The Immunopathogenic role of XIST in Sjogren's Syndrome

XIST 在干燥综合征中的免疫致病作用

• 批准号: 9979575
• 负责人: Erika Darrah
• 金额: $ 24.56万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9979575
• 关键词: Affect; Age-Years; Agonist; Antigen-Antibody Complex; Antigens; Autoantibodies; Autoantigens; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Automobile Driving; B-Lymphocyte Subsets; B-Lymphocytes; Belief; Binding Proteins; Blood Cells; Cell Nucleus; Cell model; Cells; Chemosensitization; Chronic; Complex; Cytoplasm; Data; Development; Disease; Dryness; Exhibits; Exposure to; Female; Future; Gene Dosage; Genes; Genetic Transcription; Human; Immune; Immune signaling; Immunologics; Individual; Inflammation; Interferons; Laboratories; Lead; Life; Ligands; Link; Lymphocyte; Mediating; Mediator of activation protein; Methods; Nuclear; Oral Characters; Pathogenesis; Pathogenicity; Patients; Pattern; Plasma; Play; Predisposition; Process; Production; Property; Proteins; Proteomics; RNA; RNA Binding; RNA Sequences; RNA-Binding Proteins; Role; SS-A antigen; Sex Bias; Signal Transduction; Sjogren' s Syndrome; Systemic Lupus Erythematosus; T-Lymphocyte; TLR7 gene; Time; Transcript; Untranslated RNA; Up-Regulation; Woman; Women' s Health; Work; X Chromosome; X Inactivation; XX male; base; immunogenicity; insight; men; mortality; new therapeutic target; novel; novel therapeutic intervention; patient subsets; peripheral blood; response; sex; systemic autoimmune disease; therapy development; treatment strategy

Project Summary/Abstract Sjögren’s syndrome (SS) is a systemic autoimmune disease that predominantly affects women, yet the mechanisms driving this strong gender bias are unknown. The X chromosome has been implicated in the increased female susceptibility to autoimmune diseases like SS, and compelling evidence suggests that abnormal X chromosome inactivation (XCI) may play a pathogenic role. XCI occurs during development to normalize X-linked gene dosage between men and women in a manner dependent on the X-inactive specific transcript (XIST), a long non-coding RNA (lncRNA). Although this is the only known function of XIST RNA, it continues to be synthesized throughout life in individuals with two X chromosomes. A non-classical distribution of XIST outside of the nucleus has recently been observed in a subset of B and T cells from healthy women. The mechanisms and consequences of this non-canonical XIST expression have not been explored, and several additional intriguing observations suggest that XIST possesses properties that may contribute to the pathogenesis of autoimmune diseases, independently of XCI, including: 1) XIST is a lncRNA present at high levels in individuals predisposed to the development of autoimmunity; 2) the dominantly targeted autoantigens in SS, Ro/SSA and La/SSB, are RNA-binding proteins that can be found in complexes with self-RNA; and 3) our analysis of the XIST RNA sequence reveals the presence of a known TLR7-stimulatory motif. Together with growing evidence that chronic exposure to self-RNA alone or in immune complexes can stimulate pathogenic TLR7-dependent responses, these observations support our hypothesis that XIST RNA contributes to the female susceptibility to autoimmunity by acting as an endogenous TLR7 agonist. We propose to build on our preliminary data to systemically examine the critical aspects of this hypothesis through the study of human biospecimens and cellular models. In Aim 1, high- throughput flow cytometric methods will be used to compare the expression and distribution pattern of XIST RNA in the peripheral blood cells of men and women with SS compared to sex-matched healthy controls. Aim 2 will examine XIST release from dying cells and potential interactions with SS autoantigens, to determine whether XIST could be a component of circulating immune complexes in patients with SS. Finally, in Aim 3, we will evaluate the capacity of XIST RNA to act as a TLR7 ligand. This work has the potential to define a novel proinflammatory role for XIST in the pathogenesis of SS, which could inform the future development of therapies that disrupt the disease promoting capacity of XIST for the treatment of SS and related autoimmune conditions.

项目概要/摘要 干燥综合征 (SS) 是一种系统性自身免疫性疾病，主要影响女性，但 导致这种强烈性别偏见的机制尚不清楚。 女性对 SS 等自身免疫性疾病的易感性增加，令人信服的证据表明 X染色体异常失活（XCI）可能起到致病作用。 以依赖于 X 失活特异性的方式使男性和女性之间的 X 连锁基因剂量正常化 转录本 (XIST)，一种长非编码 RNA (lncRNA)，尽管这是 XIST RNA 唯一已知的功能， 它在具有两条非经典 X 染色体的个体的一生中不断合成。 最近在 B 细胞和 T 细胞亚群中观察到 XIST 在细胞核外的分布 这种非典型 XIST 表达的机制和后果尚未得到证实。 探索，并且一些额外有趣的观察表明 XIST 具有可能的特性 与 XCI 无关，有助于自身免疫性疾病的发病机制，包括：1) XIST 是一种 lncRNA 在易发生自身免疫的个体中含量较高；2) SS、Ro/SSA 和 La/SSB 中的主要靶向自身抗原是可以发现的 RNA 结合蛋白 与自身 RNA 形成复合物；3) 我们对 XIST RNA 序列的分析揭示了已知的存在 TLR7 刺激基序越来越多的证据表明长期暴露于单独或单独的自身 RNA 中。 免疫复合物可以刺激致病性 TLR7 依赖性反应，这些观察结果支持我们的研究 假设 XIST RNA 通过充当女性对自身免疫的易感性 我们建议以我们的初步数据为基础来系统地检查关键因素。 这一假设的各个方面是通过对人类生物样本和细胞模型的研究来实现的。 将使用通量流式细胞术方法来比较 XIST 的表达和分布模式 SS 男性和女性外周血细胞中的 RNA 与性别匹配的健康对照相比。 目标 2 将检查垂死细胞的 XIST 释放以及与 SS 自身抗原的潜在相互作用，以 确定 XIST 是否可能是 SS 患者循环免疫复合物的组成部分。 在目标 3 中，我们将评估 XIST RNA 作为 TLR7 配体的能力。 定义了 XIST 在 SS 发病机制中的新型促炎作用，这可以为未来提供信息 开发破坏 XIST 疾病促进能力的疗法来治疗 SS 和 相关的自身免疫性疾病。