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: 8336614
• 负责人: Frederick Miller
• 金额: $ 193.18万
• 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/8336614
• 关键词: Adolescent; Adult; Affect; Age; Air; Alleles; American; Animal Model; Area; Autoantibodies; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Back; Blood Cells; Candidate Disease Gene; Cause of Death; Child; Chronic; Clinical; Complement; Complex; Consumption; Critical Pathways; Data; Date of birth; Dermatomyositis; Development; Diagnosis; Diagnostic; Disease; Dust; Enrollment; Environmental Exposure; Environmental Risk Factor; Eosinophilia; Eosinophilia-Myalgia Syndrome; Epidemic; Epidemiology; Epigenetic Process; Estrogens; Ethnic Origin; Evaluation; Event; Exposure to; Food; Frequencies; Gender; Gene Expression; Genes; Genetic; Genetic Risk; Genetic Transcription; Genome; Goals; Herpesvirus Type 3; Hormones; Idiopathic Inflammatory Myopathies; Immune; Immune Response Genes; Immune response; Immunization; Immunogenetics; Immunoglobulin Genes; Immunologics; Incidence; Individual; Induration; Infection; Infectious Agent; Inflammation; Inflammatory; Interferons; Interleukin-4; Investigation; Laboratories; Lead; Learning; Life; Lifting; Link; Marketing; Measures; Medical Records; Metabolic; Microarray Analysis; Molecular; Molecular Genetics; Molecular Profiling; Monozygotic Twinning; Monozygotic twins; Morbidity - disease rate; Muscle; Myalgia; Myopathy; Myositis; Neuropathy; Occupational Exposure; Odds Ratio; Onset of illness; Organic solvent product; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Pattern; Peripheral; Persons; Pharmaceutical Preparations; Phenotype; Physicians; Play; Polymyositis; Population; Pregnancy; Prevalence; Proteomics; Publishing; Questionnaires; RNA; Race; Recurrence; Regulatory Pathway; Relative (related person); Reporting; Rheumatoid Arthritis; Risk Factors; Role; Sales; Scleroderma; Siblings; Signal Pathway; Signal Recognition Particle; Signal Transduction; Silicon Dioxide; Skin; Smoking; Source; Subgroup; Sun Exposure; Syndrome; Systemic Lupus Erythematosus; TNFSF10 gene; Therapeutic; Tissue-Specific Gene Expression; Tobacco smoke; Transforming Growth Factor beta; Translations; Tryptophan; Twin Multiple Birth; Twin Studies; Ultraviolet Rays; United States Food and Drug Administration; United States National Institutes of Health; Vaccination; Water; Woman; base; cohort; cytokine; dietary supplements; environmental agent; gene environment interaction; genetic risk factor; immune activation; insight; mortality; multidisciplinary; novel; older patient; peripheral blood; proband; prognostic; response; systemic autoimmune disease

Multidisciplinary studies - including clinical, immunologic, pathologic, epidemiologic and molecular genetic investigations - are being used to complement findings in each area and overcome limitations inherent in each approach. 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 analyses; defining the associations among clinical, laboratory and immunologic features of autoimmune diseases for diagnostic, prognostic and pathogenic purposes; and understanding differences in epigenetics, gene expression and proteomic patterns between monozygotic twins discordant for disease. Evaluation of exposures to silica, organic solvents, ultraviolet light, vaccinations, selected drugs and dietary supplements, hormones and pregnancy, tobacco smoke, stressful life events and infectious agents in the development of systemic autoimmune diseases are being conducted via a study of twins and close siblings discordant for systemic autoimmune disease. One of the objectives of the NIH twin-sib study is to determine if multiple systemic autoimmune diseases (SAID) share gene expression pathways that could provide insights into pathogenic mechanisms common to these disorders. To assess this, RNA microarray analyses were used to quantify gene expression in peripheral blood cells from 20 monozygotic (MZ) twin pairs discordant for SAID. Six affected probands with systemic lupus erythematosus (SLE), six with rheumatoid arthritis (RA), eight with idiopathic inflammatory myopathies (IIM), and their same-gendered unaffected twins, were enrolled. Comparisons were made between discordant twin pairs and these were also each compared to 40 unrelated control subjects (matched 2:1 to each twin by age, gender and ethnicity) using statistical and molecular pathway analyses. Relative quantitative PCR was used to verify independently measures of differential gene expression assessed by microarray analysis. We found that probands and unrelated, matched controls differed significantly in gene expression for 104 probes corresponding to 92 identifiable genes. Differentially expressed genes involved several overlapping pathways including immune responses (16%), signaling pathways (24%), transcription/translation regulators (26%), and metabolic functions (15%). Interferon (IFN)-response genes (IFI27, OASF, PLSCR1, EIF2AK2, TNFAIP6, and TNFSF10) were up-regulated in probands compared to unrelated controls. Many of the abnormally expressed genes played regulatory roles in multiple cellular pathways. In unaffected twins intermediate ordering was observed for 84 of the 104 probes (81%) whose expression differed significantly between probands and unrelated controls. Thus, alterations in expression of a limited number of genes may influence the dysregulation of numerous, integrated immune response, cell signaling and regulatory pathways that are common to a number of SAID. Gene expression profiles in peripheral blood also suggest that for genes in these critical pathways, unaffected twins may be in a transitional or intermediate state of immune dysregulation between twins with SAID and unrelated controls, perhaps predisposing them to the development of SAID given the necessary and sufficient environmental exposures. 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, in which multiple muscles are affected by inflammation, and dermatomyositis, 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 also studying children who develop myositis and we have recently assessed whether certain environmental factors temporally associated with the onset of juvenile idiopathic inflammatory myopathies (JIIM) differ between phenotypes. Physicians completed questionnaires regarding documented infections, medications, immunizations and an open-ended question about other noted exposures within 6 months before illness onset for 285 patients with probable or definite JIIM. Medical records were reviewed for 81% of the patients. Phenotypes were defined by standard clinical and laboratory measures. We found that sixty per cent of JIIM patients had a reported exposure within 6 months before illness onset. Most patients (62%) had one recorded exposure, 26% had two and 12% had three to five exposures. Patients older than the median age at diagnosis, those with a longer delay to diagnosis and those with anti-signal recognition particle autoantibodies had a higher frequency of documented exposures odds ratios (ORs) 95% CI 3.4, 31. Infections were the most common exposure and represented 44% of the total number of reported exposures. Non-infectious exposures included medications (18%), immunizations (11%), stressful life events (11%) and unusual sun exposure (7%). Exposures varied by age at diagnosis, race, disease course and the presence of certain myositis autoantibodies. Thus, JIIM may be related to multiple exposures and these appear to vary among phenotypes. Eosinophilia-myalgia syndrome (EMS) is characterized by subacute onset of myalgias and peripheral eosinophilia, followed by chronic neuropathy and skin induration. An epidemic of EMS in 1989 was linked to L-tryptophan consumption originating from a single source. Following the Food and Drug Administration (FDA) ban on the sale of L-tryptophan, the incidence of EMS declined rapidly. Moreover, no new cases have been published since the FDA ban was lifted in 2005. We report the clinical, histopathological and immunogenetic features of a new case of L-tryptophan-associated EMS along with evidence of activated transforming growth factor-beta and interleukin-4 signaling in the lesional skin and suggest that physicians consider this diagnosis in persons with unexplained muscle pain or neuropathy now that L-tryptophan is back on the market. Regarding our genetic studies, we have defined new genetic risk and protective factors for myositis in adults and children. These data, taken together, suggest that polymorphic alleles of MHC genes, pro-inflammatory cytokines, as well as the GM and KM loci for immunoglobulin genes, are differentially associated with myositis subgroups defined by age, ethnicity, clinical features and autoantibodies, and expand the list of immune response genes possibly important in the pathogenesis of myositis. Our findings, obtained from the largest cohort of patients with myositis studied to date, add additional support to the hypothesis that the myositis syndromes comprise multiple, distinct disease entities, perhaps arising from divergent pathogenic mechanisms as a result of different gene-environment interactions.

多学科研究——包括临床、免疫学、病理学、流行病学和分子遗传学研究——被用来补充每个领域的研究结果，并克服每种方法固有的局限性。目前的研究重点是：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分析确定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联，以用于诊断、预后和致病目的；并了解疾病不一致的同卵双胞胎之间表观遗传学、基因表达和蛋白质组模式的差异。目前正在通过一项针对系统性自身免疫性疾病不一致的双胞胎和近亲兄弟姐妹的研究，对二氧化硅、有机溶剂、紫外线、疫苗、选定药物和膳食补充剂、激素和怀孕、烟草烟雾、压力生活事件和传染源的暴露对系统性自身免疫性疾病的发展进行评估。 NIH 双胞胎同胞研究的目标之一是确定多种系统性自身免疫性疾病 (SAID) 是否共享基因表达途径，从而深入了解这些疾病常见的致病机制。为了评估这一点，使用 RNA 微阵列分析来量化 20 对 SAID 不一致的同卵 (MZ) 双胞胎的外周血细胞中的基因表达。六名患有系统性红斑狼疮 (SLE) 的先证者、六名患有类风湿性关节炎 (RA) 的先证者、八名患有特发性炎症性肌病 (IIM) 的先证者以及他们的同性别未受影响的双胞胎均被纳入研究。使用统计和分子途径分析对不一致的双胞胎进行比较，并将这些双胞胎与 40 名不相关的对照受试者进行比较（按年龄、性别和种族对每对双胞胎进行 2:1 匹配）。相对定量PCR用于验证通过微阵列分析评估的差异基因表达的独立测量结果。我们发现先证者和不相关的匹配对照在对应 92 个可识别基因的 104 个探针的基因表达方面存在显着差异。 差异表达基因涉及多个重叠途径，包括免疫反应（16%）、信号传导途径（24%）、转录/翻译调节因子（26%）和代谢功能（15%）。与无关对照相比，先证者的干扰素 (IFN) 反应基因（IFI27、OASF、PLSCR1、EIF2AK2、TNFAIP6 和 TNFSF10）上调。许多异常表达的基因在多种细胞途径中发挥调节作用。在未受影响的双胞胎中，104 个探针中的 84 个（81%）观察到中间排序，其表达在先证者和无关对照之间存在显着差异。因此，有限数量的基因表达的改变可能会影响许多SAID所共有的大量整合免疫反应、细胞信号传导和调节途径的失调。外周血中的基因表达谱还表明，对于这些关键通路中的基因，未受影响的双胞胎可能处于患有 SAID 的双胞胎和不相关对照的双胞胎之间免疫失调的过渡或中间状态，如果有必要和充分的环境暴露，可能会使他们倾向于发生 SAID。 一组我们知之甚少、危及生命的自身免疫性肌肉疾病，称为肌炎综合征或特发性炎症性肌病 (IIM)，其定义是慢性肌肉炎症和无力，并与特定的自身抗体相关。肌炎的主要形式是多发性肌炎（多块肌肉受到炎症影响）和皮肌炎（患者还会出现皮肤炎症）。然而，根据临床表现、病理学和自身抗体，似乎还有其他类型的肌炎。我们还在研究患有肌炎的儿童，并且最近评估了与幼年特发性炎症性肌病 (JIIM) 发病暂时相关的某些环境因素在不同表型之间是否存在差异。医生对 285 名可能或明确的 JIIM 患者完成了关于发病前 6 个月内记录的感染、药物、免疫接种和其他已知暴露的开放式问题的调查问卷。 81% 的患者的医疗记录得到了审查。表型通过标准临床和实验室测量来定义。我们发现 60% 的 JIIM 患者在发病前 6 个月内报告过接触过病毒。大多数患者 (62%) 记录过一次暴露，26% 记录过两次，12% 记录过三到五次暴露。诊断时年龄大于中位年龄的患者、诊断延迟时间较长的患者以及具有抗信号识别颗粒自身抗体的患者记录的暴露比值比 (OR) 的频率较高，为 95% CI 3.4, 31。感染是最常见的暴露，占报告暴露总数的 44%。非感染性暴露包括药物治疗（18%）、免疫接种（11%）、生活压力事件（11%）和不寻常的阳光照射（7%）。暴露情况因诊断时的年龄、种族、病程和某些肌炎自身抗体的存在而异。因此，JIIM 可能与多次暴露有关，并且这些暴露似乎因表型而异。 嗜酸性粒细胞增多-肌痛综合征（EMS）的特点是亚急性发作的肌痛和外周嗜酸性粒细胞增多，随后出现慢性神经病变和皮肤硬结。 1989 年 EMS 的流行与单一来源的 L-色氨酸消耗有关。随着美国食品和药物管理局 (FDA) 禁止销售 L-色氨酸，EMS 的发病率迅速下降。此外，自 2005 年 FDA 禁令解除以来，没有发布新病例。我们报告了一例新的 L-色氨酸相关 EMS 病例的临床、组织病理学和免疫遗传学特征，以及病变皮肤中转化生长因子-β 和白介素-4 信号激活的证据，并建议医生在患有不明原因肌肉疼痛或神经病变的患者中考虑这一诊断，因为 L-色氨酸重新上市。 关于我们的遗传学研究，我们已经确定了成人和儿童肌炎的新遗传风险和保护因素。这些数据综合起来表明，MHC 基因、促炎细胞因子以及免疫球蛋白基因的 GM 和 KM 基因座的多态性等位基因与按年龄、种族、临床特征和自身抗体定义的肌炎亚组存在差异相关，并扩大了可能在肌炎发病机制中重要的免疫反应基因列表。我们的研究结果是从迄今为止研究的最大的肌炎患者群体中获得的，为以下假设提供了额外的支持：肌炎综合征包含多种不同的疾病实体，可能是由于不同的基因-环境相互作用导致不同的致病机制引起的。