Interaction of environment, genetics and autoimmunity in the pathogenesis of rheumatoid arthritis (RA)
Cigarette smoking and a genetic marker, the HLA-DR shared epitope, have been consistently identified as risk factors for the development of RA (see 2004 news summary). In recent years, the presence of antibodies against citrullinated peptides (anti-CCP antibodies) have been recognized as highly specific markers for RA. These antibodies can appear as early as 10 years prior to the clinical signs and symptoms of RA. A close correlation between the shared epitope and presence of anti-CCP antibodies has been previously shown. But a potential relationship between these and cigarette smoking has not been investigated. Klareksog et al (Arthritis Rheum 54:38, 2006) performed a case control study involving patients with recently diagnosed RA, and proposed a novel hypothesis for the pathophysiology of RA.
Results: Their data indicate the following:
- Prior smoking was associated with the presence of anti-CCP antibodies in a dose dependent manner;
- The shared epitope genes were associated with anti-CCP positive, but not anti-CCP negative, RA, also in a dose dependent manner;
- The combination of a positive smoking history and double copies of the shared epitope genes increased the risk for RA 21-fold compared to the risk for nonsmokers carrying no shared epitope genes.
- Citrullinated proteins were observed in the bronchoalveolar lavage cells from smokers but not from nonsmokers.
Conclusion: Smoking, in the context of genetic susceptibility (presence of shared epitope genes) may trigger RA-specific autoimmune response to citrullinated proteins.
Editorial Comment: These data indicate that smoking and the shared epitope genes convey susceptibility for RA only in patients who are anti-CCP positive. Because citrullinated peptides could be demonstrated in the BAL fluids of smokers but not nonsmokers, the implication is that smoking somehow promotes citrullination, perhaps by upregulating one or more of the iso-enzymes that cause citrullination (peptidylarginine deiminases or PADs). Interestingly, in some populations (but not all), genetic polymorphisms of the peptidylarginine diminase gene have also been associated with the development of RA. We also know from previous work that citrullinated peptides are more efficiently presented by the HLA-DR shared epitope molecules and lead to greater T cell responses (as studied in vitro).
Thus, smoking may activate or cause increased synthesis of the PAD enzyme(s) which, in turn, would cause citrullination of proteins/peptides in the lungs. Citrullination alters protein charge and can lead to unfolding and loss of tertiary structure, thus potentially unmasking neoepitopes to which neo-autoantibodies are then generated. Presentation of citrullinated peptides in the context of the shared epitopes further ramps up the immune response. Thus, the autoimmune disease that we recognize as RA may evolve.
This is a very attractive hypothesis. However, it remains unclear why CCP negative, and HLA shared epitope negative, patients also get RA (albeit less severe). Secondly, does cigarette smoke truly upregulate the citrullination process and, if so, how? The number of BALs studied here was too small to draw any definitive conclusions. Thirdly, does the substrate for citrullination matter or is it the citrulline moiety itself that is antigenic?
There are many other unanswered questions. Nonetheless, this is a fascinating observation and we look forward to further work on environmental-genetic-autoimmune interactions as potential mechanisms for all of our autoimmune diseases.