The Genetics of Silica-Induced Autoimmunity

二氧化硅诱导的自身免疫的遗传学

基本信息

批准号：
9763556
负责人：
Kenneth Michael Pollard
金额：
$ 43.54万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-15 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9763556
关键词：
Address Adult Affect Albuminuria Alleles Animal Model Antigen-Antibody Complex Autoantibodies Autoimmune Diseases Autoimmune Process Autoimmunity Choristoma Chromosomes, Human, Pair 15 Chronic Kidney Failure Connective Tissue Diseases Creatinine Deposition Dermatomyositis Detection Development Disease Disease Progression End stage renal failure Event Exposure to Fibrosis Frequencies General Population Genetic Genetic Recombination Genetic Variation Genetic study Genome Glomerulonephritis Human Hypergammaglobulinemia Immune Immune response Immunologics Inbred Mouse Individual Inflammation Inflammation Mediators Inflammatory Response Innate Immune System Kidney Kidney Diseases Leucocytic infiltrate Link Liquid substance Lung Lung Inflammation Lupus Nephritis Maps Mediating Mediator of activation protein Modeling Molecular Mouse Strains Mus Mutation Natural Immunity Nephritis Older Population Pathology Pathway interactions Patients Play Population Predisposition Prevalence Production Quantitative Trait Loci Relative Risks Resistance Rheumatoid Arthritis Role Serum Silicon Dioxide Silicosis Susceptibility Gene Symptoms Systemic Lupus Erythematosus Systemic Scleroderma Testing Tissues adaptive immune response adaptive immunity base cohort connective tissue development crystallinity cytokine environmental agent epidemiology study experimental study genetic element genetic variant genome wide association study improved insight macrophage mouse model protein biomarkers renal damage resistance allele resistance mechanism response therapeutic target tissue repair tool trait

项目摘要

Silica exposure is associated with different disorders including pulmonary silicosis and autoimmune diseases such as progressive systemic sclerosis (Pss), systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and dermatomyositis (DM). Although a number of studies have noted the association of silica exposure with nephropathy, particularly in the setting of silica-induced autoimmunity, nothing is known about the genetics of silica-induced renal disease. This identifies a critical barrier to progress in understanding how silica exposure leads to autoimmune pathology. Kidney disease is a common feature in autoimmunity particularly in SLE where 30–60% of adults may have lupus nephritis. A number of features appear to be implicated including inflammation initiated by deposition of autoantibody containing immune complexes, leading to production of inflammatory mediators involving the innate and adaptive immune responses which results in cellular infiltrates, particularly of macrophages, progression to tissue damage, aberrant tissue repair and fibrosis. Studies, predominantly in animal models, have identified numerous molecular mediators that affect glomerulonephritis (GN). However, most play roles in innate and/or adaptive immunity and do not primarily dictate renal disease. Moreover, genetic studies in mice have identified a number of GN susceptibility loci, but many of these also associate with autoantibody production arguing against a primary role in nephritis. Studies of silica-induced autoimmunity and related pathology have been hampered by the lack of suitable animal models. To address this deficiency, we have begun to characterize the spectrum of immunological responses leading to autoimmunity in Diversity Outbred (DO) mice. We have examined the immunological responses to silica including the inflammatory response in the lung and associated protein biomarkers in the BAL fluid, the spectrum of serum autoantibodies and tissue pathology in the kidney. These findings have revealed significant development of silicosis, autoimmunity and glomerulonephritis (GN). Quantitative trait locus (QTL) analysis determined the latter to be linked with a region on chromosome 15. Significantly, this locus (called Smgn1) is associated with susceptibility and resistance to silica-induced GN. None of the DO mice carrying the A/J allele at the locus developed GN suggesting a dominant inheritance trait. We proposed two distinct but interrelated aims to further characterize the genetic elements involved in the development of GN. Aim 1: Identification of the mode of resistance to silica-induced glomerulonephritis. Aim 2: Identification of the mode of susceptibility to silica-induced glomerulonephritis. These studies are of considerable importance because they will allow insight into the molecular and cellular pathways leading to glomerulonephritis following silica exposure. Such information will be essential for identification of potential therapeutic targets as well as improving our understanding of kidney disease within the context of autoimmunity.

二氧化硅暴露与不同的疾病有关，包括肺硅肺病和自身免疫性疾病例如进行性系统性硬化症（Pss）、系统性红斑狼疮（SLE）、类风湿性关节炎（RA）、尽管许多研究已经注意到二氧化硅暴露与皮肌炎（DM）之间的关联。肾病，特别是在硅诱导的自身免疫性肾病的情况下，我们对肾病的遗传学一无所知这确定了在了解二氧化硅如何暴露方面取得进展的一个关键障碍。导致自身免疫病理学是自身免疫性疾病的一个常见特征，特别是在系统性红斑狼疮 (SLE) 中。 30-60% 的成年人可能患有狼疮性肾炎，其中包括炎症等许多特征。由含有免疫复合物的自身抗体沉积引发，导致炎症的产生涉及先天性和适应性免疫反应的介质，导致细胞浸润，特别是巨噬细胞、组织损伤进展、异常组织修复和纤维化研究，主要是在。动物模型已经鉴定出许多影响肾小球肾炎（GN）的分子介质。大多数在先天性和/或适应性免疫中发挥作用，并且主要并不决定肾脏疾病。对小鼠的研究已经确定了许多 GN 易感位点，但其中许多也与自身抗体的产生反对二氧化硅诱导的自身免疫和肾炎的主要作用。由于缺乏合适的动物模型，相关的病理学研究受到了阻碍。为了解决这一缺陷，我们。已经开始表征导致自身免疫的免疫反应谱的多样性我们检查了远交 (DO) 小鼠对二氧化硅的免疫反应，包括炎症反应。肺部反应和支气管肺泡灌洗液中的相关蛋白质生物标志物、血清自身抗体谱和肾脏组织病理学这些发现揭示了矽肺的显着发展，自身免疫性和肾小球肾炎（GN）的数量性状位点（QTL）分析确定后者是。与 15 号染色体上的一个区域相连。值得注意的是，这个位点（称为 Smgn1）与易感性相关以及对二氧化硅诱导的 GN 的抵抗力。该位点携带 A/J 等位基因的 DO 小鼠均未出现 GN。我们提出了两个不同但相互关联的目标来进一步表征。与 GN 发生有关的遗传因素。目标 1：确定对二氧化硅诱导的肾小球肾炎的抵抗模式。目标 2：确定二氧化硅诱发的肾小球肾炎的易感性模式。这些研究非常重要，因为它们将有助于深入了解分子和细胞这些信息对于接触二氧化硅后导致肾小球肾炎的主要途径至关重要。确定潜在的治疗靶点以及提高我们对肾脏疾病的了解自身免疫的背景。