title: Smoking increases peptidylarginine deiminase 2 enzyme expression in human lungs and increases citrullination in BAL cells.
abstract: OBJECTIVE
  A gene-environment interaction between HLA-DR shared epitope genes and smoking in anti-cyclic citrullinated peptide antibody-positive rheumatoid arthritis (RA) has been reported. Identification of citrullinated proteins in bronchoalveolar lavage (BAL) cells from smokers has led to the suggestion that citrullination induced by smoking might be the first step in the pathogenic chain of RA.
  
  
  OBJECTIVE
  To confirm and extend these findings.
  
  
  METHODS
  Immunohistochemistry was performed on BAL cells and bronchial mucosal biopsy sections obtained through bronchoscopy from 14 healthy smokers and 16 healthy non-smokers. Two antibodies recognising citrullinated proteins, two antibodies recognising peptidylarginine deiminase (PAD)2 enzyme and one recognising PAD4 enzyme were used.
  
  
  RESULTS
  Citrullinated proteins are upregulated in BAL cells of healthy smokers compared with healthy non-smokers. This was associated with higher expression of the PAD2 enzyme. The same level of citrullinated proteins was present in bronchial mucosal biopsy specimens of healthy smokers and non-smokers, despite higher expression of PAD2 in smokers.
  
  
  CONCLUSIONS
  This study provides evidence that smoking enhances PAD2 expression in the bronchial mucosal and alveolar compartment, with consequent generation of citrullinated proteins in the latter. Smoking is an environmental factor that may lead to citrulline autoimmunity in genetically susceptible subjects.
authors.affiliation: Department of Medicine, Division of Rheumatology, Karolinska University Hospital, Solna, Karolinska Institutet, Stockholm, Sweden.
authors.forename: D
authors.initials: D
authors.lastname: Makrygiannakis
authors.forename: M
authors.initials: M
authors.lastname: Hermansson
authors.forename: A-K
authors.initials: AK
authors.lastname: Ulfgren
authors.forename: A P
authors.initials: AP
authors.lastname: Nicholas
authors.forename: A J W
authors.initials: AJ
authors.lastname: Zendman
authors.forename: A
authors.initials: A
authors.lastname: Eklund
authors.forename: J
authors.initials: J
authors.lastname: Grunewald
authors.forename: C M
authors.initials: CM
authors.lastname: Skold
authors.forename: L
authors.initials: L
authors.lastname: Klareskog
authors.forename: A I
authors.initials: AI
authors.lastname: Catrina
mesh_terms: D000328:Adult; D001706:Biopsy; D001980:Bronchi / Q000378:metabolism / Q000473:pathology; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D002956:Citrulline / Q000378:metabolism*; D005260:Female; D006801:Humans; D006867:Hydrolases / Q000378:metabolism*; D008168:Lung / Q000201:enzymology*; D008297:Male; D011446:Prospective Studies; D000080064:Protein-Arginine Deiminase Type 2; D000076342:Protein-Arginine Deiminases; D020545:Respiratory Mucosa / Q000378:metabolism / Q000473:pathology; D012907:Smoking / Q000378:metabolism* / Q000473:pathology
chemical_list: D002956:Citrulline; D006867:Hydrolases; C000620352:PADI2 protein, human; D000080064:Protein-Arginine Deiminase Type 2; D000076342:Protein-Arginine Deiminases