ANCA GLOMERULONEPHRITIS: FROM MOLECULES TO MAN

本项目包括5个项目和两个核心，重点是抗中性粒细胞胞浆自身抗体（ANCA）坏死性月牙性肾小球肾炎（GN）和小血管炎（SVV）。调查的范围和研究人员的多样性允许对与抗髓过氧化物酶（MPO）和蛋白酶3 （PR3）自身免疫反应相关的基本分子和临床免疫学和流行病学研究进行综合评估。项目1考虑小鼠抗mpo自身抗体的衍生，涉及抗体重链和轻链的相对贡献以及其中的体细胞突变，使用基本的分子免疫学技术和转基因小鼠。与此同时，项目2研究了人类ANCA自身免疫反应中轻链和重链以及其中的体细胞突变的贡献，以及在疾病发作或复发期间负责ANCA产生的特定表位的精细特异性。一种新的自身免疫反应范式，涉及轻链和重链以及其中的体细胞突变的贡献，并考虑了特定表位的精细特异性；也就是说，ANCA免疫反应不仅针对MPO或PR3，还针对MPO或PR3翻译的互补肽。项目3验证ANCA直接参与ANCA免疫应答发病机制的假说，确定ANCA激活中性粒细胞和单核细胞的机制，描绘ANCA抗原MPO和PR3直接诱导血管损伤的机制。项目4利用循环抗髓过氧化物酶抗体共同产生GN的动物模型，研究ANCA GN的体外培养。项目5使用最先进的流行病学技术在大量的ANCA GN患者中确定易导致ANCA免疫反应发展和恶化的环境因素。特别是二氧化硅暴露在诱导ANCA GN中的作用将在动物研究和人体研究中进行测试。这些调查使用最先进的技术紧密地交织在一起。总之，这些重点突出的综合项目将阐明整个项目的核心问题。是什么导致了ANCA GN？如果我们知道这种最具侵略性的肾小球损伤的原因，靶向治疗就会出现。该项目包括来自医学院医学、病理学、微生物学和免疫学系、公共卫生学院流行病学系、药学院药物化学系和国家环境健康科学研究所的研究人员。

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.