ANCA GLOMERULONEPHRITIS: FROM MOLECULES TO MAN

我们的项目包括5个项目和两个核心，重点是抗中性粒细胞胞浆抗体（ANCA）、坏死性和新月体性肾小球肾炎（GN）和小血管炎（SVV）。研究范围和研究者的多样性允许对与抗髓过氧化物酶（MPO）和蛋白酶3（PR 3）自身免疫反应相关的基础分子和临床免疫学和流行病学研究进行综合评价。项目1考虑了使用基本分子免疫学技术和转基因小鼠，根据抗体重链和轻链的相对贡献以及其中的体细胞突变，推导出鼠抗MPO自身抗体。与此同时，项目2研究了人类ANCA自身免疫反应，包括轻链和重链的贡献以及其中的体细胞突变，以及疾病发作或复发期间负责生成ANCA的特定表位的精细特异性。关于轻链和重链以及其中的体细胞突变的贡献以及所考虑的特异性表位的精细特异性的自身免疫应答的新范例;即，ANCA免疫应答不仅针对MPO或PR 3，而且针对与MPO或PR 3翻译互补的肽。项目3验证了ANCA直接参与ANCA免疫应答的发病机制的假设，确定了ANCA激活中性粒细胞和单核细胞的机制，描绘了ANCA抗原MPO和PR 3直接诱导血管损伤的机制。项目4使用循环抗髓过氧化物酶抗体协同产生GN的动物模型研究ANCA GN的体外发展。项目5在大量ANCA GN患者中使用最先进的流行病学技术，以确定易导致ANCA免疫应答发展和恶化的环境因素。特别是二氧化硅暴露在ANCA GN诱导中的作用将在动物研究和人体研究中进行测试。这些研究使用最先进的技术紧密交织在一起。总之，这些尖锐的重点和综合项目将阐明整个项目的中心问题。什么导致ANCA GN？如果我们知道这种最具侵袭性的肾小球损伤的原因，靶向治疗将指日可待。该计划涉及来自医学，病理学，微生物学和免疫学系的研究人员在医学院，流行病学系在公共卫生学院，药物化学系在药学院，和环境健康科学的国家研究所。

Our program project consists of 5 projects and two cores focusing on anti- neutrophil cytoplasmic autoantibody (ANCA) necrotizing and crescentic glomerulonephritis (GN) and small vessel vasculitis (SVV). The scope of the investigation and the diversity of the investigators allow for an integrated evaluation of basic molecular and clinical immunological and epidemiological studies pertaining to both anti-myeloperoxidase (MPO) and proteinase 3 (PR3) autoimmune response. Project 1 considers the derivation of murine anti-MPO autoantibodies with respect to relative contributions of antibody heavy and light chains and somatic mutations within them using basic molecular immunologic techniques and transgenic mice. In parallel, Project 2 investigates the human ANCA autoimmune response with respect to the contribution of light and heavy chains and somatic mutations within them, and the fine specificity of specific epitopes responsible for the generation of ANCA during disease onset or relapse. A novel paradigm of autoimmune response with respect to the contribution of light and heavy chains and somatic mutations within them, and the fine specificity of specific epitopes considered; that is, that the ANCA immune response is directed not only to MPO or PR3, but also to peptides complimentary in translation to MPO or PR3. Project 3 tests the hypothesis that ANCA directly participate in the pathogenesis of the ANCA immune response, determines the mechanism by which ANCA activate neutrophils and monocytes, delineates the mechanism by which the ANCA antigens MPO and PR3 directly induce vascular damage. Project 4 studies in vitro development of ANCA GN using animal models in which circulating anti-myeloperoxidase antibodies conspire to produce to GN. Project 5 uses state of t he art epidemiological techniques in a large population of ANCA GN patients to ascertain those environmental factors that predispose to the development and exacerbation of the ANCA immune response. In particular the role of silica exposure in the induction of ANCA GN will be tested in animal studies as well as in man. These investigations are tightly interwoven using state of the art techniques. Together, these sharpy focused and integrated projects will shed light on the central question of the overall project. What causes ANCA GN? If we knew the causes of this most aggressive form of glomerular injury targeted therapy would be in the offing. The program involves investigators from the Department of Medicine, Pathology, Microbiology and Immunology in the School of Medicine, the Department of Epidemiology in the School of Public Health, the Department of Medicinal Chemistry in the School of Pharmacy, and the National Institute of Environmental Health Sciences.