Cigarette smoke-initiated autoimmunity facilitates sensitisation to elastin-induced COPD-Like pathologies in mice
Cigarette smoke-initiated autoimmunity facilitates sensitisation to elastin-induced COPD-Like pathologies in mice
复制标题
香烟烟雾引发的自身免疫促进小鼠对弹性蛋白诱导的慢性阻塞性肺病样病理的敏感性
DOI：
10.1183/13993003.00404-2020
复制
发表时间：
2020-09-01
影响因子：
24.3
通讯作者：
Shen, Hua-Hao
中科院分区：
文献类型：
--
作者：
Zhou, Jie-Sen;Li, Zhou-Yang;Shen, Hua-Hao
目前尚不清楚香烟烟雾暴露是否促进对自身抗原的敏感性，以及随之而来的自身反应性T细胞是否驱动慢性阻塞性肺病（COPD）相关的病理。休息2周后，用弹性蛋白对小鼠进行3天或1个月的气管内攻击。Rag 1（-）（/-）、Minp 12（-）（/-）和Il 17 a（-/-）小鼠和针对活性弹性蛋白片段的中和抗体用于机理研究。合成人GVAPGVGVAPGV/HLA-A*02：01四聚体以评估COPD患者中弹性蛋白特异性T细胞的存在。我们观察到2周的香烟烟雾暴露诱导了弹性蛋白特异性T细胞应答，导致弹性蛋白回忆激发后的嗜中性气道炎症和粘液分泌过多。反复弹性蛋白激发1个月后，气道重塑，肺功能下降，肺泡腔扩大。弹性蛋白特异性T细胞回忆反应呈剂量依赖性，记忆持续时间超过6个月。在T细胞缺陷型Rag 1（-/-）小鼠中进行的连续性T细胞转移和研究最终表明T细胞参与了这些过程。从机制上讲，香烟烟雾诱导的弹性蛋白特异性T细胞反应是基质金属蛋白酶（MMP）12依赖性的，而随后的免疫炎症过程是白细胞介素17 A驱动的。抗弹性蛋白抗体和弹性蛋白肽特异性T细胞在COPD患者中增加。这些数据表明，MMP 12产生的弹性蛋白片段作为自身抗原，驱动香烟烟雾诱导的小鼠自身免疫过程，导致支气管炎样表型和气道扩大。这项研究提供了香烟烟雾诱导的自身免疫过程的概念证据，并可能作为一种新的COPD小鼠模型。
It is currently not understood whether cigarette smoke exposure facilitates sensitisation to self-antigens and whether ensuing auto-reactive T cells drive chronic obstructive pulmonary disease (COPD)-associated pathologies.To address this question, mice were exposed to cigarette smoke for 2 weeks. Following a 2-week period of rest, mice were challenged intratracheally with elastin for 3 days or 1 month. Rag1(-)(/-), Minp12(-)(/-), and Il17a(-/-) mice and neutralising antibodies against active elastin fragments were used for mechanistic investigations. Human GVAPGVGVAPGV/HLA-A*02:01 tetramer was synthesised to assess the presence of elastin-specific T cells in patients with COPD.We observed that 2 weeks of cigarette smoke exposure induced an elastin-specific T cell response that led to neutrophilic airway inflammation and mucus hyperproduction following elastin recall challenge. Repeated elastin challenge for 1 month resulted in airway remodelling, lung function decline and airspace enlargement. Elastin-specific T cell recall responses were dose dependent and memory lasted for over 6 months. Adoptive T cell transfer and studies in T cells deficient Rag1(-/-)mice conclusively implicated T cells in these processes. Mechanistically, cigarette smoke exposure-induced elastin-specific T cell responses were matrix metalloproteinase (MMP)12-dependent, while the ensuing immune inflammatory processes were interleukin 17A-driven. Anti-elastin antibodies and T cells specific for elastin peptides were increased in patients with COPD.These data demonstrate that MMP12-generated elastin fragments serve as a self-antigen and drive the cigarette smoke-induced autoimmune processes in mice that result in a bronchitis-like phenotype and airspace enlargement. The study provides proof of concept of cigarette smoke-induced autoimmune processes and may serve as a novel mouse model of COPD.