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.

初级IgA肾病是主要的最常见的 全球肾小球素磷脂，大量 患者发展为末期肾脏疾病。 其他疾病， 例如Henoch-Schoenlein紫pura和疱疹性皮炎， 共享该疾病的特征免疫病理学，即 IgA的肾小球沉积是最普遍的免疫球蛋白 同种型；所有这些疾病一起称为IgA 肾病（IgA NP）。 IgA NP的发病机理尚不清楚。 但是，由于大多数IgA NP患者的水平升高 包含IgA的循环免疫复合物（CIC）（通常是共同 与IgG复合），并且由于补体的C3成分是 通常在肾脏中发现与IgA共同定型，许多 研究人员推测，IgA NP是免疫复合物 - 介导的疾病。 可以期待CIC的特征 提供对IgA NP致病机制的见解。 因此 这是拟议调查的目的 患有这种疾病的患者的CIC，具体 复合矩阵中包含的免疫球蛋白分子。 因此，我们将对IgA和IgG进行频谱分析 蛋白质（在血清，唾液，CIC，淋巴样细胞和肾小球上 Iga np的沉积物），并确定存在疾病的存在 这些免疫球蛋白的特定白痴标记。 我们也会 在IgA类风湿因素上搜索交叉反应性的惯用型 以及研究自体IgG抗IDiotypic的可能性 针对IgA类风湿因子特异的抗体有助于 CIC的形成。 此外，我们将确定潜力 对自体IgA Fab的抗体的贡献。 所有这些研究都将在纵向样品上进行 从大量患者那里获得，其中许多患者 家族疾病。 其他研究将表征 先前的免疫球蛋白重链和轻链限制 在IgA NP中报告：我们将确定血清中的IgG亚类 CIC和IgG与IgA在Mesangia编码的IgG；此外，推定 Lambda链限制将研究定义 可变区域子组的。 最后，我们将研究潜力 通过检查对B的影响，CIC的功能意义 和T细胞体外。 提出的实验设计为 定义IgA NP中CIC结合免疫球蛋白的克隆起源 并最终阐明了这些疾病的发病机理。