PR3-ANCA Subsets and Disease Phenotype

PR3-ANCA 亚群和疾病表型

• 批准号: 6551467
• 负责人: ULRICH SPECKS
• 金额: $ 26.58万
• 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 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6551467
• 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（由申请方提供）：韦格纳肉芽肿病（WG）是与抗神经细胞胞质抗体（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。 大量的实验证据支持ANCA在血管炎发展中的致病作用的假设。 然而，并不是每一个持续ANCA治疗后的患者都有活动性疾病，复发的ANCA并不总是预示着血管炎发作。WG中ANCA最突出的靶抗原是蛋白酶3（PR 3），这是一种包含在中性粒细胞嗜天青颗粒内的丝氨酸蛋白酶。 初步研究表明，不仅ANCA类型（例如，抗PR 3或抗髓过氧化物酶抗体），但特别是PR 3-ANCA亚群可能影响预后和临床表现谱。 开发新的、基于机制的治疗干预措施需要详细了解这些抗体与其靶抗原的特异性致病相互作用。 因此，所提出的研究旨在检验以下一般假设：PR 3-ANCA亚型与PR 3的不同结构表位反应，调节PR 3功能，从而影响临床疾病表达。 为了解决这一假设，我们将追求以下具体目标。 (1)我们将确定PR 3-与pro-PR 3反应的ANCA与与成熟PR 3反应的ANCA相比对疾病复发的预测值。 (2)我们将确定PR 3-ANCA反应性与PR 3的不同糖基化变体的临床相关性。 (3)我们将鉴定PR 3-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PR 3-ANCA亚群对PR 3的功能影响及其与器官表现、疾病活动和疾病持续时间的关系。 将使用在韦格纳肉芽肿依那西普试验（WGET）背景下收集的样本进行拟定研究。 通过研究来自这个独特患者群体的样本，根据疾病活动和器官表现以前瞻性方式进行严格表征，我们将能够识别临床相关的PR 3-ANCA子集并确定其对疾病表现的影响。 这项研究将为PR 3-ANCA的潜在致病作用提供新的见解，这是无法以任何其他方式获得的，并将构成迄今为止对这些抗体的最确定性研究。