Smoking increases peptidylarginine deiminase 2 enzyme expression in human lungs and increases citrullination in BAL cells.
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.
Makrygiannakis
D
D
Department of Medicine, Division of Rheumatology, Karolinska University Hospital, Solna, Karolinska Institutet, Stockholm, Sweden.
Hermansson
M
M
Ulfgren
A-K
AK
Nicholas
A P
AP
Zendman
A J W
AJ
Eklund
A
A
Grunewald
J
J
Skold
C M
CM
Klareskog
L
L
Catrina
A I
AI
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
D002956:Citrulline; D006867:Hydrolases; C000620352:PADI2 protein, human; D000080064:Protein-Arginine Deiminase Type 2; D000076342:Protein-Arginine Deiminases