Cellular and Genetic Basis of Systemic Lupus

描述(申请人提供)：系统性红斑狼疮(SLE)是一种 自身免疫性疾病影响多个器官，发病率相当高， 死亡率。这种疾病的特征是产生多种自身抗体。 包括抗核抗体(ANA和抗dsDNA抗体)与免疫 复杂的形态导致强烈的炎症和最终的器官损害。免疫 复杂介导性肾小球肾炎(GN)是其主要表现。 无序。遗传和环境因素在ITS中都起着重要的作用 发病机制。我们实验室一直在关注自身抗体的来源(S) 在系统性红斑狼疮中检测到的以及在ANA和ANA产生中重要的遗传因素 抗dsDNA抗体与狼疮性肾炎最近，一款新型号的SLE NZM2328 已经被刻画出来。在这种毒株中，女性对ANA和 慢性肾炎。在回交(NZM2328×C57L/J F1)×NZM2328的分析中， 已在NZM2328的1号染色体上确定了控制该基因的区间 慢性肾小球肾炎的发展。4号染色体上的一个区间被证明是连锁的 ANA和抗dsDNA抗体的产生。由一个辅助的记号笔 方法将NZM2328.C57Lc1和NZM2328.C57L.c4两个同源基因通过 将感兴趣的基因片段分别从1号和4号染色体上移走 从C57L/J至NZM2328。NZM2328.C57Lc1少见抗核抗体、抗dsDNA或慢性肾炎 被人看到了。相比之下，在NZM2328.C57Lc4中，尽管 ANA和抗dsDNA显著减少，解离ANA和抗dsDNA 狼疮性肾炎的产物。看来，基因片段上的 1号染色体控制狼疮性肾炎，调节抗核抗体和抗dsDNA抗体 制作。这些遗传位点被命名为LNC1，即狼疮性肾炎 控制基因1和Adn1，抗dsDNA和ANA产生基因1。 建议，假定LNC%1不同于Adn1。此应用程序是 重点阐述了细胞和免疫化学基础 自身抗体的产生和GN的产生及其基因LNC的鉴定 1和Adn1.提出了四个具体目标：(1)进一步表征NZM2328 及其两个同源品系NZM2328.C57Lc1和NZM2328.C57Lc4；(2) 从疾病肾脏中洗脱出的免疫球蛋白的特异性 NZM2328.LC4，阐明了抗dsDNA抗体解离的基础 以及严重蛋白尿和慢性肾炎的ANA产生；(3)测定 严重蛋白尿、慢性肾炎和自身抗体产生的细胞学基础 通过过继细胞转移分析；以及(4)产生同源基因 来自亲本菌株NZM2328.C57Lc1的重组菌株，含有 C57LIJ来源的1号染色体较小的遗传间隔 最小C57L/J基因片段(S)抑制抗双链DNA抗体和抗核抗体 产生，和/或严重蛋白尿为慢性肾炎。因此，我们将细化 这一区间的遗传学，以便我们可以识别基因Lnc 1和Adn1， 通过位置克隆与表型表达相关。结果来自于 这些实验将使我们进一步了解糖尿病的发病机制。 SLE。这一信息将导致对同源基因(S)的鉴定 并为我们提供了更具体和更新颖的潜在靶点 治疗性干预。

DESCRIPTION (provided by applicant): Systemic lupus erythematosus (SLE) is an autoimmune disorder affecting multiple organs with considerable morbidity and mortality. The disorder is characterized by multiple autoantibody production including antinuclear antibodies (ANA and anti-dsDNA antibodies with immune complex formation leading to intense inflammation and end organ damage. Immune complex-mediated glomerulonephritis (GN) is a major manifestation of this disorder. Both genetic and environmental factors play important roles in its pathogenesis. Our laboratory has focused on the origin(s) of the autoantibodies detected in SLE and the genetic factors important in the generation of ANA and anti-dsDNA antibodies and lupus nephritis. Recently, a new model of SLE NZM2328 has been characterized. In this strain, there is female bias for ANA and chronic GN. In a backcross (NZM2328 X C57L/J F1) X NZM2328 analysis, a genetic interval has been identified on chromosome 1 in NZM2328 to control the development of chronic GN. An interval on chromosome 4 was shown to be linked to the production of ANA and anti-dsDNA antibodies. By a marker assisted method, two congenics NZM2328.C57Lc1 and NZM2328.C57L.c4 were generated by moving the genetic segments of interest from chromosomes 1 and 4 respectively from C57L/J to NZM2328. In NZM2328.C57Lc1 little ANA, anti-dsDNA or chronic GN were seen. In contrast in NZM2328.C57Lc4, chronic GN was detected despite marked reductions in ANA and anti dsDNA, dissociating ANA and anti-dsDNA production from lupus nephritis. It appeared that the genetic segment on chromosome 1 controls lupus nephritis and regulates ANA and anti-dsDNA production. These genetic loci have been named Lnc 1, the lupus nephritis controlling gene 1 and Adn1, the anti-dsDNA and ANA production gene 1. For this proposal, Lnc 1 is assumed to be different from Adn1. This application is focused on the elucidation of the cellular and immunochemical basis for autoantibody production and the generation of GN and to identify the genes, Lnc 1 and Adn1. Four specific aims proposed are (1) to characterize further NZM2328 and its two congenic lines NZM2328.C57Lc1 an NZM2328.C57Lc4; (2) to determine the specificities of immunoglobulins eluted from diseased kidneys from NZM2328.Lc4, clarifying the basis for the dissociation of anti-dsDNA antibody and ANA production from sever proteinuria and chronic GN; (3) to determine the cellular basis of severe proteinuria, chronic GN, and autoantibody production by adoptive cell transfer analysis; and (4) to generate intra c1 congenic recombinant strains from the parental strain NZM2328.C57Lc1, which contain smaller genetic intervals of chromosome 1 derived from C57LIJ to determine the minimal C57L/J genetic segment(s) to suppress anti-dsDNA antibody and ANA production, and/or severe proteinuria an chronic GN. Thus, we will refine the genetics for this interval so that we may identify the genes, Lnc 1 and Adn1, relevant to the phenotypic expression by positional cloning. The results from these experiments will provide us further understanding of the pathogenesis of SLE. This information should lead to orthologous gene(s) identification in the SLE patients and provide us potential targets for more specific and novel therapeutic interventions.