% 0期刊文章%周,Jie-Sen %李,Zhou-Yang %A Xu, Xu-Chen %A Zhao, Yun %A Wang, Yong %A Chen, Hai-Pin %A Zhang, Min %A Wu, Yin-Fang %A Lai, Tian-Wen %A Di, Chun-Hong %A Dong, Ling-Ling %A Liu, Juan %A Xuan, Nan-Xia %A Zhu, Chen %A Wu, Yan-Ping %A Huang, Hua-Qiong %A Yan, Fu-Gui %A Hua, Wen %A Wang, Yi %A Xiong, Wei-Ning %A Qiu, Hui %A Chen, Tao %A Weng, Dong %A Li, Hui-Ping %A Zhou, Xiaobo %A Wang, Lie %A Liu, Fang %A Lin, Xin %A Ying, Song-Min %A Li, Wen %A Imamura, Mitsuru %A Choi, Mary E. %A Stampfli, Martin R. %A Choi, Augustine M.K. %A Chen, Zhi-Hua %A Shen, Hua-Hao %T Cigarette smoke-initiated autoimmunity facilitates sensitisation to elastin-induced COPD-like pathologies in mice %D 2020 %R 10.1183/13993003.00404-2020 %J European Respiratory Journal %P 2000404 %V 56 %N 3 %X 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−/−, Mmp12−/−, 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.MMP12-generated elastin fragments serve as a self-antigen and drive cigarette smoke-induced autoimmune processes in mice. These findings provide experimental evidence for cigarette smoke-induced autoimmunity and represent a novel mouse model of COPD. https://bit.ly/2XK9dC6 %U //www.qdcxjkg.com/content/erj/56/3/2000404.full.pdf