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: 7385152
• 负责人: Edward K. Wakeland
• 金额: $ 57.84万
• 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/7385152
• 关键词: Alleles; Autoantibodies; Autoantigens; Autoimmune Process; Autoimmunity; B-Lymphocytes; Benign; Bone Marrow; Bone Marrow Transplantation; Candidate Disease Gene; Cell Lineage; Chromosomes, Human, Pair 7; Code; Collection; Congenic Strain; Control Locus; Cytokine Gene; Dendritic Cells; Development; Disease; Gene Expression; Gene Expression Profiling; Genes; Genetic; Genetic Polymorphism; Genomics; Glomerulonephritis; Goals; Immune Sera; Immune Tolerance; Immunoglobulin G; Immunoglobulin M; Immunologics; Kidney; Kidney Diseases; Localized; Location; Lupus; Lupus Nephritis; Maps; Measures; Mediating; Meiotic Recombination; Microsatellite Repeats; Modeling; Molecular Profiling; Mus; Nuclear; Nucleic Acid Regulatory Sequences; Oryctolagus cuniculus; Pathogenesis; Pathway interactions; Phenotype; Predisposition; Production; Resolution; Role; Series; Variant; congenic; genetic analysis; in vivo; insight; macrophage

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.

我们建议识别和表征介导的遗传和免疫学机制 在我们的B6鼠模型中，从良性自身免疫到致病自身免疫性的过渡 狼疮。我们以前证明了SLE1Mediat会导致免疫耐受性违反。 相对良性自身免疫表型，其特征是产生抗核自身抗体 很少或没有肾脏疾病。将s/e3或sle5渗入bq.siel（生产bq.sie1sle3或 B6.S/E7S/E5双元素）将推动严重的全身自身免疫性和致命的发展 肾小球肾炎。该项目的总体目标是确定负责该项目的基因或基因 S/E3和S/E5表型，以及在“良性”转化中的功能作用 自身免疫性为致病性自身免疫性。我们有两个具体的目标。 AIM 1将罚款地图并确定 与S/E3相关间隔相关的三种表型的致病等位基因。 S/E3表型是： 1）在体内向致命的狼疮性肾炎过渡，严重的IgG体内自身免疫与SLE1结合； 2）B6与B6.S/E3骨row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； 3）增加了B6.S/E3小鼠对肾脏的敏感性 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，并评估它们在自身免疫发病机理中的作用。这 第二个具体目的是确定在S/E5先天性间隔中的因果等位基因或等位基因 负责两种表型。这些表型是：1）在体内向致命疾病结合过渡 与sle1; 2）B细胞功能多态性导致体内B细胞扩张并增加 识别各种自身抗原的IgM自身抗体的产生。我们制作了一系列 S/E3和S/E5的截短的截短的相对菌株，将有助于精细地图 控制这些表型并采用基因组制定了综合策略的基因座 分析和高分辨率减数分裂重组以鉴定特定的疾病基因。这些研究会 对介导良性过渡的遗传机制提供重要的新见解 自身免疫性患有严重疾病。