Fine specificity of scleroderma autoantibodies

硬皮病自身抗体的精细特异性

• 批准号: 6761762
• 负责人: JUDITH A JAMES
• 金额: $ 31.38万
• 依托单位: OKLAHOMA MEDICAL RESEARCH FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-26 至 2006-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6761762
• 关键词: DNA topoisomerases; Raynaud' s disease; antibody specificity; antigen antibody reaction; autoantibody; biopsy; blood chemistry; enzyme inhibitors; enzyme linked immunosorbent assay; epitope mapping; histocompatibility typing; human genetic material tag; human subject; humoral immunity; immunodiffusion; immunoprecipitation; pathologic process; patient oriented research; protein sequence; ribonucleoproteins; scleroderma; tissue resource /registry; western blottings

DESCRIPTION (provided by applicant): Systemic sclerosis (scleroderma) is a disfiguring, multi-system disease of unknown etiology, which is characterized by a broad spectrum of disease manifestations with varying organ involvement. Raynaud's phenomenon, the dysregulated vascular contraction of the terminal arteries of the circulatory system, is present in almost every case. Vascular insufficiency in these patients is associated with a vasculopathy causing tissue ischemia, which is directly linked to progressive fibrosis of specific target organs, such as the skin, lung, heart, gastrointestinal tract, and kidney. Although the underlying pathophysiology of this disorder remains an enigma, the presence of anti-nuclear antibodies in scleroderma patients is nearly universal. Targets of these autoantibodies include topoisomerase 1 (Scl-70), nuclear ribonucleoproteins (nRNP), centromere, PM-Scl, and Ku. Anti-topoisomerase-1 (topo-1) autoantibodies are quite specific for scleroderma. and are present in precipitating levels in 20-40% of patients. Anti-topo 1 is associated with diffuse skin thickening, lung involvement, and the development of lung, colon, and brain cancer. Scleroderma patients with anti-nRNP autoantibodies may have a more cutaneous form of the disease and universally suffer from Raynaud's phenomenon. Over the past decade we have extensively characterized the immunochemistry of lupus autoantigens. These previous studies provide the technical background for this proposal. Epitope mapping experiments of the lupus spliceosomal autoantigens have led to a peptide induced model of lupus autoimmunity. These studies have identified a potential etiological trigger and pathogenic mechanisms. We will now apply these well-honed techniques, as well as a similar scientific strategy, to analyze the humoral fine specificity of the anti-nRNP and anti-topoisomerase autoantibodies found in scleroderma. Preliminary data suggest a dramatic difference in the anti-nRNP response of SLE patients and scleroderma patients with nRNP autoantibodies. This project seeks to identify the common humoral epitopes of nRNP and topoisomerase-1 in scleroderma and primary Raynaud's, to describe the development of these humoral autoimmune responses over time (and with therapy), to establish potential etiological triggers of these rheumatic diseases, and to understand the role of these specific autoantibodies in scleroderma, disease pathogenesis.

描述（由申请人提供）：系统性硬化症（硬皮病）是一种 病因不明的毁容性多系统疾病，其特征是 具有广泛的疾病表现和不同的器官受累。 雷诺现象，末梢血管收缩失调 循环系统的动脉，几乎在所有情况下都存在。血管 这些患者的功能不足与血管病变有关 组织缺血，与特定部位的进行性纤维化直接相关 靶器官，如皮肤、肺、心脏、胃肠道等 肾。尽管这种疾病的潜在病理生理学仍然是一个 硬皮病患者体内是否存在抗核抗体是一个谜 几乎普遍。这些自身抗体的靶标包括拓扑异构酶 1 (Scl-70)、核核糖核蛋白 (nRNP)、着丝粒、PM-Scl 和 Ku。 抗拓扑异构酶 1 (topo-1) 自身抗体对于 硬皮病。 20-40% 的患者中存在沉淀水平。 抗拓扑蛋白 1 与弥漫性皮肤增厚、肺部受累和 肺癌、结肠癌和脑癌的发展。硬皮病患者 抗 nRNP 自身抗体可能会导致更多皮肤形式的疾病，并且 普遍患有雷诺现象。 在过去的十年中，我们广泛地表征了免疫化学 狼疮自身抗原。这些先前的研究提供了技术背景 这个建议。狼疮剪接体表位作图实验 自身抗原导致了狼疮自身免疫的肽诱导模型。这些 研究已确定潜在的病因触发因素和致病因素 机制。我们现在将应用这些经过精心打磨的技术以及类似的技术 科学策略，分析抗nRNP的体液精细特异性 以及硬皮病中发现的抗拓扑异构酶自身抗体。初步数据 表明 SLE 患者的抗 nRNP 反应存在显着差异 具有 nRNP 自身抗体的硬皮病患者。该项目旨在确定 硬皮病中 nRNP 和拓扑异构酶 1 的常见体液表位 原发性雷诺氏病，描述这些体液自身免疫性疾病的发展 随着时间的推移（以及治疗）的反应，以确定潜在的病因 这些风湿性疾病的触发因素，并了解这些疾病的作用 硬皮病中的特异性自身抗体，疾病发病机制。