BL/6J) or CD45+ cells (SJL/J). Bulk OMNI ATAC-seq and RNA-seq were performed on the C57BL/6J cells while the 10X genomics multiome was used to construct libaries from SJL/J cells. GSE249828 parent_bioproject PRJNA1050811