Defining genetic pathways to severe systemic autoimmunity

定义严重系统性自身免疫的遗传途径

基本信息

批准号：
7193418
负责人：
Edward K. Wakeland
金额：
$ 57.39万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
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/7193418
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

项目摘要

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 同类小鼠狼疮模型中鉴定和表征介导从良性自身免疫向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，而很少或没有肾脏疾病。 Sle3 或 Sle5 渗入 B6.SIe1（产生 B6.SIe1Sle3 或 B6.Sle1Sle5 双同源基因）将导致严重的全身性自身免疫和致命性肾小球肾炎的发展。该项目的总体目标是鉴定负责 Sle3 和 Sle5 表型的基因，并表征它们在“良性”自身免疫向致病性自身免疫转化中的功能作用。我们有两个具体目标。目标 1 将精细绘制图谱并识别与 Sle3 同源区间相关的三种表型的致病等位基因。 Sle3表型是：1)与Sle1结合体内转变为致命性狼疮性肾炎，伴有严重的IgG体液自身免疫； 2) B6与B6.Sle3骨髓来源的巨噬细胞和树突细胞培养物的细胞因子和基因表达谱的变化； 3)B6.Sle3小鼠对兔抗小鼠肾小球抗血清诱导的肾小球肾炎的易感性增加。该分析将确定每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 同源区间中导致两种表型的致病等位基因或等位基因。这些表型是：1) 与 Sle1 结合体内转变为致命疾病； 2) B 细胞功能多态性导致 B 细胞在体内扩增并增加识别多种自身抗原的 IgM 自身抗体的产生。我们已经生产了一系列跨越 Sle3 和 Sle5 同源间隔的截短同源菌株，这将有助于控制这些表型的基因座的精细定位，并开发了一种采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向严重疾病转变的遗传机制提供重要的新见解。