RT Journal Article SR Electronic T1 Cigarette smoke-initiated autoimmunity facilitates sensitisation to elastin-induced COPD-like pathologies in mice JF European Respiratory Journal JO Eur Respir J FD European Respiratory Society SP 2000404 DO 10.1183/13993003.00404-2020 VO 56 IS 3 A1 Jie-Sen Zhou A1 Zhou-Yang Li A1 Xu-Chen Xu A1 Yun Zhao A1 Yong Wang A1 Hai-Pin Chen A1 Min Zhang A1 Yin-Fang Wu A1 Tian-Wen Lai A1 Chun-Hong Di A1 Ling-Ling Dong A1 Juan Liu A1 Nan-Xia Xuan A1 Chen Zhu A1 Yan-Ping Wu A1 Hua-Qiong Huang A1 Fu-Gui Yan A1 Wen Hua A1 Yi Wang A1 Wei-Ning Xiong A1 Hui Qiu A1 Tao Chen A1 Dong Weng A1 Hui-Ping Li A1 Xiaobo Zhou A1 Lie Wang A1 Fang Liu A1 Xin Lin A1 Song-Min Ying A1 Wen Li A1 Mitsuru Imamura A1 Mary E. Choi A1 Martin R. Stampfli A1 Augustine M.K. Choi A1 Zhi-Hua Chen A1 Hua-Hao Shen YR 2020 UL http://erj.ersjournals.com/content/56/3/2000404.abstract AB 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