Defining genetic pathways to severe systemic autoimmunity

我们建议确定和表征介导这种疾病的遗传和免疫机制。 在我们的B6同类小鼠模型中从良性自身免疫向致病性自身免疫的转变 狼疮我们以前证明，Sle 1介导免疫耐受的破坏，导致免疫耐受的发生。 相对良性的自身免疫表型，其特征在于产生抗核自身抗体， 很少或没有肾脏疾病。将S/e3或Sle 5基因渗入BQ.SIe1（以产生BQ.SIe1Sle 3或Sle 5）。 B6.S/e7S/e5双同源基因）将导致严重的全身性自身免疫和致命的 肾小球肾炎该项目的总体目标将是确定基因或基因负责 S/e3和S/e5表型，并描述其在"良性"转化中的功能作用。 自身免疫转化为致病性自身免疫。我们有两个具体目标。目标1将精细映射并识别 与S/e3同源间隔相关的三种表型的致病等位基因。S/e3表型为： 1)与Sle 1联合，体内转变为致命的狼疮性肾炎，伴有严重的IgG体液自身免疫; 2)B6与B6.S/e3骨髓来源的细胞因子和基因表达谱的变化 巨噬细胞和树突状细胞培养物;和3）B6.S/e3小鼠对肾脏的易感性增加 兔抗小鼠肾小球抗血清诱导的肾小球肾炎。该分析将确定 这些表型中的每一种的致病等位基因，并评估它们在自身免疫发病机制中的作用。的 第二个具体目标是鉴定S/e5同源区间中的致病等位基因， 负责两种表型。这些表型是：1）在体内转化为致命性疾病的组合 和2）B细胞功能多态性导致体内B细胞扩增和增加 产生识别多种自身抗原的IgM自身抗体。我们制作了一系列 跨S/e3和S/e5同源区间的截短同源菌株，这将有助于对 控制这些表型的基因座，并已开发出一种采用基因组 分析和高分辨率减数分裂重组以鉴定特定的疾病基因。这些研究将 提供了重要的新见解的遗传机制，介导的良性过渡， 自身免疫转化为严重疾病。

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.