PR3-ANCA Subsets and Disease Phenotype

PR3-ANCA 亚群和疾病表型

• 批准号: 6935240
• 负责人: ULRICH SPECKS
• 金额: $ 22.27万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-15 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6935240
• 关键词: Wegener' s granulomatosis; autoantibody; autoantigens; biomarker; clinical research; disease /disorder classification; endopeptidases; human tissue; immunopathology; molecular pathology; myeloperoxidase; neutrophil; patient oriented research; protein isoforms; serine proteinases

DESCRIPTION (provided by applicant): Wegener's granulomatosis (WG) is the prototype of vasculitides associated with antineutrophil cytoplasmic antibodies (ANCA). The determinants of specific organ involvement and disease relapses remain unclear. A large body of experimental evidence supports the hypothesis of a pathogenic role of ANCA in the development of vasculitis. Yet not every patient with persistent ANCA following treatment has active disease, and recurrent ANCA do not invariably herald vasculitis flares. The most prominent target antigen for ANCA in WG is proteinase 3 (PR3), a serine protease contained within azurophilic granules of the neutrophil. Preliminary studies indicate that not only the type of ANCA (e.g., anti-PR3 or anti-myeloperoxidase antibodies), but particularly PR3-ANCA subsets may influence the prognosis and spectrum of clinical presentations. The development of novel, mechanism-based therapeutic interventions requires detailed understanding of the specific pathogenetic interactions of these antibodies with their target antigen. Consequently, the proposed studies are designed to test the following general hypothesis: PR3-ANCA subtypes, reacting with different structural epitopes of PR3, modulate PR3 functions and thereby affect clinical disease expression. To address this hypothesis, we will pursue the following specific aims. (1) We will determine the predictive value for disease relapse of PR3-ANCA reacting with pro-PR3, compared to that of ANCA reacting with mature PR3. (2) We will determine the clinical relevance of PR3-ANCA reactivity with different glycosylation variants of PR3. (3) We will identify PR3-ANC reactivity with specific epitopes and their relationship to organ manifestations, disease activity and duration of disease. (4) We will determine the functional impact of PR3-ANCA subsets on PR3 and its relation to organ manifestations, disease activity and duration of disease. The proposed studies will be performed using samples collected in the context of the Wegener's Granulomatosis Etanercept Trial (WGET). By investigating samples from this unique patient population, rigorously characterized in a prospective fashion according to disease activity and organ manifestations, we will be able to identify clinically relevant PR3-ANCA subsets and determine their impact upon disease manifestations. This study will provide new insights into the potential pathogenic role of PR3-ANCA that are not obtainable in any other way, and will constitute the most definitive study of these antibodies to date.

描述（由申请人提供）：韦格纳肉芽肿病（WG）是与抗中性粒细胞胞浆抗体（ANCA）相关的血管炎的原型。 特定器官受累和疾病复发的决定因素仍不清楚。 大量实验证据支持 ANCA 在血管炎发展中发挥致病作用的假设。 然而，并非所有治疗后持续存在 ANCA 的患者都会出现活动性疾病，并且复发性 ANCA 并不总是预示着血管炎发作。 WG 中 ANCA 最重要的靶抗原是蛋白酶 3 (PR3)，这是一种包含在中性粒细胞嗜天青颗粒中的丝氨酸蛋白酶。 初步研究表明，不仅 ANCA 的类型（例如抗 PR3 或抗髓过氧化物酶抗体），而且尤其是 PR3-ANCA 子集可能会影响预后和临床表现的范围。 新型基于机制的治疗干预措施的开发需要详细了解这些抗体与其靶抗原的特定致病相互作用。 因此，拟议的研究旨在检验以下一般假设：PR3-ANCA 亚型与 PR3 的不同结构表位发生反应，调节 PR3 功能，从而影响临床疾病表达。 为了解决这个假设，我们将追求以下具体目标。 (1)我们将确定与PR3原反应的PR3-ANCA与与成熟PR3反应的ANCA相比对疾病复发的预测价值。 (2) 我们将确定 PR3-ANCA 反应性与 PR3 不同糖基化变体的临床相关性。 (3)我们将鉴定PR3-ANC与特定表位的反应性及其与器官表现、疾病活动性和疾病持续时间的关系。 (4)我们将确定PR3-ANCA亚群对PR3的功能影响及其与器官表现、疾病活动性和疾病持续时间的关系。 拟议的研究将使用在韦格纳肉芽肿病依那西普试验 (WGET) 中收集的样本进行。 通过调查来自这一独特患者群体的样本，并根据疾病活动和器官表现以前瞻性方式严格表征，我们将能够识别临床相关的 PR3-ANCA 子集并确定它们对疾病表现的影响。 这项研究将为 PR3-ANCA 的潜在致病作用提供以任何其他方式无法获得的新见解，并将构成迄今为止对这些抗体最明确的研究。

项目成果

A novel capture-ELISA for detection of anti-neutrophil cytoplasmic antibodies (ANCA) based on c-myc peptide recognition in carboxy-terminally tagged recombinant neutrophil serine proteases.

一种新型捕获 ELISA，用于检测抗中性粒细胞胞浆抗体 (ANCA)，基于羧基末端标记的重组中性粒细胞丝氨酸蛋白酶中的 c-myc 肽识别。

• DOI: 10.1016/j.jim.2005.09.004
• 发表时间: 2005
• 期刊: Journal of immunological methods.
• 作者: Lee,AugustineS;Finkielman,JavierD;Peikert,Tobias;Hummel,AmberM;Viss,MargaretA;Specks,Ulrich
• 通讯作者: Specks,Ulrich