Crosstalk Between Environmental Tobacco Smoke and Gut Microbiota Shapes Autoimmune Disease by Modulating the Th17 Response of Lung-gut-axis

环境烟草烟雾与肠道微生物群之间的串扰通过调节肺肠轴的 Th17 反应塑造自身免疫性疾病

• 批准号: 9388109
• 负责人: Hsin-Jung Joyce Wu
• 金额: $ 23.03万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-15 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9388109
• 关键词: Ablation; Activated Lymphocyte; Address; Adolescent; Adult; Affect; Age; Antibody Formation; Area; Arthritis; Autoantibodies; Autoantigens; Autoimmune Diseases; Autoimmune Process; Autoimmune Responses; Autoimmunity; B cell differentiation; B-Lymphocytes; Bacteria; Bronchoalveolar Lavage; Cells; Child; Childhood; Data; Development; Diagnostic; Disease; Environmental Hazards; Environmental Risk Factor; Environmental Tobacco Smoke; Escherichia coli; Future; Glucosephosphate Isomerase; Health; Home environment; Homing; Human; IgG1; Immune; Immune response; Immune system; Industrialization; Interleukin-17; Joints; K/BxN model; Link; Location; Lung; Lung diseases; Mediating; Memory; Modeling; Molecular; Molecular Profiling; Monozygotic twins; Mucous Membrane; Mus; Organ; Pathogenicity; Patients; Play; Population; Production; Public Health; Pulmonary Pathology; Recruitment Activity; Regulatory T-Lymphocyte; Reporting; Rheumatoid Arthritis; Rheumatoid Factor; Risk; Role; Serum; Severity of illness; Shapes; Site; Smoking; Spleen; Spondylarthritis; Stimulus; Symbiosis; Systemic disease; T-Lymphocyte; Testing; Therapeutic; Transgenic Organisms; Work; arthropathies; autoimmune arthritis; base; clinically relevant; commensal microbes; differentiated B cell; environmental tobacco smoke exposure; gut microbiota; immunoregulation; insight; microbiota; mortality; mucosal site; prevent; receptor; response; theories

PROJECT SUMMARY Rheumatoid arthritis (RA) is an autoimmune disorder that classically involves joints. Pulmonary complications are common and major contributors to RA mortality. The etiopathogenesis of RA remain unclear. The low concordance rate of RA in monozygotic twins ( 15%) suggests the importance of environmental factors in RA. Secondhand smoke, or environmental tobacco smoke (ETS) is an important environmental hazard to both children and adults, but children are especially susceptible. Gut microbiota is another potential environmental trigger for disease. We have reported that segmented filamentous bacteria (SFB), a type of gut commensal, drives autoimmune arthritis by inducing Th17-mediated B cell differentiation. Excitingly, our most recent data show that a human commensal Escherichia coli isolate 2A (termed E.coli 2A) from spondyloarthritis patients also cause autoimmune augmentation. Immune cells activated at the environmental frontline, the mucosa, share similar homing receptors and thus lymphocytes activated from one mucosal site can home to other mucosal tissues. Based on this “common mucosal immune system” principle, we hypothesize that ETS and gut microbiota crosstalk at the mucosal interface of the lung-gut axis to prime the Th17-mediated autoantibody (auto-Ab) response in the lung, triggering the RA-related lung disease that sets off systemic joint disease. We will test our hypothesis in both juvenile and adult K/BxN mice by determining: 1) the age-based window and mechanism for the ETS-mediated lung-gut axis of Th17 response with and without SFB or E.coli 2A; and 2) the role of the ETS- and SFB- (or E.coli 2A-) mediated Th17 of lung-gut axis in causing auto-Abs and disease. Remarkably, our new data support our hypothesis by showing that a robust SFB-induced Th17 response is accompanied by much higher auto-Ab level in the lung than spleen, the organ traditionally considered as the primary auto-Ab producing site in K/BxN mice. Next, we will determine the mechanism underlying ETS- and microbiota-mediated Th17 response by regulating survival, proliferation, differentiation, and/or recruitment of Th17 cells; or by affecting regulatory T cells, altering Th17 response. Because Th17 can exist as long-lived memory cells and the detrimental effect from childhood-exposure to ETS can last a lifetime, we will also examine the Th17 response after ETS cessation. As Th17 cells help B cell differentiation in K/BxN mice, we hypothesize that ETS- and microbiota-mediated lung Th17 cells can cause lung disease by inducing auto-Abs. We will perform a temporal comparison, and expect that ETS and microbiota will induce an earlier Th17 response, accompanied by B cell differentiation in the lung prior to the spleen. We will use Th17 ablation and molecular signatures of pathogenic and non-pathogenic Th17 cells to study the role of Th17 cells in ETS/microbiota-induced autoimmunity. Mucosal immunoregulation remains poorly understood but is of profound importance, as the mucosa harbors the frontline immune response to environmental stimuli, and their interactions can subsequently shape both mucosal and systemic diseases.

项目总结 类风湿性关节炎(RA)是一种自身免疫性疾病，典型的累及关节。肺部并发症 是RA死亡率的常见和主要贡献者。类风湿关节炎的发病机制尚不清楚。低谷 同卵双生子RA的符合率为15%，提示环境因素在RA发病中的重要性。 二手烟或环境烟草烟雾(ETS)对两者都是一种重要的环境危害 儿童和成人都有，但儿童尤其容易感染。肠道微生物区系是另一个潜在的环境 引发疾病。我们已经报道了节段性丝状细菌(SFB)，一种肠道共生细菌， 通过诱导Th17介导的B细胞分化来驱动自身免疫性关节炎。令人兴奋的是，我们最新的数据 显示一株来自脊柱炎患者的人类共生大肠杆菌分离株2A(称为E.Coli2A) 也会导致自身免疫增强。在环境前线激活的免疫细胞，粘膜， 共享相似的归巢受体，因此从一个粘膜部位激活的淋巴细胞可以归宿到另一个粘膜部位 粘膜组织。基于这一“共同粘膜免疫系统”的原理，我们假设ETS和 肺-肠轴粘膜界面的肠道微生物区系串扰启动Th17介导的 肺内自身抗体(Auto-Ab)反应，引发RA相关肺部疾病 系统性关节疾病。我们将在幼年和成年K/BxN小鼠身上测试我们的假设，方法是确定：1) ETS介导的肺肠轴在有无Th17反应时的年龄窗口和机制 2)ETS和SFB-(或E.Coli2A-)介导的Th17在肺肠轴中的作用。 导致自身抗体和疾病。值得注意的是，我们的新数据支持了我们的假设，因为它表明 SFB诱导的Th17反应伴随着肺中的自身抗体水平远远高于器官脾中的自身抗体水平 传统上被认为是K/BxN小鼠产生自身抗体的主要部位。接下来，我们将确定 ETS和微生物区系通过调节生存，增殖， Th17细胞的分化和/或募集；或通过影响调节性T细胞，改变Th17反应。 因为Th17可以作为长寿命的记忆细胞存在，以及童年时期暴露于ETS的有害影响 可以持续一生，我们还将检测ETS停止后的Th17反应。作为Th17细胞帮助B细胞 在K/BxN小鼠中，我们假设ETS和微生物区系介导的肺Th17细胞可以导致 通过诱导自身抗体引起的肺部疾病。我们将执行时间比较，并预计ETS和 微生物区系将诱导更早的Th17反应，伴随着B细胞在肺内的分化 脾。我们将利用Th17消融和致病和非致病Th17细胞的分子特征来 研究Th17细胞在ETS/微生物区系诱导的自身免疫中的作用。粘膜免疫调节残留 人们对此知之甚少，但这一点非常重要，因为粘膜承载着一线免疫反应。 环境刺激，以及它们之间的相互作用，可随后形成粘膜和系统性疾病。