GENETIC ANOMALIES OF C4,CR1 & FCGR IN JUVENILE IGA-N

这项工作将检验以下假设：1)补体异常 和/或用于处理和清算循环的FCR机制。免疫 复合体(LC)经常出现在LGA肾炎(LGA-N)中，2) 这些异常的程度可以决定患者是否会 有青少年或成人发病的LGA-N经验。异常现象的概念 在LC中的处理和清除可以促进LGA-N的发展 部分基于LGA-N与LGA-N的良好关联 补充性组件和调节器的缺陷导致 C3b生成受损。C3b生成受损被认为是易患上的 对因LC处理和清除异常引起的LC病。因此， 参与LC处理或清除的缺陷或功能障碍的蛋白质， 可能在LGA-N的发病机制中起一定作用。之前的研究还没有 对这一假设进行了批判性的检验。LC中异常的概念 处理和清除可易患青少年发病的LGA-N IS 投机性的。然而，如本文所讨论的，归纳很可能 LGA-N的发生需要各种异常组合的同时发生 包括LGA异常生产、异常LGA生产、以及 信用证处理和清关异常。我们认为，越大的 这类异常的数量，可能较早的LGA的发病年龄- 为了查找信用证处理和清关过程中的异常情况，我们将 LC炮制过程中关键蛋白的基因组DNA和cDNA分析 许可机制。目的是确定是否存在等位基因 一级结构(氨基酸序列)的差异或差异 参与LC加工和清除的关键蛋白质可以 区分LGA-N患者与正常人，或成人起病的LGA-N与 青少年发病的LGA-N。这种差异将定义LGA-N的风险因素。 然后，需要确定这种风险的机制。的力量 目前的方法是定义等位基因，或氨基上的蛋白质 酸度，可以揭示蛋白质之间的关键差异，而不是 通过对完整蛋白质的分析来揭示。的关键组件 选定的LC处理和清算机制是第四个 补体成分(C4)，补体受体1型(CR1)，即 在红细胞(E)和FcGammaRII上表达。这些组件是 之所以选择，是因为之前研究的证据表明， 这些蛋白质可以与LGA-N(C4和E-CR1)相关，或者在这种情况下 FcGammaRII，某些异构体与IC- 系统性红斑狼疮介导性肾小球肾炎FcGammaRII是相关的，因为在LGA中- N、循环LC和肾小球LC沉淀物中常含有Ig G。上一首 使用预制LC探头评价LGA-N中LC清除率的研究 静脉注射。这些LC探头可能不适合用于 致病循环LC，如本文所讨论的。因此，这样的研究不能 被认为是对信用证处理和清关作用的关键测试 在LGA-N中。我们有大量的队列需要研究：35名青少年发病(16岁) 年)，以及105例成人起病(中位年龄37岁)LGA-N患者。控制 将是35名LGA-N患者的未受影响的兄弟姐妹，以及35名无关的正常人。 综上所述，本研究将提供 LGA-N中LC处理和清算机制的关键组件 与正常人相比。更重要的是，这项研究代表了一部小说 和更明确的方法寻找LC的异常 免疫球蛋白A-N的处理和清关以及这种异常现象是否会 BE是青少年发病的IgA-N决定因素

This work will test the hypotheses that: 1) Abnormalities in complement and/or FcR mechanisms for processing and clearing circulating. immune complexes (lC) are often present in lgA nephritis (lgA-N) and, 2) The extent of these abnormalities can determine whether the patient will experience juvenile or adult-onset lgA-N. The concept that abnormalities in lC processing and clearance can contribute to the development of lgA-N is based in part on the well described association of lgA-N with deficiencies of complement components and regulators that result in impaired C3b generation. Impaired C3b generation is thought to predispose to lC disease because of abnormal lC processing and clearance. Thus, deficient or dysfunctional proteins involved in lC processing or clearing, could play a role in the pathogenesis of lgA-N. Previous studies have not critically tested this hypothesis. The concept that abnormalities in lC processing and Clearance can predispose to juvenile-onset lgA-N is speculative. However, as discussed herein, it is likely that the induction of lgA-N requires the concurrence of various combinations of abnormalities including abnormal production of lgA, production of abnormal lgA, and abnormal lC processing and clearance. We suggest that, the greater the number of such abnormalities, the earlier might be the age of onset of lgA- N. To search for abnormalities in lC processing and clearance, we will analyze both genomic DNA and cDNA of key proteins of the lC processing an clearance mechanism. The goal is to determine whether there are allelic differences or differences in the primary structure (amino acid sequence) of key proteins involved in lC processing and clearance that can distinguish lgA-N patients from normals, or adult-onset lgA-N from juvenile-onset lgA-N. Such differences would define risk factors for lgA-N. The mechanism of that risk would then need to be determined. The power of the present approach is that defining alleles, or proteins at the amino acid level, can reveal critical differences between proteins that can not be revealed by analyses of the intact proteins. The key components of the lC processing and clearing mechanisms chosen for study are the fourth component of complement (C4), complement receptor Type 1 (CR1) that is expressed on erythrocytes (E), and FcgammaRII. These components were chosen because of evidence from previous studies that deficient amounts of these proteins can be associated with lgA-N (C4 and E-CR1) or, in the case of FcgammaRII, that certain isoforms are strongly associated with IC- mediated glomerulonephritis of SLE. FcgammaRII is relevant because in lgA- N, circulating lC and glomerular lC deposits often contain IgG. Previous studies assessing lC clearance in lgA-N used preformed lC probes infused intravenously. These lC probes are probably not suitable surrogates for pathogenic circulating lC, as discussed herein. Thus, such studies cannot be regarded as a critical test of the role of lC processing and clearance in lgA-N. We have large cohorts to study: 35 juvenile-onset (age < 16 years), and 105 adult-onset (median age 37 years) lgA-N patients. Controls will be 35 unaffected siblings of lgA-N patients, and 35 unrelated normals. In summary, the present study will provide a genetic characterization of key components of the lC processing and clearing mechanisms in lgA-N compared to normals. More importantly the present study represents a novel and more definitive approach to the search for abnormalities in lC Processing and clearance in IgaA-N. and whether such abnormalities might be determinants of juvenile onset IgA-N.