A novel mechanism of gene-environment interaction in autoimmune arthritis

自身免疫性关节炎基因-环境相互作用的新机制

• 批准号: 8768943
• 负责人: Joseph Holoshitz
• 金额: $ 23.32万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8768943
• 关键词: ARNT gene; ARNT protein; Abbreviations; Address; Agonist; Amino Acid Sequence; Arthritis; Aryl Hydrocarbon Receptor; Autoimmune Diseases; Autoimmunity; Bone Marrow Cells; CD4 Positive T Lymphocytes; CTLA4 gene; Carbazoles; Cells; Collagen Arthritis; Complement; Cyclic GMP; Cyclic GMP-Dependent Protein Kinases; Cytochrome P450; Cytotoxic T-Lymphocyte-Associated Protein 4; Dendritic Cells; Dependence; Dioxins; Disease susceptibility; Dominant-Negative Mutation; Elements; Embryo; Endothelial Cells; Environmental Pollutants; Environmental Risk Factor; Epitopes; Event; Exposure to; Fibroblasts; Future; Genes; Genetic Risk; Genetic Transcription; HLA Antigens; HLA-DR Antigens; Helper-Inducer T-Lymphocyte; Human; Immune system; In Vitro; Interferon Type II; Interleukin-17; Interleukins; Laboratories; Lead; Ligands; Major Histocompatibility Complex; Mediating; Molecular; Mus; NF-kappa B; Nitric Oxide; Nitric Oxide Synthase; Nuclear Translocation; Osteoclasts; Oxidative Stress; Pathway interactions; Patients; Phase; Play; Public Health; RNA; Reactive Oxygen Species; Reagent; Receptor Signaling; Regulatory T-Lymphocyte; Research; Research Personnel; Rheumatoid Arthritis; Role; Signal Transduction; Signal Transduction Pathway; Small Interfering RNA; Source; T-Lymphocyte; Tetrachlorodibenzodioxin; Transforming Growth Factors; Transgenic Mice; Transgenic Organisms; Umbilical vein; Wild Type Mouse; Xenobiotics; aryl hydrocarbon receptor ligand; autoimmune arthritis; base; calreticulin; carbazole; cytokine; disorder risk; gene environment interaction; genetic risk factor; human disease; in vivo; inhibitor/antagonist; insight; mouse Ahr protein; novel; pollutant; public health relevance; receptor; research study; synergism; tartrate-resistant acid phosphatase; transcription factor

DESCRIPTION (provided by applicant): The mechanisms governing genetic and environmental risk factors in rheumatoid arthritis (RA) are presently unknown. This laboratory has recently gained novel mechanistic insights into the mode of action of the main genetic risk factor in RA, the shared epitope (SE). The investigators have recently demonstrated that the SE, a 5-amino acid sequence motif in the HLA-DR ? chain shared by the majority of RA patients, acts as an innate immune system ligand, which triggers oxidative stress, facilitates differentiation of Th17 cells (T helper cells that produce IL-17), and induces pro-osteoclastogenic effects both in vitro and in vivo. Intriguingly, the aryl hydrocarbon receptor (AhR), a well-studied transcription factor that mediates the xenobiotic effects of many pollutants, has been shown by others to activate similar biologic effects. Prompted by the parallels between the mode of action of AhR and the SE ligand, and the epidemiologically well-documented synergism between the SE and exposure to environmental pollutants in RA disease risk, the investigators carried out preliminary experiments to determine whether the SE and AhR pathways interact in autoimmune arthritis. The findings demonstrate that the SE ligand and AhR pathway agonists produce additive or multiplicative biologic effects, which lead to enhanced osteoclast differentiation, Th17 polarization and more severe erosive arthritis. Additionally, preliminary findings suggest that the SE activates the nuclear factor kappa B (NF-?B) pathway. In this project the investigators will determine the hierarchy and inter-dependence of the two respective pathways as an exploratory phase before embarking on detailed characterization of the molecular mechanisms involved in SE- AhR interaction in the future. Successful completion of the research proposed here could open the door to advancing our understanding of the mechanisms involved in environmental pollutants-associated autoimmunity.

描述(由申请人提供)：控制类风湿性关节炎(RA)遗传和环境风险因素的机制目前尚不清楚。该实验室最近对类风湿性关节炎的主要遗传风险因素--共享表位(SE)的作用模式有了新的机制见解。研究人员最近证实，人类白细胞抗原-DR？作为天然免疫系统的配体，可触发氧化应激，促进Th17细胞(产生IL-17的辅助性T细胞)的分化，并在体外和体内诱导促破骨细胞生成作用。有趣的是，芳烃受体(AhR)是一种被广泛研究的转录因子，它介导了许多污染物的异生效应， 已经被其他人证明可以激活类似的生物效应。由于AhR和SE配体的作用模式相似，以及SE和暴露于环境污染物的环境污染物在RA疾病风险中的协同作用已得到流行病学的充分证明，研究人员进行了初步实验，以确定SE和AhR通路是否在自身免疫性关节炎中相互作用。结果表明，SE配体和AhR途径激动剂产生相加或相乘的生物效应，导致破骨细胞分化增强，Th17极化和更严重的侵蚀性关节炎。此外，初步研究结果表明，SE激活了核因子-kappaB(NFkappaB)途径。在这个项目中，研究人员将在未来开始详细描述SE-AhR相互作用的分子机制之前，作为一个探索阶段确定两条各自途径的层级和相互依赖。这里提出的研究的成功完成可能会为我们进一步了解与环境污染物相关的自身免疫机制打开大门。