Environmental/genetic Risk Factors and Pathogenesis of Autoimmune Disease

环境/遗传风险因素与自身免疫性疾病的发病机制

• 批准号: 10924954
• 负责人: Lisa Rider
• 金额: $ 232.56万
• 依托单位: NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10924954
• 关键词: Adolescent; Adult; Affect; Age; Air; Air Pollution; Alcohol consumption; Alleles; American; Animal Model; Antibodies; Area; Aryl Hydrocarbon Receptor; Autoantibodies; Autoimmune; Autoimmune Diseases; Autoimmunity; B-Lymphocytes; BCL2 gene; Binding Proteins; Biological; Biological Products; Blood; CCR5 gene; Candidate Disease Gene; Cathepsins; Caucasians; Cause of Death; Child; Chronic; Clinical; Collaborations; Complement component C4a; Complex; Cytokine Receptors; Cytoplasmic Granules; Data; Date of birth; Dermatomyositis; Development; Diagnosis; Diagnostic; Dioxins; Disease; Dust; Elderly; Environmental Exposure; Environmental Risk Factor; Enzymes; Epidemiology; Estrogens; European ancestry; Evaluation; Exposure to; Flagellin; Food; Galectin 3; Gene Expression; Genes; Genetic; Genetic Transcription; Geography; Goals; Granzyme; HLA-DRB1; Haplotypes; Herpesvirus Type 3; High Prevalence; Hormones; Idiopathic Inflammatory Myopathies; Immune; Immunologic Markers; Immunologics; Individual; Infectious Agent; Inflammation; Interferons; Investigation; Juvenile Dermatomyositis; Laboratories; Learning; Life; Lung diseases; MAP Kinase Gene; Major Histocompatibility Complex; Malignant Neoplasms; Measures; Molecular Genetics; Monozygotic twins; Morbidity - disease rate; Muscle; Myopathy; Myositis; National Health and Nutrition Examination Survey; Not Hispanic or Latino; Nuclear; Obesity; Occupational Exposure; Odds Ratio; Onset of illness; Organic solvent product; PI3K/AKT; Pathogenesis; Pathogenicity; Pathologic; Pathology; Pathway Analysis; Pathway interactions; Patients; Pattern; Peripheral; Pharmaceutical Preparations; Phenotype; Polychlorinated Biphenyls; Polymyositis; Population; Predisposition; Pregnancy; Prevalence; Prevention strategy; Proteins; Proteomics; Receptor Signaling; Recording of previous events; Recurrence; Registries; Research Personnel; Rheumatoid Arthritis; Risk; Risk Factors; Role; STAT4 gene; Sampling; Scleroderma; Seasons; Signal Transduction; Silicon Dioxide; Single Nucleotide Polymorphism; Sirtuins; Skin; Smoker; Smoking; Stressful Event; Subgroup; Sunburn; Syndrome; Systemic Lupus Erythematosus; Systemic Scleroderma; T-Lymphocyte; Therapeutic; Time; Tobacco smoke; Tobacco smoking behavior; Transcript; Ubiquitination; Ultraviolet Rays; United States; Up-Regulation; Urine; Vaccination; Water; Xenobiotics; autoimmune pathogenesis; candidate marker; disease diagnostic; environmental agent; genetic association; genetic risk factor; genome wide association study; genome-wide; gut bacteria; immune activation; improved; mortality; multidisciplinary; national surveillance; neutrophil; novel; p38 Mitogen Activated Protein Kinase; patient registry; prognostic; protective factors; prototype; surveillance data; systemic autoimmune disease; transcription factor; trend; whole genome; young woman

Multidisciplinary studies, including immunologic, pathologic, epidemiologic and molecular genetic investigations, are being used. Current studies are focusing on: exploring possible environmental risk and protective factors; identifying genetic risk and protective factors by candidate gene and whole genome SNP and sequencing analyses; defining the associations among clinical, laboratory and immunologic features of autoimmune diseases for diagnostic, prognostic and pathogenic purposes; and understanding differences in gene expression and proteomic patterns between monozygotic twins discordant for disease. Evaluation of exposures to silica, organic solvents and other xenobiotics, ultraviolet light, vaccinations, selected drugs, hormones and pregnancy, tobacco smoke, stressful life events and infectious agents in the development of systemic autoimmune diseases are being conducted. A group of poorly-understood, life-threatening autoimmune muscle diseases called the myositis syndromes or idiopathic inflammatory myopathies (IIM) are defined by chronic muscle inflammation and weakness and are associated with specific autoantibodies. The major forms of myositis are polymyositis (PM), in which multiple muscles are affected by inflammation, and dermatomyositis (DM), in which patients also develop skin inflammation. Yet there appear to be other types of myositis based on the clinical presentations, pathology and autoantibodies. We are studying both the adult and juvenile (JIIM) forms of these diseases to understand possible differences in pathogenesis and risk factors. One area of investigation in which we have made recent advances involves identifying new genetic associations with juvenile and adult IIM. To accomplish this goal, we formed collaborations with investigators around the world, called the Myositis Genetic Consortium (MYOGEN). We performed a genome-wide association study (GWAS) of adult and juvenile myositis patients of European ancestry. Single-nucleotide polymorphisms showing strong associations in GWAS were identified in the major histocompatibility complex (MHC) region, specifically the 8.1 ancestral haplotype (AH8.1), for all myositis, as well as for the four clinical and autoantibody phenotypes. Although the HLA DRB1*03:01 allele showed stronger associations with adult and juvenile DM, and HLA B*08:01 with PM and anti-Jo-1 autoantibody-positive myositis, multiple alleles of AH8.1 were required for full risk. Our findings establish that alleles of the AH8.1 comprise the primary genetic risk factors associated with the major myositis phenotypes in geographically diverse Caucasian populations. These studies have found that genes associated with other autoimmune diseases are also seen in myositis phenotypes. Low copy numbers of C4T, C4L, and C4A, that result in C4A deficiency, were found to be present in IIM. C4A deficiency was found to be a risk factor for IIM, including for all subgroups (DM, JDM, PM, IBM) and for those with IIM autoantibodies. For DM and JDM, C4A deficiency was independent of the presence of HLA-DRB1*03, while in PM and IBM there was an interaction of C4A deficiency with HLA-DRB1*03 that increased risk. From a larger study of 2565 IIM patients involving more detailed genome-wide imputations using the Immunochip array, the HLA region was re-confirmed as the most significant risk factor. Additionally, STAT4 and DGKQ were confirmed as risk factors in all IIM. New risk factors were identified, including SDK2 and LINC00924, as well as subgroup specific associations of NAB1 and FAM167A-BLK in PM, and CCR5 in IBM. A number of these loci were intergenic, but associated with active transcription within B and T cells. These loci overlap with risks for other autoimmune disease, including RA, SLE, and systemic sclerosis. We have examined environmental factors as risk factors for myositis. Tobacco smoking has been associated with clinical and autoantibody myositis phenotypes in Caucasians. Caucasian ever-smokers were more likely to have PM (adjusted odds ratio, OR=2.24), and anti-Jo-1 autoantibodies (adjusted OR=1.94) and less likely to have anti-p155/140 autoantibodies. In Caucasians, ever-smokers with HLA-DRB1*03:01 allele had the highest odds of PM, ILD, and anti-Jo-1 autoantibodies. In a national myositis patient registry, differences in the prevalence of myositis subgroups was evident across the continental United States, with higher concentrations of patients with DM and IBM in the Northeast, with lung disease in the East and one pocket in the South, and of PM in the Southeast. There was a trend of higher prevalence near major roadways, esp in IBM, possibly due to air pollution exposure. From data in this registry, ambient UV radiation and a history of sunburn prior to diagnosis was associated with DM compared by PM and IBM. Antibody reactivity to flagellin, seen in gut bacteria, was frequent in JDM, especially in younger children who are anti-TIF1g antibody-positive. We have found through national surveillance data, NHANES, that the prevalence of a positive anti-nuclear autoantibody (ANA), as a common precursor and surrogate for autoimmune disease, has risen in recent years: 11.0% of the population sample had a positive ANA in 1998-1991, and 15.9% are positive in 2011-2012, corresponding to 22 million and 41 million affected individuals in the United States. ANA prevalence notably increased among adolescents ages 12-19 years, in older adults and non-Hispanic whites. Trends in obesity, smoking and alcohol usage did not explain the rise in ANA prevalence over this period of time. Further investigation has supported associatitons of ANA with dioxin-like compounds, including certain polychlorinated biphenyls. Further investigation is ongoing to determine factors underlying these increases in ANA prevalence, which may enable the development of preventable measures for autoimmune diseases. In examining gene expression and proteomic data in the blood of patients with adult and juvenile DM/JDM, we found a subset of interferon-stimulated genes was elevated. Innate immune markers specific to neutrophil granules and NETs were up-regulated in both DM and JDM. Pathway analysis revealed up-regulation of PI3K/AKT, ERK, and p38 MAPK signaling, whose central components were broadly up-regulated in DM, while peripheral upstream and downstream components were differentially regulated in both DM and JDM. Up-regulated components shared by DM and JDM included several cytokine:receptor pairs, Bcl-2 components, and glycolytic enzymes. Pathways unique to DM included sirtuin signaling, aryl hydrocarbon receptor signaling, protein ubiquitination, and granzyme B signaling. The combination of proteomics and transcript expression by multi-enrichment analysis broadened the identification of dysregulated pathways in DM/JDM. From a proteomics study of JDM patient urine, cathepsin D and galectin-3 binding protein were confirmed as candidate biomarkers of JDM disease activity and damage. We also found frequent presence of autoantibodies to Sp4, a transcription factor, in patients with JDM with anti-TIF1g autoantibodies. This autoantibody was protective for cancer in adult DM, and here associated with Raynaud's and milder weakness. Anti-TPM4 autoantibodies were found to be associated with vasculopathic features in JDM.

正在使用多学科研究，包括免疫学、病理学、流行病学和分子遗传学调查。目前的研究主要集中在：探索可能的环境风险和保护因素；通过候选基因和全基因组SNP及测序分析，识别遗传风险和保护因素；确定自身免疫性疾病的临床、实验室和免疫学特征之间的关系，以用于诊断、预后和致病目的；了解同卵双胞胎之间基因表达和蛋白质组模式的差异与疾病不一致。目前正在评估暴露于二氧化硅、有机溶剂和其他异种生物制剂、紫外线、疫苗接种、选定药物、激素和妊娠、烟草烟雾、生活压力事件和感染因子在发生全身性自身免疫性疾病中的作用。

项目成果

The Geospatial Distribution of Myositis and Its Phenotypes in the United States and Associations With Roadways: Findings From a National Myositis Patient Registry.

• DOI: 10.3389/fmed.2022.842586
• 发表时间: 2022
• 期刊: Frontiers in medicine
• 影响因子: 3.9
• 作者: Hossain MM;Wilkerson J;McGrath JA;Farhadi PN;Brokamp C;Khan MTF;Goldberg B;Brunner HI;Macaluso M;Miller FW;Rider LG
• 通讯作者: Rider LG

Mast cells and type I interferon responses in the skin of patients with juvenile dermatomyositis: are current therapies just scratching the surface?

幼年皮肌炎患者皮肤中的肥大细胞和 I 型干扰素反应：当前的治疗方法只是触及表面吗？

• DOI: 10.1002/art.27525
• 发表时间: 2010
• 期刊: Arthritis and rheumatism
• 作者: Rider,LisaG;Miller,FrederickW
• 通讯作者: Miller,FrederickW

The Climate Emergency and the Health of Our Patients: The Role of the Rheumatologist.

气候紧急情况与我们患者的健康：风湿病学家的作用。

• DOI: 10.1002/art.42279
• 发表时间: 2023-01
• 期刊: ARTHRITIS & RHEUMATOLOGY
• 影响因子: 13.3
• 作者: Dellaripa, Paul. F. F.;Bush, Thomas;Miller, Frederick. W. W.;Feldman, Candace. H. H.
• 通讯作者: Feldman, Candace. H. H.

Anti-FHL1 autoantibodies in juvenile myositis are associated with anti-Ro52 autoantibodies but not with severe disease features.

青少年肌炎中的抗 FHL1 自身抗体与抗 Ro52 自身抗体相关，但与严重疾病特征无关。

• DOI: 10.1093/rheumatology/keac428
• 发表时间: 2023
• 期刊: Rheumatology (Oxford, England)
• 作者: Sherman,MatthewA;Graf,Rose;Sabbagh,SaraE;Galindo-Feria,AngelesS;Pinal-Fernandez,Iago;Pak,Katherine;Kishi,Takayuki;Flegel,WillyA;Targoff,IraN;Miller,FrederickW;Lundberg,IngridE;Rider,LisaG;Mammen,AndrewL;ChildhoodMyositi
• 通讯作者: ChildhoodMyositi

Low copy numbers of complement C4 and C4A deficiency are risk factors for myositis, its subgroups and autoantibodies.

• DOI: 10.1136/ard-2022-222935
• 发表时间: 2023-02
• 期刊: Annals of the rheumatic diseases
• 影响因子: 27.4