Redefining membranous nephropathy by autoantibody-specific subclassification

特发性膜性肾病(IMN)是一种肾脏自身免疫性疾病，是成人肾病综合征的常见病因。除了伴随这种疾病的体重增加、肿胀和血栓的风险外，相当一部分患者还将发展为进行性肾功能丧失，需要透析或移植。IMN的治疗通常需要有毒的免疫抑制剂，这本身就会导致健康问题和严重感染的风险。由于不完全了解哪些患者将自行缓解这种疾病，哪些患者将进展为终末期肾病，谁、何时和多长时间接受治疗的问题一直难以回答。我们实验室最近在大多数IMN患者中发现了针对肾脏蛋白--磷脂酶A2受体(PLA2R)的循环抗体，这不仅允许根据这些自身抗体重新定义IMN，而且还提供了一种潜在的机制，用于监测疾病的免疫活动并指导这些通常难以做出的治疗决定。这份提案概述了我们的计划，使用来自150名IMN患者的样本和数据集，以更好地描述新发现的IMN亚组。目的1根据血流中抗PLA2R抗体的存在或为本研究收集的活检组织免疫沉积中PLA2R抗原的存在，将150名IMN患者分为两个亚组。这将把队列分为抗PLA2R相关疾病或抗PLA2R阴性疾病。我们将使用大量的海王星数据集的基线人口和临床数据，以及在这些患者的活检中看到的准确特征，以找到区分这两种IMN亚型的特征。这一目标的第二部分将检查一段时间内的抗PLA2R水平，并使用这些信息来跟踪免疫性疾病的活动，从而定义“免疫缓解”。我们将使用来自这一目标的数据来验证我们的假设，即由水平反映的免疫活性 抗PLA2R的检测发生在临床反应之前，通常可能是疾病活动性的更好衡量标准。AIMS 2和3将利用来自海王星IMN患者队列的强大基因转录数据集。目的2旨在明确活检组织中抗PLA2R相关的转录网络，以更好地了解IMN的分子发病机制。AIM 3旨在利用从循环血细胞和基线肾活检组织收集的基因表达数据集，识别能够在功能上定义和预测免疫缓解的基因表达谱。总而言之，该项目将产生以下数据：(1)定义和全面描述抗PLA2R相关的IMN，(2)建立免疫缓解的定义及其与临床缓解的关系，以及(3)定义描述性和预测性基因通路，这将极大地影响我们未来对膜性肾病的理解。

DESCRIPTION (provided by applicant): Idiopathic membranous nephropathy (IMN) is an autoimmune disease of the kidney and a common cause of the nephrotic syndrome in adults. In addition to the weight gain, swelling, and risk of blood clots that accompany this disease, a substantial fraction of patients will develop progressive loss of kidney function and require dialysis or transplantation. Treatment for IMN often requires toxic immunosuppressive agents, which themselves cause health problems and risk of serious infection. The questions of who, when, and how long to treat have been difficult to answer due to an incomplete understanding of which patients will undergo remission from this disease on their own and who will progress to end-stage kidney disease. The recent identification by our laboratory of circulating antibodies that target a kidney protein, the phospholipase A2 receptor (PLA2R), in the majority of patients with IMN has not only allowed a redefinition of IMN based on these autoantibodies, but has also provided a potential mechanism by which to monitor the immunologic activity of the disease and guide these often-difficult treatment decisions. This proposal outlines our plans to use samples and data sets from the 150 patients with IMN to be enrolled in NEPTUNE (Nephrotic Syndrome Study Network) to better characterize the newly-recognized subgroups of IMN. Aim 1 will classify each of the 150 IMN patients into two subgroups based on the presence of anti-PLA2R antibodies in the bloodstream or the presence of the PLA2R antigen within immune deposits of biopsy tissue already collected for this study. This will stratify the cohort into anti-PLA2R-associated or anti-PLA2R-negative disease. We will use the extensive NEPTUNE data sets of baseline demographic and clinical data, as well as the precise features seen in the biopsies of these patients, to find features that distinguish these two subtypes of IMN. A second portion of this aim will examine anti-PLA2R levels over time and use this information to follow immunological disease activity and thereby define 'immunological remission.' We will use the data from this aim to validate our hypothesis that immunological activity as reflected by the level of anti-PLA2R occurs prior to the clinical response, and may be a better measure of disease activity in general. Aims 2 and 3 will harness the powerful gene transcription data sets available from the NEPTUNE cohort of IMN patients. Aim 2 seeks to define anti-PLA2R-associated transcriptional networks in biopsy tissue in order to better understand molecular mechanisms of disease in IMN. Aim 3 is designed to identify gene expression profiles that can functionally define and predict immunological remission, using gene expression data sets collected from circulating blood cells as well as the baseline kidney biopsy tissue. In aggregate, this project wil generate data that (1) defines and fully characterizes anti-PLA2R-associated IMN, (2) establishes the definition of immunological remission and its relationship to clinical remission, and (3) defines descriptive and predictive gene pathways that will greatly impact our future understanding of membranous nephropathy.