Distribution of T-Cell Subsets in BAL Fluid of Patients With Mild to Moderate COPD Depends on Current Smoking Status and Not Airway Obstruction

Forsslund, Helena; Mikko, Mikael; Karimi, Reza; Grünewald, Johan; Wheelock, Åsa M.; Wahlström, Jan; Sköld, C. Magnus

doi:10.1378/chest.13-0873

Cited by 72 publications

(73 citation statements)

References 54 publications

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“…2D ). In most individuals, the majority of lung CD56+ T cells were CD8 single-positive (50.4±25.3%), as has recently been shown for CD56+ T cells in bronchoalveolar lavage [36] There were no differences in the frequency of these three subsets of lung CD56+ T cells between groups of subjects ( Fig. 2E ) and no relationship of CD8 or CD4 co-expression with FEV 1 % predicted ( Fig.…”

Section: Resultssupporting

confidence: 73%

Human CD56+ Cytotoxic Lung Lymphocytes Kill Autologous Lung Cells in Chronic Obstructive Pulmonary Disease

et al. 2014

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CD56+ natural killer (NK) and CD56+ T cells, from sputum or bronchoalveolar lavage of subjects with chronic obstructive pulmonary disease (COPD) are more cytotoxic to highly susceptible NK targets than those from control subjects. Whether the same is true in lung parenchyma, and if NK activity actually contributes to emphysema progression are unknown. To address these questions, we performed two types of experiments on lung tissue from clinically-indicated resections (n = 60). First, we used flow cytometry on fresh single-cell suspension to measure expression of cell-surface molecules (CD56, CD16, CD8, NKG2D and NKp44) on lung lymphocytes and of the 6D4 epitope common to MICA and MICB on lung epithelial (CD326+) cells. Second, we sequentially isolated CD56+, CD8+ and CD4+ lung lymphocytes, co-cultured each with autologous lung target cells, then determined apoptosis of individual target cells using Annexin-V and 7-AAD staining. Lung NK cells (CD56+ CD3−) and CD56+ T cells (CD56+ CD3+) were present in a range of frequencies that did not differ significantly between smokers without COPD and subjects with COPD. Lung NK cells had a predominantly “cytotoxic” CD56+ CD16+ phenotype; their co-expression of CD8 was common, but the percentage expressing CD8 fell as FEV1 % predicted decreased. Greater expression by autologous lung epithelial cells of the NKG2D ligands, MICA/MICB, but not expression by lung CD56+ cells of the activating receptor NKG2D, correlated inversely with FEV1 % predicted. Lung CD56+ lymphocytes, but not CD4+ or CD8+ conventional lung T cells, rapidly killed autologous lung cells without additional stimulation. Such natural cytotoxicity was increased in subjects with severe COPD and was unexplained in multiple regression analysis by age or cancer as indication for surgery. These data show that as spirometry worsens in COPD, CD56+ lung lymphocytes exhibit spontaneous cytotoxicity of autologous structural lung cells, supporting their potential role in emphysema progression.Trial RegistrationClinicalTrials.gov NCT00281229

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Section: Resultssupporting

confidence: 73%

Human CD56+ Cytotoxic Lung Lymphocytes Kill Autologous Lung Cells in Chronic Obstructive Pulmonary Disease

et al. 2014

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“…We also investigated the gene expression profile of bronchial epithelial cells in bronchial brush biopsies harvested from healthy subjects by selecting data of interest from a broad mRNA analyses of the COSMIC cohort material (22,23). Here, we found that these bronchial epithelial cells contain mRNA for IL26, TLR3, TLR7 and TLR8 among others ( Figure 6A), which are compatible with our finding on primary bronchial epithelial cells in vitro.…”

Section: Interleukin-26 and Its Archetype Signaling Responses In Bronsupporting

confidence: 85%

“…The data (raw signals) were presented as relative fluorescence units (RFU). Here, 10 randomly selected bronchial brush biopsy samples from the human (4 male and 6 female) donors were selected from the pool of the COSMIC cohort (22,23). The analyses of mRNA were then performed on the cells in the bronchial brush biopsy samples as previously described (27).…”

Section: Cell Culture and Stimulationmentioning

confidence: 99%

“…Thus, data and samples from 37 control subjects in the Karolinska Institutet COSMIC cohort (ClinicalTrials.gov Identifier: NCT02627872) were utilized and some of the clinical data sets have been utilized in other studies (22,23). The COSMIC cohort study was previously approved by the Regional committee for ethical review in Stockholm, Sweden (Diary No 2006/ 959-31/1).…”

Section: Bronchoscopy and Collection Of Bronchial Biopsies Bronchoalmentioning

confidence: 99%

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Interleukin-26 Production in Human Primary Bronchial Epithelial Cells in Response to Viral Stimulation: Modulation by Th17 cytokines

Fru

Kaarteenaho

Lappi‐Blanco

et al. 2017

Mol Med

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Interleukin (IL)-26 is abundant in human airways and this cytokine is involved in the local immune response to a bacterial stimulus in vivo. Specifically, local exposure to the toll-like receptor (TLR) 4 agonist endotoxin does increase IL-26 in human airways and this cytokine potentiates chemotactic responses in human neutrophils. In addition to T-helper (Th) 17 cells, alveolar macrophages can produce IL-26, but it remains unknown whether this cytokine can also be produced in the airway mucosa per se in response to a viral stimulus. Here, we evaluated whether this is the case using primary bronchial epithelial cells from the airway epithelium in vitro and explored the signaling mechanisms involved, including the modulatory effects of additional Th17 cytokines. Finally, we assessed IL-26 and its archetype signaling responses in healthy human airways in vivo. We found increased transcription and release of IL-26 protein after stimulation with the viral-related double stranded (ds) RNA polyinosinic-polycytidylic acid (poly-IC) and showed that this IL-26 release involved mitogen-activated protein (MAP) kinases and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). The release of IL-26 in response to a viral stimulus was modulated by additional Th17 cytokines. Moreover, there was transcription of IL26 mRNA and expression of the protein in epithelial cells of bronchial brush and tissue biopsies respectively after harvest in vivo. In addition, the extracellular IL-26 protein concentrations in bronchoalveolar lavage (BAL) samples did correlate with increased epithelial cell transcription of an archetype intracellular signaling molecule downstream of the IL-26-receptor complex, STAT1, in the bronchial brush biopsies. Thus, our study suggests that viral stimulation causes the production of IL-26 in lining epithelial cells of human airways, structural cells that constitute a critical immune barrier and that this production is modulated by Th17 cytokines.

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“…Most studies on pathophysiological mechanisms in COPD are cross-sectional and include highly selected study populations unrelated to population-based samples [36,37]. When recruiting participants to groups A and B in the current study, non-participation was fairly high among subjects with COPD.…”

Section: Discussionmentioning

confidence: 96%

From COPD epidemiology to studies of pathophysiological disease mechanisms: challenges with regard to study design and recruitment process

Lindberg

Linder

Bäckman

et al. 2017

European Clinical Respiratory Journal

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Background: Chronic obstructive pulmonary disease (COPD) is a largely underdiagnosed disease including several phenotypes. In this report, the design of a study intending to evaluate the pathophysiological mechanism in COPD in relation to the specific phenotypes non-rapid and rapid decline in lung function is described together with the recruitment process of the study population derived from a population based study. Method: The OLIN COPD study includes a population-based COPD cohort and referents without COPD identified in 2002–04 (n = 1986), and thereafter followed annually since 2005. Lung function decline was estimated from baseline in 2002–2004 to 2010 (first recruitment phase) or to 2012/2013 (second recruitment phase). Individuals who met the predefined criteria for the following four groups were identified; group A) COPD grade 2–3 with rapid decline in FEV1 and group B) COPD grade 2–3 without rapid decline in FEV1 (≥60 and ≤30 ml/year, respectively), group C) ever-smokers, and group D) non-smokers with normal lung function. Groups A–C included ever-smokers with >10 pack years. The intention was to recruit 15 subjects in each of the groups A-D. Results: From the database groups A–D were identified; group A n = 37, group B n = 29, group C n = 41, and group D n = 55. Fifteen subjects were recruited from groups C and D, while this goal was not reached in the groups A (n = 12) and B (n = 10). The most common reasons for excluding individuals identified as A or B were comorbidities contraindicating bronchoscopy, or inflammatory diseases/immune suppressive medication expected to affect the outcome. Conclusion: The study is expected to generate important results regarding pathophysiological mechanisms associated with rate of decline in lung function among subjects with COPD and the in-detail described recruitment process, including reasons for non-participation, is a strength when interpreting the results in forthcoming studies.

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Distribution of T-Cell Subsets in BAL Fluid of Patients With Mild to Moderate COPD Depends on Current Smoking Status and Not Airway Obstruction

Cited by 72 publications

References 54 publications

Human CD56+ Cytotoxic Lung Lymphocytes Kill Autologous Lung Cells in Chronic Obstructive Pulmonary Disease

Human CD56+ Cytotoxic Lung Lymphocytes Kill Autologous Lung Cells in Chronic Obstructive Pulmonary Disease

Interleukin-26 Production in Human Primary Bronchial Epithelial Cells in Response to Viral Stimulation: Modulation by Th17 cytokines

From COPD epidemiology to studies of pathophysiological disease mechanisms: challenges with regard to study design and recruitment process

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