Molecular Basis of Pathogenicity of IgA1-containing Immune Complexes

含 IgA1 的免疫复合物致病性的分子基础

• 批准号: 10381499
• 负责人: JAN NOVAK
• 金额: $ 40.15万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10381499
• 关键词: Affect; Age; Antigen-Antibody Complex; Autoantibodies; Autoantigens; Autoimmune; Binding; Biological; Blood; Blood Circulation; Characteristics; Clinical; Clinical Research; Clinical Trials; Complement; Complement Factor H; Complex; Data; Defect; Department of Defense; Deposition; Development; Diagnosis; Disease; Disease Progression; End stage renal failure; Ethnic Origin; Event; Extracellular Matrix Proteins; Funding; Future; Galactose; Generations; Glomerulonephritis; Human; IGA Glomerulonephritis; IgA1; IgG autoantibodies; Immunoglobulin G; Immunologics; In Vitro; Individual; Injury to Kidney; Kidney; Lead; Measures; Modeling; Molecular; Mus; Onset of illness; Pathogenesis; Pathogenicity; Pathologic; Pathway interactions; Patients; Polysaccharides; Predisposition; Production; Proteins; Publishing; Reagent; Recombinants; Research Personnel; Role; Sampling; Serum; Severity of illness; Signal Pathway; Signal Transduction; Specimen; Testing; Therapeutic; Time; TimeLine; Vitronectin; base; biobank; chromosome 3 loss; clinical development; cohort; cytokine; detection test; disease diagnosis; effective therapy; experimental study; follow-up; genome wide association study; mesangial cell; mouse model; novel; patient stratification; prevent; renal damage; risk variant; specific biomarkers; sulfated glycoprotein 2

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.

摘要 伊加肾病（IgAN）是世界上最常见的原发性肾小球肾炎。由于缺乏 在疾病特异性治疗的情况下，许多患者进展为终末期肾病。IgAN由以下定义： 特征性IgA 1系膜沉积。根据我们公布的数据，我们开发了一个原始的 描述疾病发展的顺序步骤和分子候选物的发病机理模型。 该模型被该领域的其他研究人员认为是开发疾病特异性药物的蓝图。 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， 不分年龄和种族，有免疫缺陷，导致产生致病性IgA 1- 含有免疫复合物。我们进一步表明，致病性免疫复合物由IgA 1 某些O-聚糖缺乏半乳糖（Gd-IgA 1），尽管单独的Gd-IgA 1不足以诱导IgAN。 IgAN发病机制中的第二个关键步骤是产生结合Gd-IgA 1的自身抗体， 形成致病性免疫复合物。我们的新数据显示，从肾小球沉积物中提取的IgG， IgAN患者对Gd-IgA 1具有特异性。重要的是，Gd-IgA 1（自身抗原）和IgG的血清水平 Gd-IgA 1特异性自身抗体各自与疾病严重程度和进展相关。我们的分析还 揭示了在Gd-IgA 1-IgG循环免疫复合物中存在补体蛋白。这一发现 与我们的GWAS一致，GWAS确定了补体因子H-1的常见缺失的主要作用， 相关因子1和3（CFHR 1，3 del）影响C3激活。我们已经确定了主要的激活 Gd-IgA 1-IgG复合物在原代人肾小球系膜细胞中诱导的信号通路，并显示阻断Gd-IgA 1-IgG复合物的作用， 最初的信号步骤防止了异常的细胞活化。此外，我们已经开始验证这些 在我们开发的一种新型IgAN小鼠模型中发现。在此修订后的竞争性续期申请中，我们 假设，在具有自身免疫倾向的个体中，Gd-IgA 1升高与 特异于Gd-IgA 1的IgG自身抗体的开发。这些事件直接导致致病性 免疫复合物和其他蛋白质调节这些复合物的致病潜力， 影响疾病的表现和进展。我们将使用独特的，临床和 遗传学特征良好的IgAN患者队列。我们将定义IgG的生物学和临床影响 自身抗体，包括疾病发作前产生的时间轴（目标1）。我们将评估 Gd-IgA 1-IgG免疫复合物在循环中与在肾小球沉积物（IgG）中的组成 亚类，补体蛋白）（目的2），并确定补体在生物活性的作用， 致病性Gd-IgA 1-IgG复合物（目的3）。相关性：我们的研究将定义与 IgAN的发展和进展，从而提供关于患者分层的信息， 临床试验和未来疾病特异性治疗的开发。