Complement in Pathogenesis and Experimental Therapy of ANCA Disease

尽管补体在历史上没有被怀疑与‘少食免疫’抗中性粒细胞有关 细胞质抗体(ANCA)相关性小血管炎(AAV)，最近的临床和实验证据 表明它在放大先天和后天的炎症和随后的协调方面发挥了关键作用 AAV中的适应性自身免疫器官损伤。人类AAV是一种严重的系统性自身免疫性疾病，影响 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，AAV是 死亡，平均存活时间只有5个月。目前甲型肝炎病毒的治疗方案仅限于非特异性 免疫抑制具有明显的副作用，在预防复发方面并不总是有效的。 因此，需要更有效和毒性更低的治疗方法。AAV的一个定义特征是 ANCA患者血液中存在对两种中性粒细胞胞浆抗原之一具有特异性的ANCA 髓过氧化物酶和蛋白水解酶3.补体在ANCA等介导的器官损伤中的作用 作为坏死性新月体肾小球肾炎(NCGN)和肺出血尚不完全清楚。在这 项目中，我们将使用我们最近开发的MPO ANCA疾病的健壮小鼠模型来解剖 补体在NCGN和肺出血中的作用此外，我们将使用这个鼠标模型来测试反 补体疗法为以特定补体蛋白为靶点的治疗提供概念证据 NCGN和肺出血。我们的具体目标是：目标1.检验两种疾病发病机制的假设 小鼠MPO ANCA病的坏死性新月体肾炎(NCGN)和肺出血 模型要求MPO特异性抗体、补体的替代途径和前- 存在抗MPO细胞免疫；目的2.检测补体蛋白的作用和作用机制 和效应物，包括备解素、C5aR和膜攻击复合体(MAC)在MPO的发展中 目的3.系统检测和比较丹参治疗ANCA的疗效。 阻断备解素、C5、C5a或C5aR防治MPO-ANCA致NCGN及肺损伤 大出血。我们创新的MPO ANCA病小鼠模型完全概括了人类疾病 表型，包括NCGN的发展和肺出血。通过使用这种模式，我们希望摆脱 对补体在AAV发病机制中作用的新认识，并验证了补体在AAV治疗中的潜力 阻断补体治疗NCGN和肺出血两大表现 人类AAV病毒。

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.