title: Oxidative stress-induced antibodies to carbonyl-modified protein correlate with severity of chronic obstructive pulmonary disease.
abstract: BACKGROUND
  There is increasing evidence for the presence of autoantibodies in chronic obstructive pulmonary disease (COPD). Chronic oxidative stress is an essential component in COPD pathogenesis and can lead to increased levels of highly reactive carbonyls in the lung, which could result in the formation of highly immunogenic carbonyl adducts on "self" proteins.
  
  
  OBJECTIVE
  To determine the presence of autoantibodies to carbonyl-modified protein in patients with COPD and in a murine model of chronic ozone exposure. To assess the extent of activated immune responses toward carbonyl-modified proteins.
  
  
  METHODS
  Blood and peripheral lung were taken from patients with COPD, age-matched smokers, and nonsmokers with normal lung function, as well as patients with severe persistent asthma. Mice were exposed to ambient air or ozone for 6 weeks. Antibody titers were measured by ELISA, activated compliment deposition by immunohistochemistry, and cellular activation by ELISA and fluorescence-activated cell sorter.
  
  
  RESULTS
  Antibody titer against carbonyl-modified self-protein was significantly increased in patients with Global Initiative for Chronic Obstructive Lung Disease stage III COPD compared with control subjects. Antibody levels inversely correlated with disease severity and showed a prevalence toward an IgG1 isotype. Deposition of activated complement in the vessels of COPD lung as well as autoantibodies against endothelial cells were also observed. Ozone-exposed mice similarly exhibited increased antibody titers to carbonyl-modified protein, as well as activated antigen-presenting cells in lung tissue and splenocytes sensitized to activation by carbonyl-modified protein.
  
  
  CONCLUSIONS
  Carbonyl-modified proteins, arising as a result of oxidative stress, promote antibody production, providing a link by which oxidative stress could drive an autoimmune response in COPD.
authors.affiliation: National Heart and Lung Institute, Imperial College London, Dovehouse Street, London SW3 6LY UK. p.kirkham@imperial.ac.uk
authors.forename: Paul A
authors.initials: PA
authors.lastname: Kirkham
authors.forename: Gaetano
authors.initials: G
authors.lastname: Caramori
authors.forename: Paolo
authors.initials: P
authors.lastname: Casolari
authors.forename: Alberto A
authors.initials: AA
authors.lastname: Papi
authors.forename: Matt
authors.initials: M
authors.lastname: Edwards
authors.forename: Betty
authors.initials: B
authors.lastname: Shamji
authors.forename: Kostas
authors.initials: K
authors.lastname: Triantaphyllopoulos
authors.forename: Farhana
authors.initials: F
authors.lastname: Hussain
authors.forename: Mariona
authors.initials: M
authors.lastname: Pinart
authors.forename: Younis
authors.initials: Y
authors.lastname: Khan
authors.forename: Lucy
authors.initials: L
authors.lastname: Heinemann
authors.forename: Laurie
authors.initials: L
authors.lastname: Stevens
authors.forename: Mike
authors.initials: M
authors.lastname: Yeadon
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Barnes
authors.forename: Kian F
authors.initials: KF
authors.lastname: Chung
authors.forename: Ian M
authors.initials: IM
authors.lastname: Adcock
mesh_terms: D000368:Aged; D000818:Animals; D001249:Asthma / Q000276:immunology; D001323:Autoantibodies / Q000097:blood / Q000378:metabolism*; D016022:Case-Control Studies; D005260:Female; D006801:Humans; D008297:Male; D016555:Matched-Pair Analysis; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D018384:Oxidative Stress / Q000276:immunology*; D010126:Ozone; D050050:Protein Carbonylation / Q000276:immunology*; D029424:Pulmonary Disease, Chronic Obstructive / Q000276:immunology* / Q000473:pathology; D020545:Respiratory Mucosa / Q000473:pathology; D012720:Severity of Illness Index; D012907:Smoking / Q000009:adverse effects
chemical_list: D001323:Autoantibodies; D010126:Ozone