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，包括肺硅和自身免疫性疾病 例如进行性全身性硬化症（PSS），全身性红斑狼疮（SLE），类风湿关节炎（RA）， 尽管有许多研究指出，二氧化硅暴露与 肾病，特别是在二氧化硅引起的自身免疫性的环境中，对 二氧化硅引起的肾脏疾病。这确定了在了解二氧化硅暴露方式方面进步的关键障碍 导致自身免疫性病理学。肾脏疾病是自身免疫性的常见特征，特别是在SLE中 30–60％的成年人可能患有狼疮性肾炎。似乎有许多功能包括炎症 通过沉积含有免疫复合物的自身抗体发起的，导致炎症的产生 涉及先天和适应性免疫调查的介体，导致细胞浸润，特别是 巨噬细胞，向组织损伤的进展，异常组织修复和纤维化。研究，主要是 动物模型已经确定了许多影响肾小球肾炎（GN）的分子介质。然而， 大多数在先天和/或适应性免疫学中起着作用，并且不主要决定肾脏疾病。而且，遗传 在小鼠中的研究已经确定了许多GN敏感性局部，但其中许多也与 自身抗体的产生反对肾炎中的主要作用。二氧化硅引起的自身免疫性和 缺乏合适的动物模型阻碍了相关病理。为了解决这一缺陷，我们 已经开始表征免疫反应的范围，导致自身免疫多样性 繁殖（do）小鼠。我们已经检查了包括炎症在内的二氧化硅的免疫学反应 在BAL液中的肺和相关蛋白质生物标志物中的反应，血清自身抗体的光谱 和肾脏的组织病理学。这些发现揭示了硅氧病的显着发展， 自身免疫性和肾小球肾炎（GN）。定量性状基因座（QTL）分析确定了以后的 与15染色体上的区域有关。重要的是，该基因座（称为SMGN1）与易感性有关 和对二氧化硅诱导的GN的抗性。在基因座上携带A/J等位基因的小鼠都没有 提出了主要的继承特征。我们提出了两个不同但相互关联的目的，以进一步表征 GN发展涉及的遗传因素。 目标1：鉴定对二氧化硅诱导的肾小球肾炎的抗性模式。 AIM 2：鉴定二氧化硅诱导的肾小球肾炎的易感模式。 这些研究非常重要，因为它们可以深入了解分子和细胞 二氧化硅暴露后导致肾小球肾炎的途径。这样的信息对于 鉴定潜在的治疗靶点，并提高我们对肾脏疾病的理解 自身免疫的背景。