ANCA GLOMERULONEPHRITIS: FROM MOLECULES TO MAN

我们的计划项目包括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)、坏死性和新月体肾炎(GN)和小血管血管炎(SVV)。调查的范围和调查人员的多样性允许对与抗髓过氧化物酶(MPO)和蛋白酶3(PR3)自身免疫反应有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使用基本分子免疫学技术和转基因小鼠，考虑了相对于抗体重链和轻链的相对贡献以及其中的体细胞突变来衍生小鼠抗MPO自身抗体。同时，项目2调查了人类ANCA自身免疫反应，涉及其中的轻链和重链和体细胞突变的贡献，以及在疾病发病或复发期间导致ANCA产生的特定表位的良好特异性。一种新的关于自身免疫反应的范例，涉及轻链和重链的贡献以及其中的体细胞突变，以及所考虑的特定表位的良好特异性；即ANCA免疫反应不仅针对MPO或PR3，还针对翻译为MPO或PR3的互补多肽。项目3验证了ANCA直接参与ANCA免疫反应发病机制的假设，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PR3直接导致血管损伤的机制。项目4使用循环中的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来确定那些容易导致ANCA免疫反应发展和恶化的环境因素。特别是，接触二氧化硅在诱发ANCA GN中的作用将在动物研究中以及在人类中进行测试。这些研究使用最先进的技术紧密地交织在一起。综合起来，这些突出重点和综合的项目将阐明整个项目的核心问题。ANCA GN的病因是什么？如果我们知道这种最具侵袭性的肾小球损伤的原因，靶向治疗就会迫在眉睫。该项目的调查人员来自医学院的医学、病理学、微生物学和免疫学系、公共卫生学院的流行病学系、药学院的药物化学系和国家环境健康科学研究所。

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.