%0 Journal Article %A Jie-Sen Zhou %A Zhou-Yang Li %A Xu-Chen Xu %A Yun Zhao %A Yong Wang %A Hai-Pin Chen %A Min Zhang %A Yin-Fang Wu %A Tian-Wen Lai %A Chun-Hong Di %A Ling-Ling Dong %A Juan Liu %A Nan-Xia Xuan %A Chen Zhu %A Yan-Ping Wu %A Hua-Qiong Huang %A Fu-Gui Yan %A Wen Hua %A Yi Wang %A Wei-Ning Xiong %A Hui Qiu %A Tao Chen %A Dong Weng %A Hui-Ping Li %A Xiaobo Zhou %A Lie Wang %A Fang Liu %A Xin Lin %A Song-Min Ying %A Wen Li %A Mitsuru Imamura %A Mary E. Choi %A Martin R. Stampfli %A Augustine M.K. Choi %A Zhi-Hua Chen %A Hua-Hao Shen %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 https://erj.ersjournals.com/content/erj/56/3/2000404.full.pdf