Xist ribonucleoproteins promote female sex-biased autoimmunity

Abstract

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.

Altered X-chromosome inactivation predisposes to autoimmunity

“…This result seems in apparent contradiction with observations of the present study in which reduced levels of Xist in female immune cells, associated with altered XCI, trigger spontaneous systemic autoimmunity. The study by Dou et al ( 60 ) indicates that Xist RNP itself harbors immunogenic properties upon release from dying male cells that are not naturally expressing Xist , whereas, in the present study, altered XCI is constitutive and triggers spontaneous autoimmunity in aged female mice of the non-autoimmune prone background (C57/BL6). These two findings are, however, not mutually exclusive and may reflect the wide variety of causes, manifestations, and onset of autoimmunity.…”

“…Alterations of XCI as a cause of different autoimmune manifestations have not been reported so far but not thoroughly investigated either. Two independent studies have recently reported that (i) XIST levels were elevated in blood leucocytes from women with SLE ( 59 ) and that (ii) transgenic expression of Xist lncRNAs in male mice can promote autoantibodies directed against Xist RNP in the context of pristane-induced lupus in a permissive genetic background (SJL/J) ( 60 ). This result seems in apparent contradiction with observations of the present study in which reduced levels of Xist in female immune cells, associated with altered XCI, trigger spontaneous systemic autoimmunity.…”

“…Further studies using uniformized genetic backgrounds associated with tailored ways to either increase or reduce Xist expression will be required to establish the effect of Xist RNP and of XCI alteration on the kinetics and types of autoimmune manifestations that are promoted. Together, it is possible that autoreactivity to Xist RNP and escape from XCI may both synergize to promote female-biased autoimmunity in the context of tissue damage ( 60 ).…”

Ribonuclease activity undermines immune sensing of naked extracellular RNA

“…Supporting the role of extracellular RNases in the regulation of inflammatory responses, several reports have shown that ectopic administration of extracellular RNases reduces inflammation in mouse models of Lupus-like disease (Sun et al 2013), traumatic brain injury (Krämer et al 2022), and myocardial infarction (Cabrera-Fuentes et al 2014). In humans, sterile inflammation causing cell death and the release of RNPs into the extracellular space seems to be an important trigger of Systemic Lupus Erythematosus (Dou et al 2024). In addition, polytrauma induces exRNA release followed by TLR7-dependent systemic inflammation in mice (Suen et al 2023).…”

“…However, several RNA species are stable in the extracellular space even when not associated with EVs. These resilient extracellular RNAs include ribonucleoprotein particles (RNPs) such as Ago2/miRNA complexes (Turchinovich et al 2011; Arroyo et al 2011; Geekiyanage et al 2020), and protein-protected RNA fragments (LaPlante et al 2023) derived from the ribosome (Tosar et al 2020, 2022; Costa et al 2023), U2 snRNPs (Tosar et al 2022), and possibly Xist RNPs (Dou et al 2024). Additionally, a population of intrinsically stable nicked tRNAs circulates in human biofluids, probably unprotected or naked (Costa et al 2023).…”