Defining genetic pathways to severe systemic autoimmunity

我们建议识别和描述介导这种疾病的遗传和免疫机制。 我们建立的小鼠B6基因同源免疫模型中良性自身免疫向致病性自身免疫的转变 狼疮。我们之前证明，Sle1介导了免疫耐受的破坏，导致了 相对良性的自身免疫表型，其特征是产生抗核自身抗体 很少或根本没有肾病。S/E3或Sle5导入BQ.SIel(产生BQ.SIe1Sle3或 B6.S/e7S/e5双基因)将推动严重的系统性自身免疫的发展和致命 肾小球肾炎。这个项目的总体目标将是确定一个或多个基因负责 S/e3和S/e5表型及其在“良性”转化中的作用 自身免疫转变为致病性自身免疫。我们有两个具体目标。目标1将绘制精细地图并确定 S/E3等位基因区间三种表型的致病等位基因S/E3的表型为： 1)体内转化为致死性狼疮性肾炎伴严重的免疫球蛋白G体液自身免疫，并伴有Sle1； 2)B6和B6S/E3骨髓细胞因子和基因表达谱的差异 巨噬细胞和树突状细胞培养；3)B6.S/E3小鼠对肾脏的易感性增加 兔抗鼠肾小球抗血清诱导肾小球肾炎。这一分析将确定 这些表型的致病等位基因，并评估它们在自身免疫发病机制中的作用。这个 第二个具体目标将是识别S/e5同源基因区间中的一个或多个致病等位基因 负责两种表型。这些表型是：1)体内转变为致命性疾病的组合 和2)B细胞功能多态导致体内B细胞扩增和增加 产生识别多种自身抗原的IgM自身抗体。我们已经生产了一系列 S/e3和S/e5同源区间的截短同源菌株将有助于精细定位 控制这些表型的基因座，并已发展出一种利用基因组的综合策略 分析和高分辨率减数分裂重组，以确定特定的疾病基因。这些研究将 为调节良性转化的遗传机制提供了重要的新见解 自身免疫性转化为严重疾病。

We propose to identify and characterize the genetic and immunologic mechanisms that mediate the transition from benign autoimmunity into pathogenic autoimmunity in our B6-congenic models of murine lupus. We previously demonstrated that Sle1mediates a breach in immunologic tolerance that causesa relatively benign autoimmune phenotype characterized by the production of anti-nuclear autoantibodies with little or no kidney disease. The introgression of either S/e3 or Sle5 onto BQ.SIel (to produce BQ.SIe1Sle3 or B6.S/e7S/e5 bi-congenics) will drive the development of severe systemic autoimmunity and fatal glomerulonephritis. The overall goal of this project will be to identify the gene or genes responsible for the S/e3 and S/e5 phenotypes and to characterizetheir functional roles in the conversion of "benign" autoimmunity into pathogenic autoimmunity. We have two specific aims. Aim 1 will fine map and identify the causative alleles for three phenotypes associated with the S/e3 congenic interval. The S/e3 phenotypes are: 1) in vivo transition to fatal lupus nephritis with severe IgG humoral autoimmunity in combination with Sle1; 2) variations in cytokine and gene expression profiles of B6 versus B6.S/e3 bone-marrow derived macrophage and dendritic cell cultures; and 3) increased susceptibility of B6.S/e3 mice to kidney glomerulonephritis induced by rabbit anti-mouse glomerulus antiserum. This analysis will identify the causative alleles for each of these phenotypes and assess their role in autoimmune pathogenesis. The second specific aim will be to identify the causative allele or alleles in the S/e5 congenic interval that are responsible for two phenotypes. These phenotypes are:1) in vivo transition to fatal disease in combination with Sle1; and 2) B cell functional polymorphisms leading to B cell expansions in vivo and increased production of IgM autoantibodies recognizing a variety of autoantigens. We have produced a series of truncated congenic strains across the S/e3 and S/e5 congenic intervals that will facilitate the fine mapping of the loci that control these phenotypes and have developed an integrated strategy employing genomic analysis and high resolution meiotic recombination to identify specific disease genes. These studies will provide important new insights into the genetic mechanisms that mediate the transition of benign autoimmunity into severe disease.