Cigarette smoke-initiated autoimmunity facilitates sensitisation to elastin-induced COPD-like pathologies in mice

Jie Sen Zhou, Zhou Yang Li, Xu Chen Xu, Yun Zhao, Yong Wang, Hai Pin Chen, Min Zhang, Yin Fang Wu, Tian Wen Lai, Chun Hong Di, Ling Ling Dong, Juan Liu, Nan Xia Xuan, Chen Zhu, Yan Ping Wu, Hua Qiong Huang, Fu Gui Yan, Wen Hua, Yi Wang, Wei Ning XiongHui Qiu, Tao Chen, Dong Weng, Hui Ping Li, Xiaobo Zhou, Lie Wang, Fang Liu, Xin Lin, Song Min Ying, Wen Li, Mitsuru Imamura, Mary E. Choi, Martin R. Stampfli, Augustine M.K. Choi, Zhi Hua Chen, Hua Hao Shen

Research output: Contribution to journalArticlepeer-review

19 Scopus citations


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.

Original languageEnglish (US)
Article number2000404
JournalEuropean Respiratory Journal
Issue number3
StatePublished - Sep 1 2020

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine


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