IDIOTYPES AND IMMUNE COMPLEXES IN IGA NEPHROPATHIES

IGA 肾病的独特型和免疫复合物

• 批准号: 3240215
• 负责人: SUSAN JACKSON
• 金额: $ 11.42万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-01-15 至 1993-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3240215
• 关键词: antiidiotype antibody; autoantibody; electrofocusing; enzyme linked immunosorbent assay; glomerulonephritis; human subject; immune complex diseases; immunoglobulin A; immunoglobulin G; immunoglobulin idiotypes; monoclonal antibody; rheumatoid factor; spectrometry

Primary IgA nephropathy is the most common of the primary glomerulonephritides worldwide, with a significant number of patients progressing to end-stage renal disease. Other disorders, such as Henoch-Schoenlein purpura and dermatitis herpetiformis, share the characteristic immunopathology of this disease, i.e., mesangial deposition of IgA as the most prevalent immunoglobulin isotype; together all of these disorders are called the IgA nephropathies (IgA NP). The pathogenesis of IgA NP is unknown. However, because most patients with IgA NP have elevated levels of circulating immune complexes (CIC) containing IgA (often co- complexed with IgG), and because the C3 component of complement is usually found codeposited with IgA in the kidney, many investigators have speculated that the IgA NP are immune complex- mediated diseases. Characterization of the CIC would be expected to provide insight into pathogenetic mechanisms of IgA NP. Thus it is the objective of the proposed investigation to describe fully the CIC of patients with this disease, with specific respect to the immunoglobulin molecules contained within the complex matrices. Therefore, we will perform spectrotypic analyses of IgA and IgG proteins (in serum, saliva, CIC, lymphoid cells, and mesangial deposits) of IgA NP as well as determine the presence of disease- specific idiotypic markers of these immunoglobulins. We will also search for crossreactive idiotypes on IgA rheumatoid factors as well as study the possibility that autologous IgG anti-idiotypic antibodies specific for IgA rheumatoid factors contribute to the formation of the CIC. Further, we will ascertain the potential contribution to the antibodies specific for Fab of autologous IgA. All of these studies will be performed on longitudinal samples obtained from a large population of patients, many of whom have familial disease. Other studies will characterize both immunoglobulin heavy chain and light chain restrictions previously reported in IgA NP: we will determine IgG subclasses in serum and CIC and in IgG codeposited in mesangia with IgA; further, putative lambda chain restriction will be studied with respect to definition of variable region subgroups. Finally, we will study the potential functional significance of the CIC by examining the effects on B and T cells in vitro. The proposed experiments are designed to define the clonal origins of CIC-bound immunoglobulins in IgA NP and ultimately elucidate the pathogenesis of these disease.

原发性伊加肾病是最常见的原发性肾病。 肾小球肾炎在世界范围内，有相当数量的 进展为终末期肾病的患者。 其他疾病， 如过敏性紫癜和疱疹样皮炎， 共享这种疾病的特征性免疫病理学，即， 伊加系膜沉积是最常见的免疫球蛋白 同种型;所有这些疾病一起被称为伊加 肾病（伊加NP）。 伊加NP的发病机制尚不清楚。 然而，由于大多数伊加NP患者的IgA水平升高， 含有伊加的循环免疫复合物（CIC）（通常共 与IgG复合），并且因为补体的C3组分是 通常与伊加共同沉积在肾脏中，许多 研究人员推测伊加NP是免疫复合物- 介导的疾病。 预计将对CIC进行表征 为深入了解伊加NP的发病机制提供了依据。 因此 拟议调查的目的是充分描述 这种疾病患者的CIC，特别是关于 免疫球蛋白分子包含在复杂的矩阵。 因此，我们将进行伊加和IgG的谱型分析， 蛋白质（血清、唾液、CIC、淋巴样细胞和系膜细胞） 伊加NP的沉积物）以及确定疾病的存在- 这些免疫球蛋白的特异性独特型标记。 我们还将 寻找伊加类风湿因子的交叉反应独特型， 研究自体IgG抗独特型抗体 伊加类风湿因子特异性抗体有助于 成立CIC。 此外，我们将确定潜在的 对自体伊加的Fab特异性抗体的贡献。 所有这些研究都将在纵向样本上进行 从大量患者中获得，其中许多人 家族性疾病。 其他研究将描述两者的特征 免疫球蛋白重链和轻链限制 报告伊加NP：我们将确定血清中的IgG亚类， CIC和IgG与伊加共同沉积在系膜中;进一步，假定 λ链限制将根据定义进行研究 可变区亚群的数目。 最后，我们将研究 通过检查对B的影响来确定CIC的功能意义 和体外T细胞。 拟议的实验旨在 确定伊加NP中CIC结合免疫球蛋白的克隆起源 并最终阐明这些疾病的发病机制。