PR3-ANCA Subsets and Disease Phenotype

描述(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在血管炎发展中的致病作用的假说。然而，并不是每个接受治疗的持续性ANCA患者都有活动性疾病，复发的ANCA并不总是预示着脉管炎的发作。WG中ANCA最突出的靶抗原是蛋白酶3(PR3)，这是一种中性粒细胞嗜天青颗粒中含有的丝氨酸蛋白酶。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)，尤其是PR3-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定致病相互作用。因此，建议的研究旨在检验以下一般假设：PR3-ANCA亚型与PR3的不同结构表位反应，调节PR3的功能，从而影响临床疾病的表现。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PR3-ANCA与Pro-PR3反应的疾病复发预测价值，与ANCA与成熟PR3反应的预测价值进行比较。(2)我们将确定PR3-ANCA反应性与PR3不同糖基化变异体的临床相关性。(3)我们将用特定的表位鉴定PR3-ANC的反应性及其与器官表现、疾病活动性和病程的关系。(4)我们将确定PR3-ANCA亚群对PR3的功能影响及其与器官表现、疾病活动性和病程的关系。 拟议的研究将使用在韦格纳肉芽肿病Etanercept试验(WGET)的背景下收集的样本进行。通过研究这一独特的患者群体的样本，根据疾病活动和器官表现以前瞻性的方式严格描述，我们将能够识别临床相关的PR3-ANCA亚群，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新的见解，这是任何其他方式都无法获得的，并将构成迄今为止对这些抗体最明确的研究。

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.