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Published in: Respiratory Research 1/2020

01-12-2020 | Bronchoscopy | Research

Airway regulatory T cells are decreased in COPD with a rapid decline in lung function

Authors: Jonas Eriksson Ström, Jamshid Pourazar, Robert Linder, Anders Blomberg, Anne Lindberg, Anders Bucht, Annelie F. Behndig

Published in: Respiratory Research | Issue 1/2020

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Abstract

Background

Differences in the expression of regulatory T cells (Tregs) have been suggested to explain why some smokers develop COPD and some do not. Upregulation of Tregs in response to smoking would restrain airway inflammation and thus the development of COPD; while the absense of such upregulation would over time lead to chronic inflammation and COPD. We hypothesized that—among COPD patients—the same mechanism would affect rate of decline in lung function; specifically, that a decreased expression of Tregs would be associated with a more rapid decline in FEV1.

Methods

Bronchoscopy with BAL was performed in 52 subjects recruited from the longitudinal OLIN COPD study; 12 with COPD and a rapid decline in lung function (loss of FEV1 ≥ 60 ml/year), 10 with COPD and a non-rapid decline in lung function (loss of FEV1 ≤ 30 ml/year), 15 current and ex-smokers and 15 non-smokers with normal lung function. BAL lymphocyte subsets were determined using flow cytometry.

Results

The proportions of Tregs with regulatory function (FoxP3+/CD4+CD25bright) were significantly lower in COPD subjects with a rapid decline in lung function compared to those with a non-rapid decline (p = 0.019). This result was confirmed in a mixed model regression analysis in which adjustments for inhaled corticosteroid usage, smoking, sex and age were evaluated. No significant difference was found between COPD subjects and smokers or non-smokers with normal lung function.

Conclusions

COPD subjects with a rapid decline in lung function had lower proportions of T cells with regulatory function in BAL fluid, suggesting that an inability to suppress the inflammatory response following smoking might lead to a more rapid decline in FEV1.
Trial registration Clinicaltrials.gov identifier NCT02729220
Appendix
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Literature
1.
go back to reference Barceló B, Pons J, Ferrer JM, Sauleda J, Fuster A, Agustí AGN. Phenotypic characterisation of T-lymphocytes in COPD: abnormal CD4+CD25+ regulatory T-lymphocyte response to tobacco smoking. Eur Respir J. 2008;31:555–62.CrossRefPubMed Barceló B, Pons J, Ferrer JM, Sauleda J, Fuster A, Agustí AGN. Phenotypic characterisation of T-lymphocytes in COPD: abnormal CD4+CD25+ regulatory T-lymphocyte response to tobacco smoking. Eur Respir J. 2008;31:555–62.CrossRefPubMed
2.
go back to reference Hogg JC. Pathophysiology of airflow limitation in chronic obstructive pulmonary disease. Lancet. 2004;364:709–21.CrossRefPubMed Hogg JC. Pathophysiology of airflow limitation in chronic obstructive pulmonary disease. Lancet. 2004;364:709–21.CrossRefPubMed
3.
go back to reference Saetta M, Di Stefano A, Turato G, Facchini FM, Corbino L, Mapp CE, et al. CD8+ T-lymphocytes in peripheral airways of smokers with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 1998;157:822–6.CrossRefPubMed Saetta M, Di Stefano A, Turato G, Facchini FM, Corbino L, Mapp CE, et al. CD8+ T-lymphocytes in peripheral airways of smokers with chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 1998;157:822–6.CrossRefPubMed
4.
go back to reference Eriksson Ström J, Pourazar J, Linder R, Blomberg A, Lindberg A, Bucht A, et al. Cytotoxic lymphocytes in COPD airways: increased NK cells associated with disease, iNKT and NKT-like cells with current smoking. Respir Res. 2018;19:244.CrossRefPubMedCentralPubMed Eriksson Ström J, Pourazar J, Linder R, Blomberg A, Lindberg A, Bucht A, et al. Cytotoxic lymphocytes in COPD airways: increased NK cells associated with disease, iNKT and NKT-like cells with current smoking. Respir Res. 2018;19:244.CrossRefPubMedCentralPubMed
5.
go back to reference Lane N, Robins RA, Corne J, Fairclough L. Regulation in chronic obstructive pulmonary disease: the role of regulatory T-cells and Th17 cells. Clin Sci. 2010;119:75–86.CrossRef Lane N, Robins RA, Corne J, Fairclough L. Regulation in chronic obstructive pulmonary disease: the role of regulatory T-cells and Th17 cells. Clin Sci. 2010;119:75–86.CrossRef
6.
go back to reference Smyth LJC, Starkey C, Vestbo J, Singh D. CD4-regulatory cells in COPD patients. Chest. 2007;132:156–63.CrossRefPubMed Smyth LJC, Starkey C, Vestbo J, Singh D. CD4-regulatory cells in COPD patients. Chest. 2007;132:156–63.CrossRefPubMed
7.
go back to reference Roos-Engstrand E, Ekstrand-Hammarström B, Pourazar J, Behndig AF, Bucht A, Blomberg A. Influence of smoking cessation on airway T lymphocyte subsets in COPD. J Chronic Obstr Pulm Dis. 2009;6:112–20.CrossRef Roos-Engstrand E, Ekstrand-Hammarström B, Pourazar J, Behndig AF, Bucht A, Blomberg A. Influence of smoking cessation on airway T lymphocyte subsets in COPD. J Chronic Obstr Pulm Dis. 2009;6:112–20.CrossRef
8.
go back to reference Roos-Engstrand E, Pourazar J, Behndig AF, Bucht A, Blomberg A. Expansion of CD4+CD25+ helper T cells without regulatory function in smoking and COPD. Respir Res. 2011;12:74.CrossRefPubMedCentralPubMed Roos-Engstrand E, Pourazar J, Behndig AF, Bucht A, Blomberg A. Expansion of CD4+CD25+ helper T cells without regulatory function in smoking and COPD. Respir Res. 2011;12:74.CrossRefPubMedCentralPubMed
9.
go back to reference Lindberg A, Lundbäck B. The obstructive lung disease in northern sweden chronic obstructive pulmonary disease study: design, the first year participation and mortality. Clin Respir J. 2008;2:64–71.CrossRefPubMed Lindberg A, Lundbäck B. The obstructive lung disease in northern sweden chronic obstructive pulmonary disease study: design, the first year participation and mortality. Clin Respir J. 2008;2:64–71.CrossRefPubMed
10.
go back to reference Lindberg A, Linder R, Backman H, Eriksson Ström J, Frølich A, Nilsson U, et al. From COPD epidemiology to studies of pathophysiological disease mechanisms: challenges with regard to study design and recruitment process: respiratory and cardiovascular effects in COPD (KOLIN). Eur Clin Respir J. 2017;4:1415095.CrossRefPubMedCentralPubMed Lindberg A, Linder R, Backman H, Eriksson Ström J, Frølich A, Nilsson U, et al. From COPD epidemiology to studies of pathophysiological disease mechanisms: challenges with regard to study design and recruitment process: respiratory and cardiovascular effects in COPD (KOLIN). Eur Clin Respir J. 2017;4:1415095.CrossRefPubMedCentralPubMed
11.
go back to reference Vogelmeier CF, Criner GJ, Martinez FJ, Anzueto A, Barnes PJ, Bourbeau J, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive lung disease 2017 report. GOLD executive summary. Am J Respir Crit Care Med. 2017;2017:557–82.CrossRef Vogelmeier CF, Criner GJ, Martinez FJ, Anzueto A, Barnes PJ, Bourbeau J, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive lung disease 2017 report. GOLD executive summary. Am J Respir Crit Care Med. 2017;2017:557–82.CrossRef
12.
go back to reference Standardization of Spirometry. Update. American Thoracic Society. Am J Respir Crit Care Med. 1994;1995:1107–36. Standardization of Spirometry. Update. American Thoracic Society. Am J Respir Crit Care Med. 1994;1995:1107–36.
13.
go back to reference Berglund E, Birath G, Bjure J, Grimby G, Kjellmer I, Sandqvist L, et al. Spirometric studies in normal subjects I. Acta Med Scand. 1963;173:185–92.CrossRefPubMed Berglund E, Birath G, Bjure J, Grimby G, Kjellmer I, Sandqvist L, et al. Spirometric studies in normal subjects I. Acta Med Scand. 1963;173:185–92.CrossRefPubMed
14.
go back to reference Higashimoto Y, Iwata T, Okada M, Satoh H, Fukuda K, Tohda Y. Serum biomarkers as predictors of lung function decline in chronic obstructive pulmonary disease. Respir Med. 2009;103:1231–8.CrossRefPubMed Higashimoto Y, Iwata T, Okada M, Satoh H, Fukuda K, Tohda Y. Serum biomarkers as predictors of lung function decline in chronic obstructive pulmonary disease. Respir Med. 2009;103:1231–8.CrossRefPubMed
15.
go back to reference Sales DS, Ito JT, Zanchetta IA, Annoni R, Aun MV, Ferraz LFS, et al. Regulatory T-cell distribution within lung compartments in COPD. COPD. 2017;14:533–42.CrossRefPubMed Sales DS, Ito JT, Zanchetta IA, Annoni R, Aun MV, Ferraz LFS, et al. Regulatory T-cell distribution within lung compartments in COPD. COPD. 2017;14:533–42.CrossRefPubMed
16.
go back to reference Lamprecht B, Soriano JB, Studnicka M, Kaiser B, Vanfleteren LE, Gnatiuc L, et al. Determinants of underdiagnosis of COPD in national and international surveys. Chest. 2015;148:971–85.CrossRefPubMed Lamprecht B, Soriano JB, Studnicka M, Kaiser B, Vanfleteren LE, Gnatiuc L, et al. Determinants of underdiagnosis of COPD in national and international surveys. Chest. 2015;148:971–85.CrossRefPubMed
17.
go back to reference Danielsson P, Ólafsdóttir IS, Benediktsdóttir B, Gíslason T, Janson C. The prevalence of chronic obstructive pulmonary disease in Uppsala, Sweden—the Burden of Obstructive Lung Disease (BOLD) study: cross-sectional population-based study. Clin Respir J. 2012;6:120–7.CrossRefPubMed Danielsson P, Ólafsdóttir IS, Benediktsdóttir B, Gíslason T, Janson C. The prevalence of chronic obstructive pulmonary disease in Uppsala, Sweden—the Burden of Obstructive Lung Disease (BOLD) study: cross-sectional population-based study. Clin Respir J. 2012;6:120–7.CrossRefPubMed
19.
go back to reference Pace E, Di Sano C, La Grutta S, Ferraro M, Albeggiani G, Liotta G, et al. Multiple in vitro and in vivo regulatory effects of budesonide in CD4+ T lymphocyte subpopulations of allergic asthmatics. PLoS ONE. 2012;7:e48816.CrossRefPubMedCentralPubMed Pace E, Di Sano C, La Grutta S, Ferraro M, Albeggiani G, Liotta G, et al. Multiple in vitro and in vivo regulatory effects of budesonide in CD4+ T lymphocyte subpopulations of allergic asthmatics. PLoS ONE. 2012;7:e48816.CrossRefPubMedCentralPubMed
20.
go back to reference Karagiannidis C, Akdis M, Holopainen P, Woolley NJ, Hense G, Rückert B, et al. Glucocorticoids upregulate FOXP3 expression and regulatory T cells in asthma. J Allergy Clin Immunol. 2004;114:1425–33.CrossRefPubMed Karagiannidis C, Akdis M, Holopainen P, Woolley NJ, Hense G, Rückert B, et al. Glucocorticoids upregulate FOXP3 expression and regulatory T cells in asthma. J Allergy Clin Immunol. 2004;114:1425–33.CrossRefPubMed
21.
go back to reference Agustí A, Hogg JC. Update on the pathogenesis of chronic obstructive pulmonary disease. N Engl J Med. 2019;381:1248–56.CrossRefPubMed Agustí A, Hogg JC. Update on the pathogenesis of chronic obstructive pulmonary disease. N Engl J Med. 2019;381:1248–56.CrossRefPubMed
22.
go back to reference Friedlander AL, Lynch D, Dyar LA, Bowler RP. Phenotypes of chronic obstructive pulmonary disease. J Chronic Obstr Pulm Dis. 2007;4:355–84.CrossRef Friedlander AL, Lynch D, Dyar LA, Bowler RP. Phenotypes of chronic obstructive pulmonary disease. J Chronic Obstr Pulm Dis. 2007;4:355–84.CrossRef
23.
go back to reference Koskela J, Katajisto M, Kallio A, Kilpeläinen M, Lindqvist A, Laitinen T. Individual FEV 1trajectories can be identified from a COPD cohort. J Chronic Obstr Pulm Dis. 2016;13:425–30.CrossRef Koskela J, Katajisto M, Kallio A, Kilpeläinen M, Lindqvist A, Laitinen T. Individual FEV 1trajectories can be identified from a COPD cohort. J Chronic Obstr Pulm Dis. 2016;13:425–30.CrossRef
24.
25.
go back to reference Kim C, Park YB, Park SY, Park S, Kim C-H, Park SM, et al. COPD patients with exertional desaturation are at a higher risk of rapid decline in lung function. Yonsei Med J. 2014;55:732–8.CrossRefPubMedCentralPubMed Kim C, Park YB, Park SY, Park S, Kim C-H, Park SM, et al. COPD patients with exertional desaturation are at a higher risk of rapid decline in lung function. Yonsei Med J. 2014;55:732–8.CrossRefPubMedCentralPubMed
26.
go back to reference Devanarayan V, Scholand M-B, Hoidal J, Leppert MF, Crackower MA, O’Neill GP, et al. Identification of distinct plasma biomarker signatures in patients with rapid and slow declining forms of COPD. COPD. 2010;7:51–8.CrossRefPubMed Devanarayan V, Scholand M-B, Hoidal J, Leppert MF, Crackower MA, O’Neill GP, et al. Identification of distinct plasma biomarker signatures in patients with rapid and slow declining forms of COPD. COPD. 2010;7:51–8.CrossRefPubMed
27.
go back to reference Lindberg A, Larsson L-G, Rönmark E, Jonsson A-C, Larsson K, Lundbäck B. Decline in FEV1 in relation to incident chronic obstructive pulmonary disease in a cohort with respiratory symptoms. J Chronic Obstr Pulm Dis. 2007;4:5–13.CrossRef Lindberg A, Larsson L-G, Rönmark E, Jonsson A-C, Larsson K, Lundbäck B. Decline in FEV1 in relation to incident chronic obstructive pulmonary disease in a cohort with respiratory symptoms. J Chronic Obstr Pulm Dis. 2007;4:5–13.CrossRef
28.
go back to reference Nishimura M, Makita H, Nagai K, Konno S, Nasuhara Y, Hasegawa M, et al. Annual change in pulmonary function and clinical phenotype in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2012;185:44–52.CrossRefPubMed Nishimura M, Makita H, Nagai K, Konno S, Nasuhara Y, Hasegawa M, et al. Annual change in pulmonary function and clinical phenotype in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2012;185:44–52.CrossRefPubMed
29.
go back to reference Chiappori A, Folli C, Balbi F, Caci E, Riccio AM, De Ferrari L, et al. CD4(+)CD25(high)CD127(-) regulatory T-cells in COPD: smoke and drugs effect. World Allergy Organ J. 2016;9:5.CrossRefPubMedCentralPubMed Chiappori A, Folli C, Balbi F, Caci E, Riccio AM, De Ferrari L, et al. CD4(+)CD25(high)CD127(-) regulatory T-cells in COPD: smoke and drugs effect. World Allergy Organ J. 2016;9:5.CrossRefPubMedCentralPubMed
30.
go back to reference Plumb J, Smyth LJC, Adams HR, Vestbo J, Bentley A, Singh SD. Increased T-regulatory cells within lymphocyte follicles in moderate COPD. Eur Respir J. 2009;34:89–94.CrossRefPubMed Plumb J, Smyth LJC, Adams HR, Vestbo J, Bentley A, Singh SD. Increased T-regulatory cells within lymphocyte follicles in moderate COPD. Eur Respir J. 2009;34:89–94.CrossRefPubMed
32.
go back to reference Forsslund H, Yang M, Mikko M, Karimi R, Nyrén S, Engvall B, et al. Gender differences in the T-cell profiles of the airways in COPD patients associated with clinical phenotypes. COPD. 2017;12:35–48.CrossRef Forsslund H, Yang M, Mikko M, Karimi R, Nyrén S, Engvall B, et al. Gender differences in the T-cell profiles of the airways in COPD patients associated with clinical phenotypes. COPD. 2017;12:35–48.CrossRef
34.
go back to reference Tai P, Wang J, Jin H, Song X, Yan J, Kang Y, et al. Induction of regulatory T cells by physiological level estrogen. J Cell Physiol. 2008;214:456–64.CrossRefPubMed Tai P, Wang J, Jin H, Song X, Yan J, Kang Y, et al. Induction of regulatory T cells by physiological level estrogen. J Cell Physiol. 2008;214:456–64.CrossRefPubMed
35.
go back to reference Forsslund H, Mikko M, Karimi R, Grunewald J, Wheelock ÅM, Wahlström J, et al. Distribution of T-cell subsets in BAL fluid of patients with mild to moderate COPD depends on current smoking status and not airway obstruction. Chest. 2014;145:711–22.CrossRefPubMed Forsslund H, Mikko M, Karimi R, Grunewald J, Wheelock ÅM, Wahlström J, et al. Distribution of T-cell subsets in BAL fluid of patients with mild to moderate COPD depends on current smoking status and not airway obstruction. Chest. 2014;145:711–22.CrossRefPubMed
36.
go back to reference Löfdahl JM, Cederlund K, Nathell L, Eklund A, Sköld CM. Bronchoalveolar lavage in COPD: fluid recovery correlates with the degree of emphysema. Eur Respir J. 2005;25:275–81.CrossRefPubMed Löfdahl JM, Cederlund K, Nathell L, Eklund A, Sköld CM. Bronchoalveolar lavage in COPD: fluid recovery correlates with the degree of emphysema. Eur Respir J. 2005;25:275–81.CrossRefPubMed
Metadata
Title
Airway regulatory T cells are decreased in COPD with a rapid decline in lung function
Authors
Jonas Eriksson Ström
Jamshid Pourazar
Robert Linder
Anders Blomberg
Anne Lindberg
Anders Bucht
Annelie F. Behndig
Publication date
01-12-2020
Publisher
BioMed Central
Published in
Respiratory Research / Issue 1/2020
Electronic ISSN: 1465-993X
DOI
https://doi.org/10.1186/s12931-020-01593-9

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