IMMUNOLOGICAL MECHANISMS OF NEPHRITIS IN CHILDHOOD

儿童系统性红斑狼疮(SLE)与疾病的不同之处在于 成人受肾炎的患病率较高。我们假设这是 肾炎的高患病率是由几种类型的肾炎引起的 在儿童时期的系统性红斑狼疮中同时出现的自身抗体。我们的 这些自身抗体的两个主要候选者是针对 DsDNA长期以来一直被认为在成人狼疮中发挥作用 肾炎和抗核糖体“P”蛋白自身抗体 以前有报道称与成人或儿童狼疮有关 肾炎。我们认为，在某些患者中，Ro/SSA抗体也可能 发挥引发肾病的作用。除了最近的初步临床和 支持抗P抗体在狼疮性肾炎中的作用的动物数据，两者都是抗P抗体 DsDNA和抗核糖体“P”抗体最近被发现 含有直接结合和损伤细胞的抗体亚群 在文化上。这种体外细胞损伤被认为是一种替代 它们在体内的免疫致病潜能。我们建议定义 这些自身抗体在个体患者中的致病潜力 亲和纯化自身抗体及其相互作用的研究 肾细胞在培养中。我们将描述这种模式 细胞内定位及其对细胞功能和活力的影响。 我们还将描述抗dsdna的不同致病机制。 来自个别患者的初步研究已经表明 某些人类抗体通过补体依赖机制损伤细胞 细胞表面和其他物质穿透细胞，定位于 细胞核或细胞质，并在更长的时间内影响细胞功能 一段时间。我们将把这些免疫致病特性与 体外配合患者的临床状态。 我们相信这样的研究可能会产生数据，这些数据将培育出新的 儿童狼疮性肾炎发病机制的研究进展 为管理这一问题提出新的战略和干预措施 严重的并发症。

Childhood systemic lupus erythematosus (SLE) differs from the disease in adults by a higher prevalence of nephritis. We hypothesize that this higher prevalence of nephritis is due to several types of nephritogenic autoantibodies that occur concurrently in the childhood form of SLE. Our two major candidates for these autoantibodies are those directed against dsDNA which have long been recognized to play a role in adult lupus nephritis and autoantibodies to ribosomal "P" protein which have not been reported previously to be associated with either adult or pediatric lupus nephritis. We propose that in some patients antibodies to Ro/SSA may also play a nephritogenic role. Aside from recent preliminary clinical and animal data that support a role for anti-P in lupus nephritis, both anti- dsDNA and anti-ribosomal "P" antibodies have recently been found to contain subpopulations of antibodies that directly bind and injure cells in culture. This in vitro cell injury is hypothesized to be a surrogate for their immunopathogenic potential in vivo. We propose to define the pathogenic potential of these autoantibodies in individual patients by affinity purifying their autoantibodies and by studying their interaction with renal cells in culture. We will characterize the pattern of intracellular localization and the effects on cell function and viability. We will also characterize the diverse pathogenic mechanism of anti-dsDNA from individual patients as preliminary studies already have shown that some human antibodies injure cells by a complement dependent mechanism at the cell surface and others penetrate the cell, localize in either the nucleus or the cytoplasm, and affect cellular function over a longer period of time. We will correlate these immunopathogenetic properties in vitro with the patients clinical status. We believe such studies may generate data which will foster a new perspective on the mechanism of lupus nephritis in children and may suggest new strategies and interventions for the management of this serious complication.