Molecular Basis of Pathogenicity of IgA1-containing Immune Complexes

摘要 IgA肾病(IgAN)是世界上最常见的原发性肾小球肾炎。由于缺乏 针对疾病的治疗，许多患者进展为终末期肾病。IGAN由 典型的IgA1系沉积。基于我们公布的数据，我们开发了一种原创的 描述疾病发展的顺序步骤和候选分子的致病模型。 这一模型被该领域的其他研究人员认为是疾病特异性发展的蓝图 生物标志物和治疗。在过去的资助期间，我们证明了大多数IgAN患者， 无论年龄和种族，都有免疫缺陷导致产生致病的IgA1- 含有免疫复合体。我们进一步证明致病免疫复合体由IgA1组成。 一些O-糖链缺乏半乳糖(Gd-IgA1)，但仅有Gd-IgA1不足以诱发IgAN。 IgAN发病机制的第二个关键步骤是发展与Gd-IgA1结合的自身抗体和 形成致病免疫复合体。我们的新数据显示，从肾小球沉积物中提取的抗体 IGAN患者对Gd-IgA1具有特异性。重要的是，血清中Gd-IgA1(自身抗原)和Ig G的水平 针对Gd-IgA1的自身抗体每个都与疾病的严重程度和进展相关。我们的分析还包括 揭示了Gd-IgA1-Ig G循环免疫复合物中存在补体蛋白。这一发现是 与我们确定补体因子H-共同缺失的主要作用的GWAS一致- 影响C3活化的相关因子1和3(CFHR 1，3 del)。我们已经确定了主要的激活 Gd-Ig_1-Ig G复合体诱导原代人肾小球系膜细胞的通路及阻断 最初的信号步骤防止了细胞的异常激活。此外，我们已经开始验证这些 在我们开发的一种新的IgAN小鼠模型中的发现。在这份修订后的竞争续期申请中，我们 假设，在有自身免疫易感性的人中，升高的Gd-IgA1与 抗Gd-IgA1自身抗体的研制这些事件指导了致病基因的形成 免疫复合体和额外的蛋白质调节这些复合体的致病潜力，从而 影响疾病的表现和进展。我们将使用独特的、临床的和 遗传特征良好的免疫球蛋白肾病患者队列。我们将定义免疫球蛋白的生物学和临床影响 自身抗体，包括发病前产生自身抗体的时间表(目标1)。我们将评估 循环中Gd-Ig_1-Ig G免疫复合物的组成与肾小球沉积物中Gd-Ig_1-Ig G的组成 亚类，补体蛋白)(目标2)，并确定补体在生物活性中的作用 致病Gd-IgA1-Ig G复合体(目标3)。相关性：我们的研究将定义与以下因素相关的因素 IgAN的发展和进展，从而提供有关患者分层的信息 未来疾病特异性治疗的临床试验和开发。

Abstract IgA nephropathy (IgAN) is the most common form of primary glomerulonephritis in the world. Due to lack of disease-specific therapy, many patients progress to end-stage renal disease. IgAN is defined by the characteristic IgA1 mesangial deposits. Based on our published data, we have developed an original pathogenesis model that describes sequential steps and molecular candidates for the development of disease. This model is recognized by other researchers in the field as a blueprint for development of disease-specific biomarkers and treatments. In the past funding period, we demonstrated that the majority of IgAN patients, regardless of age and ethnicity, have immunologic defects resulting in generation of pathogenic IgA1- containing immune complexes. We have further shown that the pathogenic immune complexes consist of IgA1 with some O-glycans deficient in galactose (Gd-IgA1), although Gd-IgA1 alone is not sufficient to induce IgAN. A second critical step in the pathogenesis of IgAN is the development of autoantibodies that bind Gd-IgA1 and form pathogenic immune complexes. Our new data revealed that IgG extracted from glomerular deposits of IgAN patients is specific for Gd-IgA1. Importantly, serum levels of Gd-IgA1 (autoantigen) and IgG autoantibodies specific for Gd-IgA1 each correlate with disease severity and progression. Our analyses also revealed the presence of complement proteins in Gd-IgA1-IgG circulating immune complexes. This finding is consistent with our GWAS that identified a major role for a common deletion of the complement factor H- related factors 1 and 3 (CFHR 1,3 del) that impacts C3 activation. We have identified major activation pathways induced by Gd-IgA1-IgG complexes in primary human mesangial cells and shown that blockade of the initial signaling steps prevented aberrant cellular activation. Moreover, we have begun to validate these findings in a novel mouse model of IgAN we developed. In this revised competing renewal application, we hypothesize that, in individuals with an autoimmune predisposition, elevated Gd-IgA1 is associated with the development of IgG autoantibodies specific for Gd-IgA1. These events direct the formation of pathogenic immune complexes and additional proteins modulate the pathogenic potential of these complexes, thus affecting disease presentation and progression. We will follow-up our findings using unique, clinically and genetically well-characterized, cohorts of IgAN patients. We will define the biological and clinical impact of IgG autoantibodies, including the timeline for production before disease onset (Aim 1). We will assess the composition of Gd-IgA1-IgG immune complexes in the circulation vs. in the glomerular deposits (IgG subclasses, complement proteins) (Aim 2) and determine the role of complement in biological activity of the pathogenic Gd-IgA1-IgG complexes (Aim 3). Relevance: Our studies will define factors associated with development and progression of IgAN and thus provide information concerning stratification of patients for clinical trials and development of a future disease-specific therapy.