Complement in Pathogenesis and Experimental Therapy of ANCA Disease

尽管补体在历史上不被怀疑与“缺乏免疫”的抗中性粒细胞抗体有关， 细胞质抗体（ANCA）相关性血管炎（AAV），最近的临床和实验证据， 显示它在放大最初的炎症和随后的先天性和 AAV中的适应性自身免疫器官损伤。人AAV是一种严重的全身性自身免疫性疾病， 多个器官中的小血管，但最突出的是肾脏和呼吸道。如果不治疗， 平均生存期只有5个月。目前的AAV治疗方案仅限于非特异性的， 免疫抑制具有显著的副作用，并且在预防复发方面并不总是有效。 因此，需要更有效和毒性更小的治疗方法。AAV的定义特征是 患者血液中存在对两种中性粒细胞胞质抗原之一具有特异性的ANCA， 髓过氧化物酶（MPO）和蛋白酶3。补体如何促进ANCA介导的器官损伤， 如坏死性新月体肾小球肾炎（NCGN）和肺出血尚未完全了解。在这 项目，我们将使用一个强大的小鼠模型的MPO ANCA疾病，我们最近开发的解剖 补体在NCGN和肺出血中的作用此外，我们将使用这种小鼠模型来测试抗- 补体疗法，以提供在治疗中靶向特异性补体蛋白的概念证明 NCGN和肺出血。我们的具体目标是：目标1。为了验证这一假设， 坏死性新月体肾小球肾炎（NCGN）和肺出血在我们的小鼠MPO ANCA疾病 模型需要MPO特异性抗体、补体旁路途径和前补体之间的相互作用。 现有的抗MPO细胞免疫;目的2.测试补体蛋白的作用和作用机制 以及备解素、C5 aR和膜攻击复合物（membrane attack complex，MAC）等效应因子在MPO发生发展中的作用 ANCA诱导的NCGN和肺出血;目的3。系统检测和比较 阻断备解素、C5、C5 a或C5 aR预防和治疗MPO ANCA诱导的NCGN和肺 出血我们创新的MPO ANCA疾病小鼠模型完全重现了人类疾病 表型，包括NCGN和肺出血的发展。通过使用这个模型，我们希望摆脱 新的光补体在AAV的发病机制中的作用，并验证了治疗的潜力， 封闭补体治疗NCGN和肺出血两大疾病表现 人类AAV

Although complement is historically not suspected to be implicated in the ‘pauci-immune’ anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), recent clinical and experimental evidence has shown it to play a key role in amplifying the initial inflammation and subsequent orchestration of innate and adaptive autoimmune organ injury in AAV. Human AAV is a severe systemic autoimmune disease that affects small vessels in multiple organs, but most prominently the kidney and the respiratory tract. If untreated, AAV is fatal with an average survival of only 5 months. Current treatment regimens of AAV is limited to non-specific immunosuppression which carries significant side effects and is not always efficacious in preventing relapse. Therefore, more effective and less toxic therapeutic approaches are needed. A defining feature of AAV is the presence in patient’s blood of ANCA with specificity to one of two neutrophil cytoplasmic antigens, myeloperoxidase (MPO) and proteinase 3. How complement contributes to ANCA-mediated organ injury such as necrotizing crescentic glomerulonephritis (NCGN) and lung hemorrhage is not yet fully understood. In this project, we will use a robust mouse model of MPO ANCA disease that we have recently developed to dissect the role of complement in NCGN and lung hemorrhage. Additionally, we will use this mouse model to test anti- complement therapies to provide proof of concept for targeting specific complement proteins in the treatment of NCGN and lung hemorrhage. Our specific aims are: Aim 1. To test the hypothesis that pathogenesis of both necrotizing crescentic glomerulonephritis (NCGN) and lung hemorrhage in our mouse MPO ANCA disease model requires the interplay between MPO-specific antibodies, alternative pathway of complement, and pre- existing anti-MPO cellular immunity; Aim 2. To test the role and mechanism of action of complement proteins and effectors, including properdin, C5aR and membrane attack complex (MAC), in the development of MPO ANCA-induced NCGN and lung hemorrhage; Aim 3. To test and compare therapeutic efficacy of systemically blocking properdin, C5, C5a or C5aR in preventing and treating MPO ANCA-induced NCGN and lung hemorrhage. Our innovative mouse model of MPO ANCA disease fully recapitulates the human disease phenotype, including development of NCGN and lung hemorrhage. By using this model, we expect to shed new light on the role of complement in the pathogenesis of AAV, and validate the therapeutic potential of blocking complement in the treatment of both NCGN and lung hemorrhage, two major disease manifestations of human AAV.