ANCA GLOMERULONEPHRITIS: FROM MOLECULES TO MAN

总体描述（由申请人提供）： 我们的计划项目集中在抗中性粒细胞胞浆抗体（ANCA）肾小球肾炎的研究。这种竞争性更新的目的仍然是阐明ANCA坏死性和新月体肾炎的原因和致病机制。在过去的四年里，我们对这种疾病的了解取得了实质性的进展。这一进展开辟了许多令人兴奋的探索途径，我们将其分为四个项目和两个核心。项目1是一项免疫发病机制研究，其中心是我们最近的观察结果，即蛋白酶3的互补肽可能刺激自身免疫反应。这项最有趣的研究对所有自身免疫都有广泛的意义。在项目2中，我们探索ANCA抗原（蛋白酶3和髓过氧化物酶）的作用及其与自身抗体、B细胞和T细胞的相互作用;以及它们参与诱导。血管损伤项目3的重点是ANCA肾小球肾炎的分子遗传学和探索基因是允许或修改的表型和过程中的ANCA肾小球肾炎。在目前的计划项目中，我们阐明了一种动物模型，其中抗髓过氧化物酶抗体或淋巴细胞被动地转移到NA中，ve受体小鼠，并诱导了一种类似人的少免疫性坏死性和新月体肾小球肾炎。项目4将利用这种新的动物模型来阐明致病机制。临床核心是我们所有研究的关键，使我们能够随访ANCA肾小球肾炎患者近20年。从这些患者中，我们能够获得重要的临床和病理信息以及我们所有研究的生物标本。由于三个原因，所有这些项目之间存在实质性的协同作用：（1）因为所有项目都集中在ANCA肾小球肾炎，（2）从一个项目中收集的想法对另一个项目中进行的研究有直接影响，（3）相同的假设可以在人体和动物系统的不同项目中进行体内和体外测试。在我们目前的计划项目期间，我们已经做了一些开创性的观察，不仅专门针对ANCA肾小球肾炎，而且还涉及自身免疫和炎症。虽然已经取得了实质性的进展，但是我们对“ANCA肾小球肾炎：从分子到人”还有很多需要了解的。

DESCRIPTION OVERALL (provided by applicant): Our Program Project focuses on the study of anti-neutrophil cytoplasmic autoantibody (ANCA) glomerulonephritis. The objective of this competitive renewal remains the elucidation of the causes and pathogenic mechanisms of ANCA necrotizing and crescentic glomerulonephritis. During the last four years of our current Program Project, we have made substantial progress in our understanding of this disease. This progress has opened a number of exciting avenues of exploration that we have divided into four projects and two cores. Project 1 is an immunopathogenesis study centered on our most recent observation that a complementary peptide to proteinase 3 may stimulate the autoimmune response. This most intriguing study has broad implications for all autoimmunity. In Project 2, we explore the role of ANCA-antigens (proteinase 3 and myeloperoxidase) and their interaction with autoantibodies, B cells and T cells; and their participation in the induction of. vascular injury. Project 3 focuses on the molecular genetics of ANCA glomerulonephritis and explores genes that are permissive for or that modify the phenotype and course of ANCA glomerulonephritis. During the current Program Project, we elucidated an animal model in which antimyeloperoxidase antibodies or lymphocytes were passively transferred into nave recipient mice and induced a human-like pauci-immune necrotizing and crescentic glomerulonephritis. Project 4 will take advantage of this novel animal model to elucidate pathogenic mechanisms. The Clinical Core is key to all of our studies and allows us to follow patients with ANCA glomerulonephritis for almost 20 years. From these patients, we have been able to obtain crucial clinical and pathological information and biological specimens for all of our studies. There is substantial synergy among all of these projects for three reasons: (1) because all of the projects focus on ANCA glomerulonephritis, (2) ideas gleaned from one project have direct bearing on studies performed in another project, and (3) the same hypotheses can be tested in different projects in human and animal systems both in vivo and in vitro. During our current Program Project interval, we have made a number of seminal observations pertaining not only specifically to ANCA glomerulonephritis but also to autoimmunity and inflammation in general. Substantial progress has been made, however, we have much yet to learn about "ANCA glomerulonephritis: from molecules to man".