title: Impaired Innate COPD Alveolar Macrophage Responses and Toll-Like Receptor-9 Polymorphisms.
abstract: BACKGROUND
  Dysfunctional innate responses of alveolar macrophages to nontypeable Haemophilus influenzae, Moraxella catarrhalis and Streptococcus pneumoniae contribute to morbidity in chronic obstructive pulmonary disease (COPD). Our earlier studies discovered impaired COPD alveolar macrophage responses to Toll-like receptor (TLR) ligands of nontypeable H. influenzae and provide rationale for further evaluation of TLR signaling. While the role of TLR single nucleotide polymorphisms is increasingly recognized in inflammatory diseases, TLR single nucleotide polymorphisms in COPD have only recently been explored. We hypothesized that specific TLR polymorphisms are associated with dysfunctional innate immune COPD alveolar macrophage responses and investigated polymorphisms of TLR2(Arg753Gln), TLR4(Thr399Ile; Asp299Gly), and TLR9(T1486C; T1237C).
  
  
  METHODS
  DNA was purified from cells of 1) healthy nonsmokers (n = 20); 2) COPD ex-smokers (n = 83); 3) COPD active smokers (n = 93). DNA amplifications (polymerase chain reaction) were performed for each SNP. Alveolar macrophages from each group were incubated with nontypeable H. influenzae, M. catarrhalis and S. pneumoniae. Cytokine induction of macrophage supernatants was measured and the association with TLR single nucleotide polymorphism expression was determined.
  
  
  RESULTS
  No significant inter-group differences in frequency of any TLR SNP existed. However both TLR9 single nucleotide polymorphisms were expressed in high frequency. Among COPD ex-smokers, diminished IL-8 responsiveness to nontypeable H. influenzae, M. catarrhalis and S. pneumoniae was strongly associated with carriage of TLR9(T1237C) (p = 0.02; p = 0.008; p = 0.02), but not TLR9(T1486C). Carriage of TLR9(T1237C), but not TLR9(T1486C), correlated with diminished FEV1%predicted (p = 0.037).
  
  
  CONCLUSIONS
  Our results demonstrate a notable association of TLR9(T1237C) expression with dysfunctional innate alveolar macrophage responses to respiratory pathogens and with severity of COPD.
authors.affiliation: Division of Infectious Diseases, Department of Veterans Affairs Western New York Healthcare System, State University of New York at Buffalo School of Medicine, Buffalo, New York, 14215, United States of America.
authors.forename: Charles S
authors.initials: CS
authors.lastname: Berenson
authors.affiliation: Division of Infectious Diseases, Department of Veterans Affairs Western New York Healthcare System, State University of New York at Buffalo School of Medicine, Buffalo, New York, 14215, United States of America.
authors.forename: Ragina L
authors.initials: RL
authors.lastname: Kruzel
authors.affiliation: Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Veterans Affairs Western New York Healthcare System, State University of New York at Buffalo School of Medicine, Buffalo, New York, 14215, United States of America.
authors.forename: Catherine T
authors.initials: CT
authors.lastname: Wrona
authors.affiliation: Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Veterans Affairs Western New York Healthcare System, State University of New York at Buffalo School of Medicine, Buffalo, New York, 14215, United States of America; Department of Biomedical Informatics, State University of New York at Buffalo School of Medicine, Buffalo, New York, 14215, United States of America.
authors.forename: Manoj J
authors.initials: MJ
authors.lastname: Mammen
authors.affiliation: Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Veterans Affairs Western New York Healthcare System, State University of New York at Buffalo School of Medicine, Buffalo, New York, 14215, United States of America.
authors.forename: Sanjay
authors.initials: S
authors.lastname: Sethi
mesh_terms: D000483:Alleles; D019943:Amino Acid Substitution; D016022:Case-Control Studies; D005260:Female; D005787:Gene Frequency; D006801:Humans; D007113:Immunity, Innate; D016209:Interleukin-8 / Q000096:biosynthesis; D016676:Macrophages, Alveolar / Q000276:immunology* / Q000378:metabolism*; D008297:Male; D020641:Polymorphism, Single Nucleotide; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism / Q000503:physiopathology; D012129:Respiratory Function Tests; D051217:Toll-Like Receptor 9 / Q000235:genetics*
chemical_list: D016209:Interleukin-8; D051217:Toll-Like Receptor 9