IDIOTYPES AND IMMUNE COMPLEXES IN IGA NEPHROPATHIES

原发性IgA肾病是最常见的原发性 世界各地的肾小球肾炎，有相当数量的 患者进展为终末期肾病。其他障碍， 如过敏性紫癜和疱疹样皮炎， 分享这种疾病特有的免疫病理学，即， IgA作为最常见的免疫球蛋白的系膜沉积 所有这些疾病统称为免疫球蛋白A 肾病(IgA、NP)。免疫球蛋白NP的发病机制尚不清楚。 然而，由于大多数IgA NP患者的血浆中 含有IgA的循环免疫复合物(CIC)(通常为 与免疫球蛋白络合)，而且因为补体的C3成分是 通常在肾脏中发现与IgA共同沉积，许多 调查人员推测，IgA NP是免疫复合体- 媒介疾病。中投公司的特征将是意料之中的 为深入了解IgA NP的发病机制提供依据。因此， 拟议的调查的目标是全面描述 本病患者的CIC，特别是 包含在复杂基质中的免疫球蛋白分子。 因此，我们将对免疫球蛋白A和免疫球蛋白进行光谱分析 蛋白质(在血清、唾液、CIC、淋巴样细胞和系膜细胞中 沉淀)，以及确定疾病的存在- 这些免疫球蛋白的特定独特型标志物。我们还将 寻找IgA类风湿因子的交叉反应独特型 以及研究自体免疫球蛋白抗独特型的可能性 针对IgA类风湿因子的抗体有助于 中投公司的组建。此外，我们将确定潜在的 自身免疫球蛋白A对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 从大量的患者中获得，其中许多人 家族性疾病。其他研究将对这两种情况进行描述 免疫球蛋白重链和轻链限制 在IgA NP中报告：我们将测定血清和 CIC和Ig G与IgA共同沉积在系膜中；此外，推测 将从定义的角度研究Lambda链限制 可变区亚群。最后，我们将研究潜在的 从对B的影响看CIC的功能意义 和体外培养的T细胞。拟议中的实验旨在 确定Ig A 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。

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.