Defining genetic pathways to severe systemic autoimmunity

描述（由申请人提供）：我们建议在我们的b6同源小鼠狼疮模型中确定和描述介导从良性自身免疫到致病性自身免疫转变的遗传和免疫机制。我们之前证明，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。Sle3或Sle5渗入B6。SIe1（产生B6）。SIe1Sle3或B6。sle1 （sle5双基因）将推动严重的系统性自身免疫和致命性肾小球肾炎的发展。该项目的总体目标将是确定负责Sle3和Sle5表型的基因或基因，并表征它们在“良性”自身免疫转化为致病性自身免疫中的功能作用。我们有两个具体目标。目的1将精细绘制和鉴定与Sle3基因间隔相关的三种表型的致病等位基因。Sle3表型表现为：1)体内转化为致死性狼疮性肾炎，伴严重的IgG体液自身免疫；2) B6与B6细胞因子和基因表达谱的差异。骨髓源性巨噬细胞和树突状细胞培养；3) B6易感性增加。兔抗小鼠肾小球抗血清致Sle3小鼠肾小球肾炎。该分析将确定每种表型的致病等位基因，并评估其在自身免疫发病机制中的作用。第二个具体目标将是确定致病等位基因或等位基因在Sle5基因区间负责两种表型。这些表型是：1)与Sle1联合在体内转化为致命疾病；2) B细胞功能多态性导致B细胞在体内扩增，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同源基因区间产生了一系列截断的同源菌株，这将有助于控制这些表型的位点的精细定位，并开发了一种利用基因组分析和高分辨率减数分裂重组来识别特定疾病基因的综合策略。这些研究将为介导良性自身免疫转变为严重疾病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.