The Genetics of Silica-Induced Autoimmunity

二氧化硅诱导的自身免疫的遗传学

• 批准号: 10436260
• 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 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10436260
• 关键词: Address; Adult; Affect; Albuminuria; Alleles; Animal Model; Antigen-Antibody Complex; Autoantibodies; Autoimmune; Autoimmune Diseases; Autoimmunity; Choristoma; Chromosome 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; 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; Pulmonary Inflammation; 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）、 和皮肌炎（DM）。尽管许多研究已经指出二氧化硅暴露与 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 二氧化硅诱发的肾脏疾病。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。肾脏疾病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。许多特征似乎都与此有关，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，进展为组织损伤，异常组织修复和纤维化。研究，主要是在 动物模型已经鉴定出许多影响肾小球肾炎（GN）的分子介质。然而， 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。此外，遗传 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肾炎的主要作用。二氧化硅诱导的自身免疫和 由于缺乏合适的动物模型，相关的病理学研究受到阻碍。为了解决这个缺陷，我们 已经开始表征导致自身免疫的免疫反应谱的多样性 近交系 (DO) 小鼠。我们检查了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 和肾脏的组织病理学。这些发现揭示了矽肺的显着发展， 自身免疫和肾小球肾炎（GN）。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 暗示显性遗传特征。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 接触二氧化硅后导致肾小球肾炎的途径。此类信息对于 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。

项目成果

Mechanisms of Environment-Induced Autoimmunity.

• DOI: 10.1146/annurev-pharmtox-031320-111453
• 发表时间: 2021-01-06
• 期刊: Annual review of pharmacology and toxicology
• 影响因子: 12.5
• 作者: Pollard KM;Cauvi DM;Mayeux JM;Toomey CB;Peiss AK;Hultman P;Kono DH
• 通讯作者: Kono DH

Exposure to silicates and systemic autoimmune-related outcomes in rodents: a systematic review.

• DOI: 10.1186/s12989-021-00439-6
• 发表时间: 2022-01-07
• 期刊: Particle and fibre toxicology
• 影响因子: 10
• 作者: Janssen LMF;Ghosh M;Lemaire F;Michael Pollard K;Hoet PHM
• 通讯作者: Hoet PHM

Development of experimental silicosis in inbred and outbred mice depends on instillation volume.

近交系和远交系小鼠实验性硅肺病的发生取决于滴注量。

• DOI: 10.1038/s41598-019-50725-9
• 发表时间: 2019
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Mayeux,JessicaM;Kono,DwightH;Pollard,KennethMichael
• 通讯作者: Pollard,KennethMichael

Differential Pulmonary Toxicity and Autoantibody Formation in Genetically Distinct Mouse Strains Following Combined Exposure to Silica and Diesel Exhaust Particles.

遗传上不同的小鼠品系联合暴露于二氧化硅和柴油机尾气颗粒后的差异性肺部毒性和自身抗体形成。

• DOI: 10.21203/rs.3.rs-3408546/v1
• 发表时间: 2023
• 期刊: Research square
• 作者: Janssen,LisaMf;Lemaire,Frauke;Marain,NoraFopke;Ronsmans,Steven;Heylen,Natasja;Vanstapel,Arno;Velde,GreetjeVande;Vanoirbeek,JeroenAj;Pollard,KMichael;Ghosh,Manosij;Hoet,PeterHm
• 通讯作者: Hoet,PeterHm