Smoking is associated with increased levels of extracellular peptidylarginine deiminase 2 (PAD2) in the lungs

Clin Exp Rheumatol. 2015 May-Jun;33(3):405-8. Epub 2015 Apr 16.


Objectives: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Biomarkers / analysis
  • Bronchoalveolar Lavage Fluid / chemistry
  • C-Reactive Protein / analysis
  • Case-Control Studies
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Forced Expiratory Volume
  • Humans
  • Hydrolases / analysis*
  • Lung / enzymology*
  • Lung / physiopathology
  • Male
  • Middle Aged
  • Protein-Arginine Deiminase Type 2
  • Protein-Arginine Deiminases
  • Smoking / adverse effects*
  • Smoking / metabolism*
  • Smoking / physiopathology
  • Up-Regulation
  • Vital Capacity


  • Biomarkers
  • C-Reactive Protein
  • Hydrolases
  • PADI2 protein, human
  • Protein-Arginine Deiminase Type 2
  • Protein-Arginine Deiminases