Abstract
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.
Abstract
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
Footnotes
Author contributions: Jie-Sen Zhou, Zhou-Yang Li, Xu-Chen Xu, Yun Zhao, Yong Wang, Hai-Pin Chen, Yin-Fang Wu, Min Zhang, Juan Liu, Ling-Ling Dong, Nan-Xia Xuan, Tian-Wen Lai, Chen Zhu and Yan-Ping Wu participated in data collection, analysis, and interpretation. Chun-Hong Di, Hua-Qiong Huang, Fu-Gui Yan, Wen Hua, Yi Wang, Wei-Ning Xiong, Hui Qiu, Tao Chen, Dong Weng, Hui-Ping Li, Fang Liu and Xin Lin provided materials and technical support. Xiaobo Zhou, Lie Wang, Song-Min Ying, Wen Li, M.E. Choi and M.R. Stampfli participated in critical discussion of research design and review of the manuscript. Jie-Sen Zhou, Zhou-Yang Li, A.M.K. Choi, Zhi-Hua Chen and Hua-Hao Shen participated in the conception and design of the study and wrote the manuscript.
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Conflict of interest: Jie-Sen Zhou has nothing to disclose.
Conflict of interest: Zhou-Yang Li has nothing to disclose.
Conflict of interest: Xu-Chen Xu has nothing to disclose.
Conflict of interest: Yun Zhao has nothing to disclose.
Conflict of interest: Yong Wang has nothing to disclose.
Conflict of interest: Hai-Pin Chen has nothing to disclose.
Conflict of interest: Min Zhang has nothing to disclose.
Conflict of interest: Yin-Fang Wu has nothing to disclose.
Conflict of interest: Tian-Wen Lai has nothing to disclose.
Conflict of interest: Chun-Hong Di has nothing to disclose.
Conflict of interest: Ling-Ling Dong has nothing to disclose.
Conflict of interest: Juan Liu has nothing to disclose.
Conflict of interest: Nan-Xia Xuan has nothing to disclose.
Conflict of interest: Chen Zhu has nothing to disclose.
Conflict of interest: Yan-Ping Wu has nothing to disclose.
Conflict of interest: Hua-Qiong Huang has nothing to disclose.
Conflict of interest: Fu-Gui Yan has nothing to disclose.
Conflict of interest: Wen Hua has nothing to disclose.
Conflict of interest: Yi Wang has nothing to disclose.
Conflict of interest: Wei-Ning Xiong has nothing to disclose.
Conflict of interest: Hui Qiu has nothing to disclose.
Conflict of interest: Tao Chen has nothing to disclose.
Conflict of interest: Dong Weng has nothing to disclose.
Conflict of interest: Hui-Ping Li has nothing to disclose.
Conflict of interest: Xiaobo Zhou has nothing to disclose.
Conflict of interest: Lie Wang has nothing to disclose.
Conflict of interest: Fang Liu has nothing to disclose.
Conflict of interest: Xin Lin has nothing to disclose.
Conflict of interest: Song-Min Ying has nothing to disclose.
Conflict of interest: Wen Li has nothing to disclose.
Conflict of interest: Mitsuru Imamura has nothing to disclose.
Conflict of interest: M.E. Choi has nothing to disclose.
Conflict of interest: M.R. Stampfli has nothing to disclose.
Conflict of interest: A.M.K. Choi has nothing to disclose.
Conflict of interest: Zhi-Hua Chen has nothing to disclose.
Conflict of interest: Hua-Hao Shen has nothing to disclose.
Support statement: This work was supported by the Major Projects (2016YFA0501802 to Zhi-Hua Chen) from Ministry of Science and Technology, projects (81670031 to Zhi-Hua Chen, 81930003 to Hua-Hao Shen and 8180010242 to Jie-Sen Zhou) from the National Natural Science Foundation of China, and project from US National Institutes of Health (R01 HL13219801 to M.E. Choi and A.M.K. Choi, and R01 HL132198 to A.M.K. Choi). Funding information for this article has been deposited with the Crossref Funder Registry.
- Received August 15, 2019.
- Accepted April 10, 2020.
- Copyright ©ERS 2020