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 geneenvironment 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.Conclusion. 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.

Effects of Achieving Target Measures in Rheumatoid Arthritis on Functional Status, Quality of Life, and Resource Utilization: Analysis of Clinical Practice Data

“…These findings extend data from a Swedish case–control study, which determined that smoking was dose dependently associated with occurrence of anti–cyclic citrullinated peptide (anti‐CCP) antibodies 40. An interaction between HLA–DR shared epitope genes and smoking triggered immune responses only in patients positive for anti‐CCP.…”

CD56‐expressing T cells that have features of senescence are expanded in rheumatoid arthritis

“…Expansion of CD56ϩ T 48 MICHEL ET AL cells was not associated with RF positivity, erosive disease, or medication (data not shown).…”

“…The majority of the patients with RA-associated IP were smokers. Due to the reported role of smoking in RA pathogenesis (48), lung abnormalities in patients with RA are of interest. However, our study did not show any significant infiltration of CD56ϩ cells in smokers with otherwise normal lungs.…”

Antibodies to citrullinated α‐enolase peptide 1 are specific for rheumatoid arthritis and cross‐react with bacterial enolase

“…Recent studies have demonstrated that the HLA-DRB1 shared epitope (SE) alleles, the best known genetic risk factor for RA, are associated with only anti-CCP antibody-positive RA, not anti-CCP antibody-negative RA, indicating that HLA SE alleles may be a specific risk factor for the production of ACPAs rather than the for RA itself (21,22). Furthermore, a strong geneenvironment interaction between HLA SE alleles and cigarette smoking is present in anti-CCP antibodypositive patients but not in anti-CCP antibody-negative patients (21,23). Infectious agents, both bacterial and viral, have also been proposed as potential environmental stimuli (24)(25)(26)(27), although to date, no single organism has survived as a compelling candidate for the etiology of the disease.…”

“…Infectious agents, both bacterial and viral, have also been proposed as potential environmental stimuli (24)(25)(26)(27), although to date, no single organism has survived as a compelling candidate for the etiology of the disease. Given that citrullinated proteins are target autoantigens in RA, the pathogen Porphyromonas gingivalis, which expresses the citrullinating enzyme peptidyl arginine deiminase (PAD) (28), could be an environmental trigger of RA in a manner similar to that proposed for smoking (21).…”