Skip to main content
Top
Published in: Respiratory Research 1/2018

Open Access 01-12-2018 | Research

Cytotoxic lymphocytes in COPD airways: increased NK cells associated with disease, iNKT and NKT-like cells with current smoking

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

Published in: Respiratory Research | Issue 1/2018

Login to get access

Abstract

Background

Cytotoxic lymphocytes are increased in the airways of COPD patients. Whether this increase is driven primarily by the disease or by smoking is not clear, nor whether it correlates with the rate of decline in lung function.

Methods

Bronchoscopy with BAL was performed in 52 subjects recruited from the longitudinal OLIN COPD study according to pre-determined criteria; 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

In BAL fluid, the proportions of NK, iNKT and NKT-like cells all increased with pack-years. Within the COPD group, NK cells – but not iNKT or NKT-like cells – were significantly elevated also in subjects that had quit smoking. In contrast, current smoking was associated with a marked increase in iNKT and NKT-like cells but not in NK cells. Rate of lung function decline did not significantly affect any of the results.

Conclusions

In summary, increased proportions of NK cells in BAL fluid were associated with COPD; iNKT and NKT-like cells with current smoking but not with COPD. Interestingly, NK cell percentages did not normalize in COPD subjects that had quit smoking, indicating that these cells might play a role in the continued disease progression seen in COPD even after smoking cessation.

Trial registration

Clinicaltrials.gov identifier NCT02729220.
Appendix
Available only for authorised users
Literature
1.
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
2.
go back to reference Traves SL, Smith SJ, Barnes PJ, Donnelly LE. Specific CXC but not CC chemokines cause elevated monocyte migration in COPD: a role for CXCR2. J Leukoc Biol Society for Leukocyte Biology. 2004;76:441–50.CrossRef Traves SL, Smith SJ, Barnes PJ, Donnelly LE. Specific CXC but not CC chemokines cause elevated monocyte migration in COPD: a role for CXCR2. J Leukoc Biol Society for Leukocyte Biology. 2004;76:441–50.CrossRef
3.
go back to reference Barnes PJ. Alveolar macrophages as orchestrators of COPD. COPD: J Chron Obstruct Pulmon Dis. 2004;1:59–70.CrossRef Barnes PJ. Alveolar macrophages as orchestrators of COPD. COPD: J Chron Obstruct Pulmon Dis. 2004;1:59–70.CrossRef
4.
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
5.
go back to reference Roos-Engstrand E, Pourazar J, Behndig AF, Blomberg A, Bucht A. Cytotoxic T cells expressing the co-stimulatory receptor NKG2 D are increased in cigarette smoking and COPD. Respir Res. 2010;11:S17–1.CrossRef Roos-Engstrand E, Pourazar J, Behndig AF, Blomberg A, Bucht A. Cytotoxic T cells expressing the co-stimulatory receptor NKG2 D are increased in cigarette smoking and COPD. Respir Res. 2010;11:S17–1.CrossRef
6.
go back to reference Rovina N, Koutsoukou A, Koulouris NG. Inflammation and immune response in COPD: where do we stand? Mediat Inflamm. 2013;2013:413735–9.CrossRef Rovina N, Koutsoukou A, Koulouris NG. Inflammation and immune response in COPD: where do we stand? Mediat Inflamm. 2013;2013:413735–9.CrossRef
7.
go back to reference Kim EY, Battaile JT, Patel AC, You Y, Agapov E, Grayson MH, et al. Persistent activation of an innate immune response translates respiratory viral infection into chronic lung disease. Nat Med. 2008;14:633–40.CrossRefPubMedPubMedCentral Kim EY, Battaile JT, Patel AC, You Y, Agapov E, Grayson MH, et al. Persistent activation of an innate immune response translates respiratory viral infection into chronic lung disease. Nat Med. 2008;14:633–40.CrossRefPubMedPubMedCentral
8.
go back to reference Godfrey DI, MacDonald HR, Kronenberg M, Smyth MJ, Van Kaer L. Opinion: NKT cells: what's in a name? Nat Rev Immunol. 2004;4:231–7.CrossRefPubMed Godfrey DI, MacDonald HR, Kronenberg M, Smyth MJ, Van Kaer L. Opinion: NKT cells: what's in a name? Nat Rev Immunol. 2004;4:231–7.CrossRefPubMed
9.
go back to reference Tang Y. Increased numbers of NK cells, NKT-like cells, and NK inhibitory receptors in peripheral blood of patients with chronic obstructive pulmonary disease. Chest. 2016;149:A380.CrossRef Tang Y. Increased numbers of NK cells, NKT-like cells, and NK inhibitory receptors in peripheral blood of patients with chronic obstructive pulmonary disease. Chest. 2016;149:A380.CrossRef
10.
go back to reference Stockley RA, Mannino D, Barnes PJ. Burden and pathogenesis of chronic obstructive pulmonary disease. Proc Am Thorac Soc. 2009;6:524–6.CrossRefPubMed Stockley RA, Mannino D, Barnes PJ. Burden and pathogenesis of chronic obstructive pulmonary disease. Proc Am Thorac Soc. 2009;6:524–6.CrossRefPubMed
11.
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. COPD: J Chron Obstruct Pulmon 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. COPD: J Chron Obstruct Pulmon Dis. 2016;13:425–30.CrossRef
12.
go back to reference Friedlander AL, Lynch D, Dyar LA, Bowler RP. Phenotypes of chronic obstructive pulmonary disease. COPD. 2007;4:355–84.CrossRefPubMed Friedlander AL, Lynch D, Dyar LA, Bowler RP. Phenotypes of chronic obstructive pulmonary disease. COPD. 2007;4:355–84.CrossRefPubMed
13.
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
14.
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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
15.
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;195:557–82. 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;195:557–82.
16.
go back to reference Standardization of Spirometry, 1994 Update. American Thoracic Society. Am J Respir Crit Care Med. 1995;152:1107–36. Standardization of Spirometry, 1994 Update. American Thoracic Society. Am J Respir Crit Care Med. 1995;152:1107–36.
17.
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. 2009;173:185–92.CrossRef Berglund E, Birath G, Bjure J, Grimby G, Kjellmer I, Sandqvist L, et al. Spirometric studies in Normal subjects I. Acta Med Scand. 2009;173:185–92.CrossRef
18.
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.CrossRefPubMedPubMedCentral 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.CrossRefPubMedPubMedCentral
19.
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
20.
go back to reference Hodge G, Mukaro V, Holmes M, Reynolds PN, Hodge S. Enhanced cytotoxic function of natural killer and natural killer T-like cells associated with decreased CD94 (Kp43) in the chronic obstructive pulmonary disease airway. Respirology. 2013;18:369–76.CrossRefPubMed Hodge G, Mukaro V, Holmes M, Reynolds PN, Hodge S. Enhanced cytotoxic function of natural killer and natural killer T-like cells associated with decreased CD94 (Kp43) in the chronic obstructive pulmonary disease airway. Respirology. 2013;18:369–76.CrossRefPubMed
21.
go back to reference Hansen MJ, Chan SPJ, Langenbach SY, Dousha LF, Jones JE, Yatmaz S, et al. IL-17A and serum amyloid A are elevated in a cigarette smoke cessation model associated with the persistence of pigmented macrophages, neutrophils and activated NK cells. PLoS ONE. 2014;9:e113180.CrossRefPubMedPubMedCentral Hansen MJ, Chan SPJ, Langenbach SY, Dousha LF, Jones JE, Yatmaz S, et al. IL-17A and serum amyloid A are elevated in a cigarette smoke cessation model associated with the persistence of pigmented macrophages, neutrophils and activated NK cells. PLoS ONE. 2014;9:e113180.CrossRefPubMedPubMedCentral
22.
go back to reference Freeman CM, Stolberg VR, Crudgington S, Martinez FJ, Han MK, Chensue SW, et al. Human CD56+ cytotoxic lung lymphocytes kill autologous lung cells in chronic obstructive pulmonary disease. PLoS ONE. 2014;9:e103840.CrossRefPubMedPubMedCentral Freeman CM, Stolberg VR, Crudgington S, Martinez FJ, Han MK, Chensue SW, et al. Human CD56+ cytotoxic lung lymphocytes kill autologous lung cells in chronic obstructive pulmonary disease. PLoS ONE. 2014;9:e103840.CrossRefPubMedPubMedCentral
23.
go back to reference Finch DK, Stolberg VR, Ferguson J, Alikaj H, Kady MR, Richmond BW, et al. Lung Dendritic Cells Drive NK Cytotoxicity in Chronic Obstructive Pulmonary Disease via IL-15Rα. Am J Respir Crit Care Med. 2018;198:1140-50. rccm.201712–2513OC. Finch DK, Stolberg VR, Ferguson J, Alikaj H, Kady MR, Richmond BW, et al. Lung Dendritic Cells Drive NK Cytotoxicity in Chronic Obstructive Pulmonary Disease via IL-15Rα. Am J Respir Crit Care Med. 2018;198:1140-50. rccm.201712–2513OC.
24.
go back to reference Pichavant M, Rémy G, Bekaert S, Le Rouzic O, Kervoaze G, Vilain E, et al. Oxidative stress-mediated iNKT-cell activation is involved in COPD pathogenesis. Mucosal Immunol. 2014;7:568–78.CrossRefPubMed Pichavant M, Rémy G, Bekaert S, Le Rouzic O, Kervoaze G, Vilain E, et al. Oxidative stress-mediated iNKT-cell activation is involved in COPD pathogenesis. Mucosal Immunol. 2014;7:568–78.CrossRefPubMed
25.
go back to reference Tsao C-C, Tsao P-N, Chen Y-G, Chuang Y-H. Repeated activation of lung invariant NKT cells results in chronic obstructive pulmonary disease-like symptoms. PLoS One. 2016;11:e0147710.CrossRefPubMedPubMedCentral Tsao C-C, Tsao P-N, Chen Y-G, Chuang Y-H. Repeated activation of lung invariant NKT cells results in chronic obstructive pulmonary disease-like symptoms. PLoS One. 2016;11:e0147710.CrossRefPubMedPubMedCentral
26.
27.
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
28.
go back to reference Faner R, Gonzalez N, Cruz T, Kalko SG, Agustí A. Systemic inflammatory response to smoking in chronic obstructive pulmonary disease: evidence of a gender effect. PLoS ONE. 2014;9:e97491.CrossRefPubMedPubMedCentral Faner R, Gonzalez N, Cruz T, Kalko SG, Agustí A. Systemic inflammatory response to smoking in chronic obstructive pulmonary disease: evidence of a gender effect. PLoS ONE. 2014;9:e97491.CrossRefPubMedPubMedCentral
29.
go back to reference Sørheim I-C, Johannessen A, Gulsvik A, Bakke PS, Silverman EK, DeMeo DL. Gender differences in COPD: are women more susceptible to smoking effects than men? Thorax. 2010;65:480–5.CrossRefPubMed Sørheim I-C, Johannessen A, Gulsvik A, Bakke PS, Silverman EK, DeMeo DL. Gender differences in COPD: are women more susceptible to smoking effects than men? Thorax. 2010;65:480–5.CrossRefPubMed
Metadata
Title
Cytotoxic lymphocytes in COPD airways: increased NK cells associated with disease, iNKT and NKT-like cells with current smoking
Authors
Jonas Eriksson Ström
Jamshid Pourazar
Robert Linder
Anders Blomberg
Anne Lindberg
Anders Bucht
Annelie F. Behndig
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Respiratory Research / Issue 1/2018
Electronic ISSN: 1465-993X
DOI
https://doi.org/10.1186/s12931-018-0940-7

Other articles of this Issue 1/2018

Respiratory Research 1/2018 Go to the issue