Defining genetic pathways to severe systemic autoimmunity

描述（由申请人提供）：我们建议鉴定和表征在我们的B6同类鼠狼疮模型中介导从良性自身免疫转变为致病性自身免疫的遗传和免疫机制。 我们以前证明，Sle 1介导免疫耐受的破坏，导致相对良性的自身免疫表型，其特征在于产生抗核自身抗体，很少或没有肾脏疾病。 Sle 3或Sle 5基因渗入B6.Sle 1（产生B6.Sle 1 Sle 3或B6.Sle 1 Sle 5双同源基因）将导致严重的系统性自身免疫和致命性肾小球肾炎的发生。 该项目的总体目标是鉴定负责Sle 3和Sle 5表型的基因，并表征其在“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将精细定位和鉴定与Sle 3同源间隔相关的三种表型的致病等位基因。 Sle 3表型为：1）与Sle 1组合时，在体内转变为具有严重IgG体液自身免疫的致命性狼疮肾炎; 2）B6与B6.Sle 3骨髓衍生的巨噬细胞和树突状细胞培养物的细胞因子和基因表达谱的变化;和3）B6.Sle 3小鼠对由兔抗小鼠肾小球抗血清诱导的肾小球肾炎的易感性增加。 该分析将鉴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。 第二个具体目标是鉴定Sle 5同源间隔中负责两种表型的致病等位基因。 这些表型是：1）与Sle 1组合在体内转变为致死性疾病;和2）B细胞功能多态性，其导致B细胞在体内扩增和识别多种自身抗原的IgM自身抗体的产生增加。 我们已经产生了一系列截断的同源菌株跨越Sle 3和Sle 5同源间隔，这将有助于控制这些表型的基因座的精细定位，并已开发出一种综合策略，采用基因组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.