ANCA Glomerulonephritis: From Molecules to Man

抗中性粒细胞胞浆抗体（ANCA）引起的肾小球肾炎和血管炎是最常见的快速进展性肾小球疾病。这种竞争性更新的目的是通过阐明潜在的免疫学和致病机制来改善ANCA疾病患者的生活，并将这些知识转化为改善的患者护理。在当前的计划项目中，我们在四个项目和两个核心中将追求的许多令人兴奋的勘探途径方面取得了实质性进展。项目1研究中性粒细胞基因的表观遗传调控， 改变ANCA疾病的表型。项目2从自身抗原基因的表观遗传调控、B细胞自身反应性和T细胞失调的角度探讨了独特的ANCA疾病患者队列中复发和缓解的生物学。项目3使用ANCA疾病的动物模型来研究旁路补体途径和Fc γ受体在发病机制中的参与。由不同抗原引起的疾病，以及疾病严重程度变化的遗传基础。项目4将我们的基础研究转化为临床研究，以改善ANCA疾病的结局。我们将利用我们的 通过用视黄酸治疗患者以改变髓样基因表达和用抗1-C5抗体治疗患者以阻断补体激活，发现了表观遗传调节和补体激活的致病作用。 作为在研究自身抗原互补性的同时发现抗纤溶酶原抗体的延伸，我们将确定ANCA疾病患者的静脉血栓形成是否归因于这些抗体。临床核心是我们研究的关键，使我们能够随访ANCA疾病患者近四分之一世纪。从这个有价值的患者队列中，我们获得了重要的临床和病理信息以及生物标本。行政核心为我们的工作提供了基础。所有项目之间存在实质性的协同作用，每个项目从不同的角度关注ANCA疾病，并且可以在人类和动物系统中测试假设。重要的是，我们正在学习的教训不仅涉及ANCA疾病，而且涉及自身免疫和炎症。

Glomerulonephritis and vasculitis caused by anti-neutrophil cytoplasmic autoantibodies (ANCA) Is the most common form of rapidly progressive glomerular disease. The objective of this competitive renewal is to improve the lives of patients with ANCA disease by elucidating the underlying immunologic and pathogenic mechanisms, and translating this knowledge into improved patient care. During the current Program Project, we have made substantial progress in a number of exciting avenues of exploration that will be pursued in four Projects and two Cores. Project 1 investigates epigenetic regulation of neutrophil genes, and genes that modify the phenotype of ANCA disease. Project 2 explores the biology of relapse and remission in a unique cohort of ANCA disease patients from the perspective of epigenetic regulation of autoantigen genes, B cell autoreactivity and T cell dysregualtion. Project 3 uses animal models of ANCA disease to study Involvement of the alternative complement pathway and Fcy receptors In pathogenesis. Induction of disease by different antigens, and the genetic basis for variations In disease severity. Project 4 provides translation of our more basic research Into clinical investigations to Improve ANCA disease outcomes. We will take advantage of our discoveries of pathogenic roles for epigenetic regulation and complement activation by treating patients with retinoic acid to alter myeloid gene expression and with antl-C5 antibodies to block complement activation. As an extension of the discovery of anti-plamsinogen antibodies while studying autoantigen complementarity, we will determine If venous thrombosis in ANCA disease patients is attributable to these antibodies. The Clinical Core is key to our studies and has allowed us to follow patients with ANCA disease for almost a quarter century. From this valuable patient cohort, we have obtained crucial clinical and pathological Information, and biological specimens. An Administrative Core provides underpinnings of our work. There is substantial synergy among all projects, each projects focus on ANCA disease from different perspectives, and the hypotheses can be tested In human and animal systems. Importantly, the lessons we are learning pertain not only to ANCA disease but also to autoimmunity and Inflammation in general.