PR3-ANCA Subsets and Disease Phenotype

描述（由申请人提供）：韦格纳肉芽肿病（WG）是与抗中性粒细胞细胞质抗体（ANCA）相关的血管增生的原型。特定器官受累和疾病复发的决定因素尚不清楚。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，并不是每个治疗后出现持续性ANCA的患者都有活动性疾病，而且复发性ANCA并不一定预示着血管炎的爆发。在WG中，ANCA最重要的靶抗原是蛋白酶3 (PR3)，它是一种丝氨酸蛋白酶，存在于中性粒细胞的嗜氮颗粒中。初步研究表明，不仅ANCA的类型（如抗pr3或抗髓过氧化物酶抗体），而且特别是PR3-ANCA亚群可能影响预后和临床表现。

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.