Antibodies to Ro ribonucleoproteins as biomarkers in Sjogren's syndrome

描述（申请人提供）：干燥综合征是一种常见的自身免疫性疾病，以局灶性淋巴细胞浸润外分泌腺为特征。虽然干燥综合征与显著发病率相关，但病因不明，诊断困难。迄今为止，干燥综合征最有用的生物标志物是抗ro和抗la自身抗体的存在。这些抗体直接针对由Ro60蛋白、La蛋白和称为Y rna的无编码rna组成的核糖核蛋白颗粒（RNPs）。然而，虽然Ro60和/或La抗体出现在38-90%的干燥综合征患者中，但这些抗体也出现在其他风湿病患者中，包括系统性红斑狼疮。该探索性项目的目的是确定新的生物标志物，以加快干燥综合征的正确诊断，并深入了解病因和/或疾病进展。我们的具体方法是专注于Ro60 RNPs的新鉴定组分和Ro60的氧化修饰形式。我们的第一个目标是确定九种新的ro相关蛋白中是否有任何一种是干燥综合征免疫反应的特异性靶点。我们的第二个目标是检查这些蛋白质的组织分布和亚细胞定位。一种靶向蛋白在唾液上皮细胞中最为丰富，而其他蛋白在角质形成细胞中更为丰富，这一发现可能会让我们深入了解为什么一些抗ro60抗体患者会患上干燥综合征，而另一些患者则会患上不同的风湿性疾病。我们的第三个目标是确定抗ro60自身抗体是否优先针对氧化修饰形式的蛋白质。患者靶向氧化形式Ro60的发现可能有助于区分与这些抗体相关的各种综合征，可能有助于预测临床结果，并可能深入了解干燥综合征自身免疫起源的机制。

DESCRIPTION (provided by applicant): Sjogren's syndrome is a common autoimmune disease characterized by focal lymphocytic infiltration of exocrine glands. Although Sjogren's syndrome is associated with significant morbidity, the etiology is unknown, and diagnosis is difficult. To date, the most useful biomarker for Sjogren's syndrome is the presence of anti-Ro and anti-La autoantibodies. These antibodies are directed against ribonucleoprotein particles (RNPs) consisting of the Ro60 protein, the La protein, and nocoding RNAs called Y RNAs. However, while antibodies to Ro60 and/or La occur in 38-90% of Sjogren's syndrome patients, these antibodies also occur in patients with other rheumatic diseases, including systemic lupus erythematosus. The objective of this exploratory project is to identify novel biomarkers that will expedite correct diagnosis of Sjogren's syndrome and yield insights into etiology and/or disease progression. Our specific approach is to focus on newly identified components of the Ro60 RNPs and on oxidatively modified forms of Ro60. Our first aim is to determine whether any of nine novel Ro-associated proteins are specific targets of the immune response in Sjogren's syndrome. Our second aim is to examine the tissue distribution and subcellular localization of these proteins. The finding that a targeted protein is most abundant in salivary epithelial cells, while other proteins are more abundant in keratinocytes, may give insights into why some patients with anti-Ro60 antibodies develop Sjogren's syndrome, while others develop distinct rheumatic diseases. Our third aim is to determine if anti-Ro60 autoantibodies are preferentially directed against oxidatively modified forms of the protein. The finding that patients target oxidized forms of Ro60 may be helpful for differentiating the various syndromes associated with these antibodies, may be useful for predicting clinical outcomes, and may yield insights into the mechanisms by which autoimmunity in Sjogren's syndrome originates. Lay summary: Sjogren's syndrome, a disease characterized by dry eyes and dry mouth, is often confused with other illnesses. Our goal is to identify whether Sjogren's syndrome patients produce autoantibodies that will be useful for diagnosis and for predicting the course of the disease in individual patients.