Defining genetic pathways to severe systemic autoimmunity

定义严重系统性自身免疫的遗传途径

• 批准号: 7088247
• 负责人: Edward K. Wakeland
• 金额: $ 57.54万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7088247
• 关键词: alleles; autoimmunity; genes; genetics; phenotype

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.

描述（由申请人提供）：我们建议在我们的B6鼠鼠狼疮模型中介导从良性自身免疫到致病自身免疫性的遗传和免疫机制。 我们先前证明SLE1介导了免疫耐受性的破坏，这会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几乎没有或没有肾脏疾病。 SLE3或SLE5渗入B6.SIE1（生产B6.sie1sle3或b6.sle1sle5 bi-Congenics）将推动严重的全身自身免疫性和致命的肾小球肾炎的发展。 该项目的总体目标是确定负责SLE3和SLE5表型的基因或基因，并在“良性”自身免疫性转化为致病自身免疫性中的功能作用。 我们有两个具体的目标。 AIM 1将详细地图并识别与SLE3优先间隔相关的三种表型的病因等位基因。 SLE3表型是：1）体内过渡到致命的狼疮肾炎，并与SLE1结合使用严重的IgG体液自身免疫性； 2）B6与B6的细胞因子和基因表达谱的变化。SLE3骨骼衍生的巨噬细胞和树突状细胞培养物； 3）增加了B6.SLE3小鼠对兔抗小鼠肾小球抗血清诱导的肾脏肾小球肾炎的敏感性。 该分析将确定每种表型的病因等位基因，并评估其在自身免疫发病机理中的作用。 第二个具体目的是确定造成两种表型的SLE5含量间隔中的因果等位基因或等位基因。 这些表型是：1）与SLE1结合使用的体内过渡到致命疾病； 2）B细胞功能多态性导致体内B细胞扩张，并增加IgM自身抗体的产生，以识别各种自身抗原。 我们已经在SLE3和SLE5的奇异间隔中产生了一系列截短的先天性菌株，这些菌株将有助于控制这些表型的基因座的精细映射，并采用了采用基因组分析和高分辨率减数分裂重组来鉴定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。