The Genetics of Silica-Induced Autoimmunity

二氧化硅诱导的自身免疫的遗传学

• 批准号: 9581021
• 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/9581021
• 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; 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