Defining genetic pathways to severe systemic autoimmunity

描述(由申请人提供)：我们建议在我们的B6-原生小鼠狼疮模型中鉴定和描述从良性自身免疫到病理性自身免疫转变的遗传和免疫学机制。我们先前证明，Sle1介导免疫耐受的破坏，导致相对良性的自身免疫表型，其特征是产生抗核自身抗体，很少或没有肾脏疾病。将Sle3或Sle5导入B6.SIe1(产生B6.Sle1Sle3或B6.Sle1Sle5双基因)将导致严重的全身性自身免疫和致死性肾小球肾炎。这个项目的总体目标将是确定一个或多个负责Sle3和Sle5表型的基因，并表征它们在将“良性”自身免疫转化为病理性自身免疫过程中的功能作用。我们有两个具体目标。目标1将精细定位和鉴定与Sle3同源区间相关的三种表型的致病等位基因。Sle3的表型是：1)在体内转化为严重的免疫球蛋白G狼疮性肾炎合并Sle1；2)B6和B6的细胞因子和基因表达谱的变化；Sle3骨髓来源的巨噬细胞和树突状细胞培养；3)B6Sle3小鼠对兔抗鼠肾小球抗血清诱导的肾小球肾炎的易感性增加。这项分析将确定每一种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。第二个具体目标是确定Sle5同源基因区间中负责两种表型的一个或多个致病等位基因。这些表型是：1)体内转化为致命性疾病合并Sle1；2)B细胞功能多态性导致B细胞在体内扩张，并增加识别各种自身抗原的IgM自身抗体的产生。我们已经在Sle3和Sle5同源区间产生了一系列截短的同源菌株，这将有助于控制这些表型的基因座的精细定位，并开发了一种综合策略，使用基因组分析和高分辨率减数分裂重组来识别特定的疾病基因。这些研究将为调节良性自身免疫向严重疾病转变的遗传机制提供重要的新见解。

DESCRIPTION (provided by applicant): 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 Sle1 mediates a breach in immunologic tolerance that causes a relatively benign autoimmune phenotype characterized by the production of anti-nuclear autoantibodies with little or no kidney disease. The introgression of either Sle3 or Sle5 onto B6.SIe1 (to produce B6.SIe1Sle3 or B6.Sle1Sle5 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 Sle3 and Sle5 phenotypes and to characterize their 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 Sle3 congenic interval. The Sle3 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.Sle3 bone-marrow derived macrophage and dendritic cell cultures; and 3) increased susceptibility of B6.Sle3 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 Sle5 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 Sle3 and Sle5 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.