Biology of Remission and Relapse in ANCA Disease

本项目探讨antl-中性粒细胞胞质型白血病患者缓解和复发的生物学机制。 自身抗体（ANCA）肾小球肾炎和小血管炎（ANCA病）。这一切的起源 探索源于临床观察，一些ANCA疾病患者有30年的 缓解，而其他人具有重大疾病的反复复发。理想情况下，注定要复发的患者 应该根据复发的机制进行靶向治疗， 应该不用免疫抑制治疗虽然复发的临床预测因素已经确定， 我们对复发和缓解的机制基础只有初步的了解。这个项目 利用我们的纵向ANCA疾病队列来检查几种ANCA疾病的复发和缓解， 视角目的1将考虑复发是否是异常的表观遗传调节的结果， 编码自身抗原髓过氧化物酶（MPO）和蛋白酶3（PR 3）的基因。建立在我们的基本 科学发现，在PR 3和MPO基因组位点不存在表观遗传控制的基因沉默， 患有活动性疾病的患者，自身抗原基因的表观遗传沉默是否在复发期间丢失， 将在缓解期间重新建立。目的2检查复发是否源于异常B 细胞功能在疾病发作和复发时是否存在相同的自身反应性B细胞克隆的克隆性扩增， 或者复发是新的B细胞群对MPO和PR 3的不同表位反应的结果？ 复发是否是由于循环或组织中的B细胞失调， 将研究自身抗体。在目标3中，探讨了T细胞调节，重点是T调节细胞 在复发性疾病中似乎功能上“无效”。复发是否由T调节失衡引起 细胞和促炎性Th 17细胞在缓解期间恢复？这些分析将在 在ANCA疾病患者中同时和重复进行，使我们能够获得一种机制， 了解缓解和复发的生物学。这些观察结果对 ANCA疾病患者的护理以及所有类型的复发和缓解的自身免疫性疾病。

This project explores the biology of remission and relapse in patients with antl-neutrophil cytoplasmic autoantibodies (ANCA) glomerulonephritis and small vessel vasculitis (ANCA disease). The genesis of this exploration stems from the clinical observation that some patients with ANCA disease have 30 years of remission while others have repetitive relapses of significant disease. Ideally, patients destined to relapse should have targeted therapy based on the mechanism responsible for their relapse, and those in remission should be spared immunosuppressive therapy. Although clinical predictors of relapse have been Identified, we have only a rudimentary understanding of the mechanistic basis for relapse and remission. This project takes advantage of our longitudinal ANCA disease cohort to examine relapse and remission from several perspectives. Aim 1 will consider whether relapse is a consequence of aberrant epigenetic regulation of genes encoding the autoantigens myeloperoxidase (MPO) and proteinase 3 (PR3). Building on our basic science findings that epigenetically controlled gene silencing is absent at PR3 and MPO genomic loci In patients with active disease, whether epigenetic silencing of the autoantigen genes is lost during relapse and re-established during remission will be determined. Aim 2 examines whether relapse stems from aberrant B cell function. Is there clonal expansion of the same autoreactive B cell cloneiIn disease onset and relapse, or is relapse a consequence of a new B cell population reactive to different epitopes of MPO and PR3? Whether relapse is due to dysregulated B cells, in the circulation or tissue, that permit production of autoantibodies will be Investigated. In Aim 3, T cell regulation is explored with a focus on T regulatory cells that appear functionally "ineffective" in relapsing disease. Is relapse caused by an Imbalance in T regulatory cells and proinflamatory Th17 cells that is restored during remission? These analyses will be performed simultaneously and repetitively over time in ANCA disease patients allowing us to gain a mechanistic understanding of the biology of remission and relapse. These observations have broad implications for the care of patients with ANCA disease and for relapsing and remitting autoimmune disease of all types.