title: A new model for an etiology of rheumatoid arthritis: smoking may trigger HLA-DR (shared epitope)-restricted immune reactions to autoantigens modified by citrullination.
abstract: OBJECTIVE
  To investigate whether smoking and HLA-DR shared epitope (SE) genes may interact in triggering immune reactions to citrulline-modified proteins.
  
  
  METHODS
  In a case-control study involving patients with recent-onset rheumatoid arthritis (RA), we studied interactions between a major environmental risk factor (smoking), major susceptibility genes included in the SE of HLA-DR, and the presence of the most specific autoimmunity known for RA (i.e., antibodies to proteins modified by citrullination). Immunostaining for citrullinated proteins in cells from bronchoalveolar lavage fluid was used to investigate whether smoking is associated with citrullination in the lungs.
  
  
  RESULTS
  Previous smoking was dose-dependently associated with occurrence of anticitrulline antibodies in RA patients. The presence of SE genes was a risk factor only for anticitrulline-positive RA, and not for anticitrulline-negative RA. A major gene-environment interaction between smoking and HLA-DR SE genes was evident for anticitrulline-positive RA, but not for anticitrulline-negative RA, and the combination of smoking history and the presence of double copies of HLA-DR SE genes increased the risk for RA 21-fold compared with the risk among nonsmokers carrying no SE genes. Positive immunostaining for citrullinated proteins was recorded in bronchoalveolar lavage cells from smokers but not in those from nonsmokers.
  
  
  CONCLUSIONS
  We identified an environmental factor, smoking, that in the context of HLA-DR SE genes may trigger RA-specific immune reactions to citrullinated proteins. These data thus suggest an etiology involving a specific genotype, an environmental provocation, and the induction of specific autoimmunity, all restricted to a distinct subset of RA.
authors.affiliation: Rheumatology Unit, Department of Medicine, Karolinska Institutet/Karolinska University Hospital, 171 76 Stockholm, Sweden. lars.klareskog@medks.ki.se
authors.forename: Lars
authors.initials: L
authors.lastname: Klareskog
authors.forename: Patrik
authors.initials: P
authors.lastname: Stolt
authors.forename: Karin
authors.initials: K
authors.lastname: Lundberg
authors.forename: Henrik
authors.initials: H
authors.lastname: Källberg
authors.forename: Camilla
authors.initials: C
authors.lastname: Bengtsson
authors.forename: Johan
authors.initials: J
authors.lastname: Grunewald
authors.forename: Johan
authors.initials: J
authors.lastname: Rönnelid
authors.forename: Helena Erlandsson
authors.initials: HE
authors.lastname: Harris
authors.forename: Ann-Kristin
authors.initials: AK
authors.lastname: Ulfgren
authors.forename: Solbritt
authors.initials: S
authors.lastname: Rantapää-Dahlqvist
authors.forename: Anders
authors.initials: A
authors.lastname: Eklund
authors.forename: Leonid
authors.initials: L
authors.lastname: Padyukov
authors.forename: Lars
authors.initials: L
authors.lastname: Alfredsson
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000906:Antibodies / Q000097:blood; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000209:etiology* / Q000235:genetics / Q000276:immunology; D016022:Case-Control Studies; D002956:Citrulline / Q000276:immunology; D000939:Epitopes; D005260:Female; D006684:HLA-DR Antigens / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D012907:Smoking / Q000009:adverse effects
chemical_list: D000906:Antibodies; D000939:Epitopes; D006684:HLA-DR Antigens; D002956:Citrulline