title: Smoking is associated with increased levels of extracellular peptidylarginine deiminase 2 (PAD2) in the lungs.
abstract: OBJECTIVE
  Smoking is a well-established risk factor in rheumatoid arthritis (RA), and citrullination of self-antigens plays a pathogenic role in the majority of patients. Increased numbers of peptidylarginine deiminase 2 (PAD2)-containing macrophages have been demonstrated in bronchoalveolar lavage (BAL) fluid from smokers, but intracellularly located PAD cannot be responsible for citrullination of extracellular self-antigens. We aimed to establish a link between smoking and extracellular PAD2 in the lungs.
  
  
  METHODS
  BAL fluid samples were obtained from 13 smokers and 11 nonsmoking controls. Total protein content and C-reactive protein (CRP) concentration were determined after separating cells from the samples. PAD2 content in cell-free BAL fluids was measured by means of a PAD2-specific sandwich ELISA.
  
  
  RESULTS
  Significantly increased levels of soluble PAD2 were detected in cell-free BAL fluids from smokers as compared to non-smokers (p=0.018). The PAD2 content correlated with the overall CRP levels (p=0.009) and cell count (p=0.016).
  
  
  CONCLUSIONS
  This first demonstration of increased levels of extracellular PAD2 in the lungs of smokers supports the hypothesis that smoking promotes extracellular citrullination of proteins. This may represent a pathological event upstream for the production of anti-citrullinated protein antibodies (ACPAs) among RA patients carrying HLA-molecules capable of binding citrullinated self-peptides.
authors.affiliation: Institute for Inflammation Research, Department of Infectious Diseases and Rheumatology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Dres
authors.initials: D
authors.lastname: Damgaard
authors.affiliation: Institute for Inflammation Research, Department of Infectious Diseases and Rheumatology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Michael
authors.initials: M
authors.lastname: Friberg Bruun Nielsen
authors.affiliation: Department of ENT surgery, Odense University Hospital, Odense, Denmark.
authors.forename: Maria
authors.initials: M
authors.lastname: Quisgaard Gaunsbaek
authors.affiliation: Institute for Inflammation Research, Department of Infectious Diseases and Rheumatology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Yaseelan
authors.initials: Y
authors.lastname: Palarasah
authors.affiliation: Department of ENT surgery, Odense University Hospital, Odense, Denmark.
authors.forename: Viggo
authors.initials: V
authors.lastname: Svane-Knudsen
authors.affiliation: Institute for Inflammation Research, Department of Infectious Diseases and Rheumatology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
authors.forename: Claus Henrik
authors.initials: CH
authors.lastname: Nielsen
mesh_terms: D000368:Aged; D015415:Biomarkers / Q000032:analysis; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002097:C-Reactive Protein / Q000032:analysis; D016022:Case-Control Studies; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005541:Forced Expiratory Volume; D006801:Humans; D006867:Hydrolases / Q000032:analysis*; D008168:Lung / Q000201:enzymology* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D000080064:Protein-Arginine Deiminase Type 2; D000076342:Protein-Arginine Deiminases; D012907:Smoking / Q000009:adverse effects* / Q000378:metabolism* / Q000503:physiopathology; D015854:Up-Regulation; D014797:Vital Capacity
chemical_list: D015415:Biomarkers; D002097:C-Reactive Protein; D006867:Hydrolases; C000620352:PADI2 protein, human; D000080064:Protein-Arginine Deiminase Type 2; D000076342:Protein-Arginine Deiminases