A new model for an etiology of rheumatoid arthritis: smoking may trigger HLA-DR (shared epitope)-restricted immune reactions to autoantigens modified by citrullination.
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.
Klareskog
Lars
L
Rheumatology Unit, Department of Medicine, Karolinska Institutet/Karolinska University Hospital, 171 76 Stockholm, Sweden. lars.klareskog@medks.ki.se
Stolt
Patrik
P
Lundberg
Karin
K
Källberg
Henrik
H
Bengtsson
Camilla
C
Grunewald
Johan
J
Rönnelid
Johan
J
Harris
Helena Erlandsson
HE
Ulfgren
Ann-Kristin
AK
Rantapää-Dahlqvist
Solbritt
S
Eklund
Anders
A
Padyukov
Leonid
L
Alfredsson
Lars
L
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
D000906:Antibodies; D000939:Epitopes; D006684:HLA-DR Antigens; D002956:Citrulline