RATIONALE: Patients with chronic obstructive pulmonary disease (COPD) are susceptible to respiratory viral infections that cause exacerbations. The mechanisms underlying this susceptibility are not understood. Effectors of the adaptive immune response-CD8(+) T cells that clear viral infections-are present in increased numbers in the lungs of patients with COPD, but they fail to protect against infection and may contribute to the immunopathology of the disease. OBJECTIVES: CD8(+) function and signaling through the programmed cell death protein (PD)-1 exhaustion pathway were investigated as a potential key mechanism of viral exacerbation of the COPD lung. METHODS: Tissue from control subjects and patients with COPD undergoing lung resection was infected with live influenza virus ex vivo. Viral infection and expression of lung cell markers were analyzed using flow cytometry. MEASUREMENTS AND MAIN RESULTS: The proportion of lung CD8(+) T cells expressing PD-1 was greater in COPD (mean, 16.2%) than in controls (4.4%, P = 0.029). Only epithelial cells and macrophages were infected with influenza, and there was no difference in the proportion of infected cells between controls and COPD. Infection up-regulated T-cell PD-1 expression in control and COPD samples. Concurrently, influenza significantly up-regulated the marker of cytotoxic degranulation (CD107a) on CD8(+) T cells (P = 0.03) from control subjects but not on those from patients with COPD. Virus-induced expression of the ligand PD-L1 was decreased on COPD macrophages (P = 0.04) with a corresponding increase in IFN-γ release from infected COPD explants compared with controls (P = 0.04). CONCLUSIONS: This study has established a signal of cytotoxic immune dysfunction and aberrant immune regulation in the COPD lung that may explain both the susceptibility to viral infection and the excessive inflammation associated with exacerbations.
RATIONALE: Patients with chronic obstructive pulmonary disease (COPD) are susceptible to respiratory viral infections that cause exacerbations. The mechanisms underlying this susceptibility are not understood. Effectors of the adaptive immune response-CD8(+) T cells that clear viral infections-are present in increased numbers in the lungs of patients with COPD, but they fail to protect against infection and may contribute to the immunopathology of the disease. OBJECTIVES:CD8(+) function and signaling through the programmed cell death protein (PD)-1 exhaustion pathway were investigated as a potential key mechanism of viral exacerbation of the COPD lung. METHODS: Tissue from control subjects and patients with COPD undergoing lung resection was infected with live influenza virus ex vivo. Viral infection and expression of lung cell markers were analyzed using flow cytometry. MEASUREMENTS AND MAIN RESULTS: The proportion of lung CD8(+) T cells expressing PD-1 was greater in COPD (mean, 16.2%) than in controls (4.4%, P = 0.029). Only epithelial cells and macrophages were infected with influenza, and there was no difference in the proportion of infected cells between controls and COPD. Infection up-regulated T-cell PD-1 expression in control and COPD samples. Concurrently, influenza significantly up-regulated the marker of cytotoxic degranulation (CD107a) on CD8(+) T cells (P = 0.03) from control subjects but not on those from patients with COPD. Virus-induced expression of the ligand PD-L1 was decreased on COPD macrophages (P = 0.04) with a corresponding increase in IFN-γ release from infected COPD explants compared with controls (P = 0.04). CONCLUSIONS: This study has established a signal of cytotoxic immune dysfunction and aberrant immune regulation in the COPD lung that may explain both the susceptibility to viral infection and the excessive inflammation associated with exacerbations.
Authors: K R Chapman; D M Mannino; J B Soriano; P A Vermeire; A S Buist; M J Thun; C Connell; A Jemal; T A Lee; M Miravitlles; S Aldington; R Beasley Journal: Eur Respir J Date: 2006-01 Impact factor: 16.671
Authors: M Saetta; A Di Stefano; G Turato; F M Facchini; L Corbino; C E Mapp; P Maestrelli; A Ciaccia; L M Fabbri Journal: Am J Respir Crit Care Med Date: 1998-03 Impact factor: 21.405
Authors: Peter A B Wark; Sebastian L Johnston; Fabio Bucchieri; Robert Powell; Sarah Puddicombe; Vasile Laza-Stanca; Stephen T Holgate; Donna E Davies Journal: J Exp Med Date: 2005-03-21 Impact factor: 14.307
Authors: Juliana Ruiz Fernandes; Cibele Cristine Berto Marques da Silva; Aline Grandi da Silva; Regina Maria de Carvalho Pinto; Alberto José da Silva Duarte; Celso Ricardo Carvalho; Gil Benard Journal: Lung Date: 2018-03-10 Impact factor: 2.584
Authors: Nicholas M Mark; Julia Kargl; Stephanie E Busch; Grace H Y Yang; Heather E Metz; Huajia Zhang; Jesse J Hubbard; Sudhakar N J Pipavath; David K Madtes; A McGarry Houghton Journal: Am J Respir Crit Care Med Date: 2018-02-01 Impact factor: 21.405
Authors: Eric D Morrell; Alice Wiedeman; S Alice Long; Sina A Gharib; T Eoin West; Shawn J Skerrett; Mark M Wurfel; Carmen Mikacenic Journal: JCI Insight Date: 2018-05-17