In smoking-induced chronic obstructive pulmonary disease (COPD), various comorbidities are linked to systemic inflammation and infection-induced exacerbations. The underlying mechanisms are unclear but might provide therapeutic targets. T-cell activity is central in systemic inflammation and for infection-defense mechanisms and might be influenced by comorbidities. Hypothesis: Circulating biomarkers of comorbidities modulate the activity of T-cells of the T-helper type 1 (Th1) and/or T-cytotoxic type 1 (Tc1). T-cells in peripheral blood mononuclear cells (PBMCs) from non-smokers (NS), current smokers without COPD (S), and COPD subjects (total n = 34) were ex vivo activated towards Th1/Tc1 and were then stimulated with biomarkers for metabolic and/or cardiovascular comorbidities (Brain Natriuretic Peptide, BNP; chemokine (C-C motif) ligand 18, CCL18; C-X3-C motif chemokine ligand 1, CX3CL1; interleukin-18, IL-18) or for asthma- and/or cancer-related comorbidities (CCL22; epidermal growth factor, EGF; IL-17; periostin) each at 10 or 50 ng/mL. The Th1/Tc1 activation markers interferon-γ (IFNγ), tumor necrosis factor-α (TNFα), and granulocyte-macrophage colony-stimulating factor (GM-CSF) were analyzed in culture supernatants by Enzyme-Linked Immunosorbent Assay (ELISA). Ex-vivo activation induced IFNγ and TNFα without differences between the groups but GM-CSF more in S vs. NS. At 10 ng/mL, the different biomarkers increased or reduced the T-cell activation markers without a clear trend for one direction in the different categories of comorbidities or for the different T-cell activation markers. At 50 ng/mL, there was a clear shift towards suppressive effects, particularly for the asthma— and cancer-related biomarkers and in cells of S and COPD. Comorbidities might suppress T-cell immunity in COPD. This could explain the association of comorbidities with frequent exacerbations.

Background: Severe asthma patients have an increased susceptibility to respiratory tract infections with rhinovirus (HRV) that cause exacerbations. This implicates defects in immune responses. Method: HRV-induced activation of circulating leukocytes is suppressed in severe asthma and is influenced by type-2 inflammation. Methods: Peripheral blood mononuclear cells (PBMCs) from 19 healthy never-smokers (NS) and 34 non-smokers with severe asthma (SA) were ex vivo infected with HRV16 at MOIs 0.1 and 1.0. Cytokines (activity markers) were measured in cell culture supernatants by ELISA after 24h and 7d. Data were normalized to baseline and compared between NS and SA and were analyzed for correlation with total IgE (n=31 SA) and with the type-2 inflammation markers blood eosinophils (n=32 SA), FeNO (n=25 SA) and serum-periostin (n=29 SA). Results: Baseline IL6, IL8, TNFα and IFNγ were reduced, IL1β was increased in SA vs. NS. HRV induced IFNα, IL1β, IL6, TNFα, CCL2 and CCL5 after 24h and 7d and IL8 and IFNγ after 7d in NS. Except for IFNγ, HRV-induced cytokine responses were reduced in SA vs. NS. The IL6 response was lower in SA with <300 than in SA with ≥300 eosinophils/µl blood. HRV-induced IFNα, IL1β and CCL2 correlated negatively to FeNO, periostin or both, respectively. Conclusion: Cytokine production of leukocytes in response to HRV is reduced in severe asthma. This implies systemic immune defects resulting in the suppression of the activation of circulating leukocytes after recruitment to the infected tissue. This might be affected by the severity of type-2 inflammation and can explain the impaired infection defense and the increased susceptibility to viral infections in asthma.

Background: Severe asthma patients are more susceptible to infections with the respiratory syncytial-virus (RSV) than healthy subjects. This implicates defects in immune responses and could explain frequent exacerbations. Hypothesis: Cytokine production of leukocytes in response to RSV is impaired in severe asthma and is influenced by type2 inflammation. Methods: Peripheral blood mononuclear cells from 18 healthy never-smokers (NS) and 39 non-smokers with severe asthma (SA) were ex vivo infected with RSV A2 at MOIs 0.1 and 1.0. After 24h and 7d, cytokines were measured in cell culture supernatants by ELISA. Data were normalized to baseline and compared between NS and SA. They were analyzed for correlation with total IgE (n=35 SA) and with the type2 inflammation markers blood eosinophils (n=36 SA), FeNO (n=28 SA) and serum-periostin (n=33 SA). Results: Baseline IL1β, IL6, TNFα, and CCL2 were reduced, IFNα and CCL5 were increased in SA vs. NS. RSV-induced IL1β, IL6, CCL2, and CCL5 after 24h and 7d, TNFα after 24h and IFNα, IFNγ and IL8 after 7d in NS. IL6, IL8, CCL2, and CCL5 responses were increased in SA compared to NS. The CCL2 response was lower in SA with <300 vs. ≥300 eosinophils/µl blood. The IL1β response was lower in SA with 25 ppb FeNO. IFNα correlated negatively to eosinophils; IFNα, IFNγ, CCL5, IL6, and IL8 negatively to FeNO; IFNα, IL1β, and CCL2 negatively to periostin. Conclusion: The impaired activation of circulating leukocytes in response to acute RSV infections may explain the increased susceptibility to RSV in asthma and could be influenced by the severity of type2 inflammation.