IMMUNOLOGICAL MECHANISMS OF NEPHRITIS IN CHILDHOOD

儿童系统性红斑狼疮（SLE）不同于疾病， 成人肾炎的患病率较高。我们假设这 肾炎的患病率较高是由于几种类型的致肾炎引起的 自身抗体，同时发生在儿童形式的系统性红斑狼疮。我们 这些自身抗体的两个主要候选者是针对 dsDNA长期以来被认为在成年狼疮中发挥作用， 肾炎和核糖体“P”蛋白自身抗体， 先前报告与成人或儿童狼疮相关 肾炎我们认为，在某些患者中，Ro/SSA抗体也可能 起到造肾的作用。除了最近的初步临床和 支持抗P抗体在狼疮性肾炎中作用的动物数据， 最近发现双链DNA和抗核糖体“P”抗体 含有直接结合并损伤细胞的抗体亚群 在文化中。这种体外细胞损伤被假设为替代 因为它们在体内具有免疫致病潜力。我们建议将 这些自身抗体在个体患者中的致病潜力， 亲和纯化其自身抗体，并通过研究它们的相互作用 培养的肾细胞。我们将描述 细胞内定位以及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 初步研究已经表明， 一些人抗体通过补体依赖性机制损伤细胞， 细胞表面和其他穿透细胞，定位在 细胞核或细胞质，并在更长的时间内影响细胞功能 段时间我们将把这些免疫病理特性与 体外与患者的临床状态。 我们相信这些研究可能会产生数据， 儿童狼疮性肾炎的发病机制及治疗 提出新的战略和干预措施， 严重并发症

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.