Xist 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 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.