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Dou DR, Zhao Y, Belk JA, Zhao Y, Casey KM, Chen DC, Li R, Yu B, Srinivasan S, Abe BT, Kraft K, Hellström C, Sjöberg R, Chang S, Feng A, Goldman DW, Shah AA, Petri M, Chung LS, Fiorentino DF, Lundberg EK, Wutz A, Utz PJ, Chang HY
Cell 187 (3) 733-749.e16 [2024-02-01; online 2024-02-03]
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.
Autoimmunity and Serology Profiling [Service]
PubMed 38306984
DOI 10.1016/j.cell.2023.12.037
Crossref 10.1016/j.cell.2023.12.037
pii: S0092-8674(24)00002-3