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

基本信息

批准号：
8898805
负责人：
Joseph Holoshitz
金额：
$ 19.38万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8898805
关键词：
Address Agonist Amino Acid Sequence Arthritis Aryl Hydrocarbon Receptor Autoimmune Diseases Autoimmunity CD4 Positive T Lymphocytes Cells Complement Cyclic GMP Dependence Disease susceptibility Environmental Pollutants Environmental Risk Factor Epitopes Event Exposure to Future Genes Genetic Risk Genetic Transcription HLA-DR Antigens Health Helper-Inducer T-Lymphocyte Immune system In Vitro Interleukin-17 Laboratories Lead Ligands Mediating Molecular Mus NF-kappa B Nitric Oxide Nuclear Translocation Osteoclasts Oxidative Stress Pathway interactions Patients Phase Play Public Health Reagent Receptor Signaling Research Research Personnel Rheumatoid Arthritis Role Signal Transduction Signal Transduction Pathway Small Interfering RNA Source Tetrachlorodibenzodioxin Transgenic Mice Wild Type Mouse Xenobiotics aryl hydrocarbon receptor ligand autoimmune arthritis base calreticulin cytokine disorder risk gene environment interaction genetic risk factor human disease in vivo inhibitor/antagonist insight mouse Ahr protein novel pollutant receptor research study synergism transcription factor

项目摘要

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 ß 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-κB) 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（由适用提供）：尚不清楚类风湿关节炎（RA）的遗传和环境风险因素的机制。该实验室最近获得了对RA（共享表位（SE））主要遗传危险因素的作用方式的新型机械见解。 The investigators have recently demonstrated that the SE, a 5-amino acid sequence motif in the HLA-DR ß chain shared by the majority of RA patients, acts as an innate immuno 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.有趣的是，芳基烃受体（AHR）是一种综合的转录因子，介导了许多污染物的异种作用，其他人已经显示出激活类似的生物学作用。在AHR和SE配体的作用方式之间的相似之处，以及SE与RA疾病风险中对环境污染物暴露的流行病学有据可查的协同作用，研究人员进行了初步实验，以确定SE和AHR途径在自身免疫性促进炎中是否相互作用。研究结果表明，SE配体和AHR途径激动剂会产生累加或乘生物学作用，从而导致破骨细胞分化，TH17极化和更严重的侵蚀性关节炎。另外，初步发现表明SE激活了核因子Kappa B（NF-κB）途径。在这个项目中，研究人员将确定两种相关途径作为探索阶段的层次结构和相互依存关系，然后再启动未来参与SE-AHR相互作用的分子机制的详细表征。成功完成此处提出的研究可能会为我们促进我们对与环境污染物相关的自身免疫的机制的理解打开大门。