Molecular Basis of Pathogenicity of 1gA1 - containing Immune Complexes

含 1gA1 的免疫复合物致病性的分子基础

• 批准号: 7245808
• 负责人: JAN NOVAK
• 金额: $ 25.38万
• 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 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7245808
• 关键词: Acetylgalactosamine; Affect; Antibodies; Antigen-Antibody Complex; Antigens; Arts; B-Lymphocytes; Binding; Biological Assay; Biological Markers; Biopsy; Biopsy Specimen; Cell Line; Cell Proliferation; Characteristics; Clinical; Clone Cells; Collaborations; Complex; Data; Defect; Deposition; Development; Diagnosis; Diagnostic; Disease; End stage renal failure; Ensure; Enzyme-Linked Immunosorbent Assay; Epitopes; Exhibits; Exposure to; Feasibility Studies; Foundations; Future; Galactose; Generations; Glomerulonephritis; Glycopeptides; Goals; Human; Human Herpesvirus 4; IgA-specific serine endopeptidase; Immune; Immunoglobulin A; Immunoglobulin G; Immunoglobulin M; In Vitro; Individual; Inflammatory; Interleukin-6; Kidney; Kidney Diseases; Lead; Link; Location; Mass Spectrum Analysis; Methods; Molecular; Monitor; Nephrectomy; Pathogenesis; Pathogenicity; Pathologic; Patients; Pattern; Phenotype; Play; Polysaccharides; Principal Investigator; Production; Property; Proteins; Purpose; Quality of Care; Renal function; Research Personnel; Resolution; Resources; Role; Sampling; Serum; Site; Specificity; Specimen; Structure; TFRC gene; Techniques; Testing; Transforming Growth Factors; base; clinically relevant; cohort; cytokine; glycosylation; high throughput screening; immortalized cell; improved; inhibitor/antagonist; innovation; insight; mesangial cell; noninvasive diagnosis; programs; receptor; response; size

DESCRIPTION (provided by applicant): IgA nephropathy (IgAN) is characterized by mesangial deposits of lgA1 with co-deposits of C3, and often also IgG or IgM or both. Circulating immune complexes with galactose-deficiency in the O-linked glycans in the hinge region of lgA1 play a major role in the pathogenesis of IgAN. It has been established that the content of galactose in the circulating lgA1 is lower than in healthy controls, that this results in the exposure of neoepitopes that are recognized by naturally occurring IgG or lgA1 antibodies resulting in the formation of immune complexes, and that the lgA1 eluted from nephrectomy specimens of patients with IgAN is galactose-deficient. It is not yet known whether the galactose deficiency affects all of these glycans or only a subset or single glycan. Based on our preliminary data, we have formulated the central hypothesis that the deficiency of galactose in the hinge region of lgA1 is pivotal for the pathogenesis of IgAN and that this O- glycosylation abnormality is a disease-specific epitope. We propose to test this hypothesis by defining the fine structure of the disease-specific epitope(s) and its location on the aberrantly-glycosylated lgA1; defining the characteristics of the lgA1-binding antibodies that promote their ability to form lgA1-complexes that can activate mesangial cells; and analyzing the binding of these immune complexes to mesangial cells. Based on these results, we will develop and critically evaluate the emerging serum biomarkers of IgAN and validate the findings in a separate cohort of well-characterized IgAN patients. The feasibility of these studies is enhanced greatly by our development of high through-put methods of analysis, EBV-immortalized cell lines that produce aberrantly glycosylated lgA1 or anti-glycan antibodies, state-of-the-art techniques for analysis of glycopeptides, and our extensive basic and clinical collaborations that permit testing of the hypothesis by experimental manipulation as well as clinical correlations. Relevance: IgAN is the most common primary glomerulonephritis and leads to the loss of renal function in 20-40% patients. Unfortunately, the diagnosis of IgAN still relies on renal biopsy due to the lack of noninvasive tests. Our studies will provide an improved understanding of the pathogenesis of IgAN and provide a basis for the development of a clinically applicable, high-throughput assay for noninvasive diagnosis of IgAN, and monitoring of the disease course or response to therapy. This would represent a major advance in the quality of care for IgAN patients.

描述（由申请人提供）：IgA肾病（IgAN）的特征是lgA1的肾小球系膜沉积与C3的共同沉积，通常还包括IgG或IgM，或两者兼有。循环免疫复合物在lgA1铰链区o链聚糖中缺乏半乳糖，在IgAN的发病机制中起主要作用。已经确定，循环中的lgA1中半乳糖的含量低于健康对照，这导致暴露的新表位被自然产生的IgG或lgA1抗体识别，从而形成免疫复合物，并且从IgAN患者的肾切除术标本中洗脱的lgA1是半乳糖缺乏的。目前尚不清楚半乳糖缺乏症是否会影响所有这些聚糖，还是只影响一个子集或单一聚糖。根据我们的初步数据，我们提出了一个中心假设，即lgA1铰链区域半乳糖的缺乏是IgAN发病的关键，这种O-糖基化异常是一种疾病特异性表位。我们建议通过定义疾病特异性表位的精细结构及其在异常糖基化的lgA1上的位置来验证这一假设；确定lga1结合抗体的特性，促进它们形成能够激活系膜细胞的lga1复合物的能力；并分析这些免疫复合物与系膜细胞的结合。基于这些结果，我们将开发和批判性地评估新出现的IgAN血清生物标志物，并在具有良好特征的IgAN患者的单独队列中验证这些发现。这些研究的可行性大大增强了我们开发的高通量分析方法，ebv永生化细胞系产生异常糖基化的lgA1或抗聚糖抗体，最先进的糖肽分析技术，以及我们广泛的基础和临床合作，允许通过实验操作和临床相关性来测试假设。相关性：IgAN是最常见的原发性肾小球肾炎，可导致20-40%患者肾功能丧失。不幸的是，由于缺乏无创检查，IgAN的诊断仍然依赖于肾活检。我们的研究将提供对IgAN发病机制的更好理解，并为开发临床适用的、用于IgAN无创诊断的高通量检测方法，以及监测病程或对治疗的反应提供基础。这将代表IgAN患者护理质量的重大进步。