Center for Personal Dynamic Regulomes, Program in Epithelial Biology, Department of Dermatology, Stanford University School of Medicine, Stanford, CA, USA.
Department of Comparative Medicine, Stanford University, Stanford, CA, USA.
Cell. 2024 Feb 1;187(3):733-749.e16. doi: 10.1016/j.cell.2023.12.037.
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.
自身免疫性疾病在女性中的发病率明显高于男性。XX 性染色体组成与自身免疫易感性密切相关。Xist 长链非编码 RNA（lncRNA）仅在女性中表达，随机失活两条 X 染色体中的一条，以实现基因剂量补偿。在这里，我们表明，包含许多自身抗原成分的 Xist 核糖核蛋白（RNP）复合物是性别偏倚自身免疫的重要驱动因素。在雄性小鼠中诱导表达非沉默形式的 Xist 会引入 Xist RNP 复合物，并足以产生自身抗体。表达转基因 Xist 的雄性 SJL/J 小鼠在芘诱发狼疮模型中比野生型雄性表现出更严重的多器官病理。雄性中的 Xist 表达将 T 和 B 细胞群体和染色质状态重新编程为更类似于野生型雌性。患有自身免疫性疾病的人类患者对 XIST RNP 的多个成分表现出明显的自身抗体。因此，一种性别特异性的 lncRNA 支架普遍存在的 RNP 成分，以驱动性别偏倚的免疫。
