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Smoking increases peptidylarginine deiminase 2 enzyme expression in human lungs and increases citrullination in BAL cells
  1. D Makrygiannakis1,
  2. M Hermansson1,
  3. A-K Ulfgren1,
  4. A P Nicholas2,
  5. A J W Zendman3,
  6. A Eklund4,
  7. J Grunewald4,
  8. C M Skold4,
  9. L Klareskog1,
  10. A I Catrina1
  1. 1
    Department of Medicine, Division of Rheumatology, Karolinska University Hospital, Solna, Karolinska Institutet, Stockholm, Sweden
  2. 2
    University of Alabama at Birmingham and Birmingham Veterans Administration Medical Center, Birmingham, Alabama, USA
  3. 3
    Department of Biomolecular Chemistry, Radboud University Nijmegen, Nijmegen, The Netherlands
  4. 4
    Department of Medicine, Division of Respiratory Medicine, Karolinska University Hospital, Solna, Karolinska Institutet, Stockholm, Sweden
  1. Dr A I Catrina, Rheumatology Unit, CMM L8:04, Karolinska University Hospital, Solna, Karolinska Institutet, Stockholm S-17176, Sweden; Anca.Catrina{at}


Objectives: 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.

Conclusion: 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.

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  • ▸ Additional figures are published online only at

  • Funding: This study was supported by grants from Ulla and Gustaf af Ugglas Foundation, Gustav den V:e Foundation, Swedish Medical Research Council, Swedish Heart Lung Foundation, Stockholm County Council, Torsten and Ragnar Soderberg Foundation, Clas Groschinskys Minnesfond.

  • Competing interests: None.

  • Ethics approval: Approved by the Northern Stockholm Ethical Review Board.

  • We declare that the study sponsors did not have any influence in the study design; in the collection, analysis, and interpretation of data; in the writing of the report or in the decision to submit the paper for publication.