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

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.

• Authors: 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 Xiong, Hui 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
• Journal: The European respiratory journal (Eur Respir J) Vol. 56 Issue 3 (09 2020) ISSN: 1399-3003 [Electronic] England
• PMID: 32366484 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright ©ERS 2020.

Chemical References

• Smoke
• Elastin

Topics

• Animals
• Autoimmunity
• Disease Models, Animal
• Elastin
• Humans
• Lung
• Mice
• Mice, Inbred C57BL
• Pulmonary Disease, Chronic Obstructive
• Smoke (adverse effects)
• Smoking (adverse effects)