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

项目摘要 类风湿性关节炎（RA）是一种自身免疫性疾病，典型地涉及关节。肺部并发症 是类风湿关节炎死亡率的常见和主要因素。RA的发病机制尚不清楚。低 单卵双生子RA诊断符合率为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）是一个重要的环境危害， 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种潜在的环境 疾病的触发器。我们已经报道了分节丝状细菌（SFB），一种肠道细菌， 通过诱导Th 17介导的B细胞分化驱动自身免疫性关节炎。令人兴奋的是，我们最新的数据 显示来自脊椎关节炎患者人大肠杆菌分离物2A（称为E.coli 2A 也会导致自身免疫增强免疫细胞在环境前线，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巢到另一个 粘膜组织基于这一“共同粘膜免疫系统”原理，我们假设ETS和 在肺-肠轴的粘膜界面处的肠道微生物群串扰以引发Th 17介导的 肺中的自身抗体（自身抗体）反应，引发RA相关的肺部疾病， 全身性关节疾病。我们将在幼年和成年K/BxN小鼠中测试我们的假设，通过确定： ETS介导的Th 17应答的肺肠轴的基于年龄的窗口和机制， SFB或大肠杆菌2A;和2）ETS-和SFB-（或大肠杆菌2A-）介导的肺-肠轴Th 17的作用， 导致自身抗体和疾病值得注意的是，我们的新数据支持我们的假设，表明一个强大的 SFB诱导的Th 17应答伴随着肺中比脾高得多的自身抗体水平， 传统上被认为是K/BxN小鼠中主要的自身抗体产生位点。接下来，我们将确定 ETS和微生物群介导的Th 17应答的潜在机制通过调节存活、增殖 分化和/或募集Th 17细胞;或通过影响调节性T细胞，改变Th 17应答。 因为Th 17可以作为长寿的记忆细胞存在，儿童时期暴露于ETS的有害影响 可以持续一生，我们还将检查ETS停止后的Th 17反应。因为Th 17细胞帮助B细胞 在K/BxN小鼠中，我们假设ETS和微生物介导的肺Th 17细胞可以引起 通过诱导自身抗体引起的肺部疾病。我们将进行时间比较，并期望ETS和 微生物群将诱导更早的Th 17应答，伴随着在Th 17应答之前肺中的B细胞分化。 脾脏我们将使用Th 17消融和致病性和非致病性Th 17细胞的分子特征， 研究Th 17细胞在ETS/微生物群诱导的自身免疫中的作用。粘液免疫调节仍然存在 人们对此知之甚少，但它具有深远的重要性，因为粘膜具有前线免疫反应， 环境刺激及其相互作用可随后形成粘膜和全身性疾病。

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.