Impact of lupus susceptibility loci on peripheral tolerance and onset of disease

狼疮易感位点对外周耐受性和疾病发作的影响

基本信息

批准号：
7846768
负责人：
Ziaur Rahman
金额：
$ 7.65万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-08-01 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7846768
关键词：
Animal Model Antibodies Antibody Formation Antigen Receptors Apoptosis Applications Grants Autoantibodies Autoantigens Autoimmune Diseases B-Cell Development B-Lymphocytes Binding Bone Marrow C57BL/6 Mouse Cells Chromatin Chronic Data Defect Deposition Development Disease Exhibits Fc Receptor Frequencies Genes Genome Genomics Haptens Human Hybrids Immune response Immunoglobulin G Immunoglobulin Somatic Hypermutation Individual Inflammation Kidney Knock-in Mouse Lead Lupus Lymphoid Lymphoid Follicle Mediating Memory Modeling Mus Myelogenous Myeloid Cells Names New Zealand Normal tissue morphology Nuclear Onset of illness Organ Pathogenesis Pathology Pathway interactions Peripheral Phenotype Predisposition Process Production Proteins Publishing Receptors, Antigen, B-Cell Recruitment Activity Regulation Rheumatoid Arthritis Role SLEB1 gene SLEB2 gene SLEB3 gene SLEB5 gene Staging Structure of germinal center of lymph node Surface Susceptibility Gene Systemic Lupus Erythematosus T-Lymphocyte Testing Therapeutic Tissues aged anti-IgG arsonate autoreactive B cell autoreactivity body system central tolerance congenic ds-DNA insight large scale production mouse model novel diagnostics peripheral tolerance receptor research study response systemic autoimmune disease

项目摘要

DESCRIPTION (provided by applicant): The hallmark of autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) is the production of antibodies that bind to normal tissues (autoantibodies) and, as a result are deposited in multiple organ systems in the body, resulting in inflammation and tissue destruction. Although healthy individuals have the potential to produce autoantibodies, they do not, suggesting that autoantibody producing cells are silenced by a mechanism called tolerance. Most of our understanding of the pathogenesis of autoimmune diseases such as SLE to date has come from the studies of animal models. One such model is the hybrid mouse of New Zealand Black (NZB) x White (NZW) which develop a disease that resembles human SLE. Multiple genes contribute to the pathogenesis of autoimmune diseases such as SLE in humans. Likewise, three major regions of the genome (named Sle1, Sle2 and Sle3/Sle5) containing the genes that contribute to the disease process were identified in this SLE mouse model. Mice containing each of these genomic intervals give rise to different component phenotypes (manifestations) such as autoantibody production, kidney pathology etc., while their interaction culminates in full-blown SLE. It is not well understood how these lupus susceptibility genes are altering B cell tolerance, allowing autoantibody production. Using mouse models producing a high frequency of defined, autoreactive B cells, in the current grant application we propose to study how each of these lupus susceptibility loci influence B cell tolerance and autoantibody production leading to the development of autoimmune disease SLE. This will allow us to identify the defective tolerance processes causing the disease. Subsequently, once the genes in these genomic intervals are identified, we can study how the products of these genes specifically alter the functioning of the identified B cell tolerance processes. Such a mechanistic understanding will allow novel diagnostic and therapeutic approaches for systemic autoimmune diseases to be developed.

描述（由申请人提供）：系统性红斑狼疮 (SLE) 和类风湿关节炎 (RA) 等自身免疫性疾病的特点是产生与正常组织结合的抗体（自身抗体），并沉积在体内的多个器官系统中，导致炎症和组织破坏。尽管健康个体有可能产生自身抗体，但他们却没有，这表明产生自身抗体的细胞被一种称为耐受性的机制所沉默。迄今为止，我们对系统性红斑狼疮等自身免疫性疾病发病机制的大部分了解都来自于动物模型的研究。其中一个模型是新西兰黑（NZB）x白（NZW）的杂交小鼠，它会患上类似于人类系统性红斑狼疮的疾病。多种基因导致人类系统性红斑狼疮等自身免疫性疾病的发病机制。同样，在该 SLE 小鼠模型中还鉴定出了基因组的三个主要区域（名为 Sle1、Sle2 和 Sle3/Sle5），其中包含有助于疾病过程的基因。包含这些基因组间隔中的每一个的小鼠都会产生不同的组成表型（表现），例如自身抗体产生、肾脏病理学等，而它们的相互作用最终导致全面的系统性红斑狼疮。目前尚不清楚这些狼疮易感基因如何改变 B 细胞耐受性，从而产生自身抗体。在当前的拨款申请中，我们建议使用产生高频率的确定的自身反应性 B 细胞的小鼠模型来研究这些狼疮易感性位点如何影响 B 细胞耐受性和自身抗体的产生，从而导致自身免疫性疾病 SLE 的发展。这将使我们能够识别导致疾病的有缺陷的耐受过程。随后，一旦鉴定出这些基因组间隔中的基因，我们就可以研究这些基因的产物如何特异性改变已鉴定的 B 细胞耐受过程的功能。这种机制的理解将有助于开发系统性自身免疫性疾病的新诊断和治疗方法。