1. Cigarette smoke-initiated autoimmunity facilitates sensitisation to elastin-induced COPD-like pathologies in mice
- Author
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Hai Pin Chen, Wen Li, Min Zhang, Mary E. Choi, Songmin Ying, Nan Xia Xuan, Yanping Wu, Ling Ling Dong, Hui Ping Li, Juan Liu, Martin R. Stämpfli, Jie Sen Zhou, Hui Qiu, Lie Wang, Hua Qiong Huang, Yi Wang, Dong Weng, Wei Ning Xiong, Xiaobo Zhou, Xu Chen Xu, Zhihua Chen, Yin Fang Wu, Wen Hua, Tao Chen, Fang Liu, Chen Zhu, Yun Zhao, Mitsuru Imamura, Xin Lin, Augustine M.K. Choi, Fu Gui Yan, Chun Hong Di, Zhou-Yang Li, Yong Wang, Tianwen Lai, and Huahao Shen
- Subjects
0301 basic medicine ,Pulmonary and Respiratory Medicine ,T cell ,Autoimmunity ,Human leukocyte antigen ,medicine.disease_cause ,03 medical and health sciences ,Mice ,Pulmonary Disease, Chronic Obstructive ,0302 clinical medicine ,Immune system ,Smoke ,Medicine ,Animals ,Humans ,Lung ,COPD ,biology ,business.industry ,Smoking ,medicine.disease ,Mucus ,Elastin ,Mice, Inbred C57BL ,Disease Models, Animal ,030104 developmental biology ,medicine.anatomical_structure ,030228 respiratory system ,Immunology ,biology.protein ,Antibody ,business - 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.
- Published
- 2019