The Genetics of Silica-Induced Autoimmunity

二氧化硅诱导的自身免疫的遗传学

• 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
• 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

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，包括肺矽肺病和自身免疫性疾病 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） 和皮肌炎（DM）。尽管许多研究已经注意到二氧化硅暴露与 肾病，特别是在二氧化硅诱导的自身免疫性疾病的背景下，对肾病的遗传学一无所知。 二氧化硅引起的肾病。这确定了一个关键的障碍，以了解二氧化硅暴露如何 导致自身免疫性疾病肾脏疾病是自身免疫的常见特征，特别是在SLE中， 30-60%的成年人可能患有狼疮性肾炎。许多特征似乎与此有关，包括炎症 由含有免疫复合物的自身抗体沉积引发，导致产生炎性 介体涉及先天性和适应性免疫反应，导致细胞浸润，特别是 巨噬细胞，进展为组织损伤，异常组织修复和纤维化。研究，主要是在 动物模型已经鉴定了许多影响肾小球肾炎（GN）的分子介质。然而，在这方面， 大多数在先天性和/或适应性免疫中起作用，并不主要决定肾脏疾病。此外，遗传 在小鼠中的研究已经确定了许多GN易感基因座，但其中许多也与 自身抗体的产生与肾炎的主要作用相反。矽尘诱发之自体免疫反应与 相关病理学的研究由于缺乏合适的动物模型而受到阻碍。为了弥补这一缺陷，我们 已经开始描述导致自身免疫的免疫反应谱， 远交（DO）小鼠。我们已经检查了对二氧化硅的免疫反应，包括炎症反应 肺中的反应和BAL液中的相关蛋白质生物标志物，血清自身抗体谱 以及肾脏的组织病理学这些发现揭示了矽肺的显著发展， 自身免疫和肾小球肾炎（GN）。数量性状基因座（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，这个基因座（称为Smgn 1）与易感性相关， 和对二氧化硅诱导的GN的抗性。在该位点携带A/J等位基因的DO小鼠均未发生GN 说明是显性遗传我们提出了两个不同但相互关联的目标， 参与GN发展的遗传因素。 目的1：鉴定对二氧化硅诱导的肾小球肾炎的抵抗模式。 目的2：鉴定二氧化硅诱导的肾小球肾炎的易感模式。 这些研究是相当重要的，因为它们将使深入了解分子和细胞 途径导致肾小球肾炎后二氧化硅暴露。这些信息将是必不可少的， 确定潜在的治疗靶点，并提高我们对肾脏疾病的理解， 自身免疫的背景。