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.

项目摘要 类风湿关节炎（RA）是一种经典涉及关节的自身免疫性疾病。肺并发症 是RA死亡率的常见和主要因素。 RA的疗法发生尚不清楚。低 单卵双胞胎中RA的一致性（15％）表明环境因素在RA中的重要性。 二手烟或环境烟草烟雾（ETS）对两者都是重要的环境危害 儿童和成人，但儿童特别容易受到影响。肠道微生物群是另一个潜在的环境 疾病的触发因素。我们报道了分割的丝状细菌（SFB），一种肠道分配， 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，我们的最新数据 证明来自赞助性关节炎患者的人类共生大肠杆菌分离株2A（称为E.COLI 2A） 还会引起自身免疫增强。在环境前线激活的免疫细胞，粘膜， 共享类似的归巢受体，因此从一个粘膜部位激活的淋巴细胞可以回家 粘膜组织。基于这个“常见的粘膜免疫系统”原则，我们假设ETS和 肠道的肠道菌群串扰在肺轴的粘膜接口处 肺中的自身抗体（自动AB）反应，引发与RA相关的肺部疾病 全身性关节疾病。我们将通过确定：1）在少年和成年K/BXN小鼠中检验我们的假设：1） 基于年龄的窗口和ETS介导的Th17响应的ETS介导的肺轴的机制， SFB或E.Coli 2a; 2）ETS-和SFB-（或E.COLI 2A-）的作用 引起自动侵入和疾病。值得注意的是，我们的新数据通过证明强大的 SFB诱导的Th17响应伴随着肺中的自动AB水平高于Sleen，器官 传统上，在K/BXN小鼠中被认为是主要的自动生产位点。接下来，我们将确定 通过控制生存，增殖，基础ETS和微生物群介导的TH17反应的机制 分化和/或募集Th17细胞；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以及从儿童期暴露到ET的探测器效应而存在 可以持续一生，我们还将检查ETS停止后的TH17响应。当Th17细胞帮助B细胞时 在K/BXN小鼠中分化，我们假设ETS和微生物群介导的肺Th17细胞可能引起 诱导自动ABS的肺部疾病。我们将进行临时比较，并期望ETS和 微生物群将诱导较早的Th17反应，这是通过在肺中B细胞分化完成的 脾。我们将使用病原和非病原性TH17细胞的Th17消融和分子特征 研究Th17细胞在ETS/微生物群诱导的自身免疫性中的作用。粘膜免疫调节仍然存在 不了解，但非常重要，因为粘膜具有前线的免疫反应 环境刺激及其相互作用随后可以塑造粘膜和全身性疾病。