Smoking as a Trigger

No one knows for sure how genes and smoking work together to ignite the spark of RA, but many researchers speculate about how smoke exposure might trigger faulty immune functioning and autoantibody production in a genetically predisposed person. One leading theory involves smoking, the SE gene, and “citrullinated” proteins.

A citrullinated protein is a protein that has undergone a change in one of its amino acids (a switch from arginine to citrulline). This change puts a tag on the protein, letting it be spotted by immune system scouts looking to get rid of old, defective, or problematic cells. Although citrullination is a normal cellular process, several inflammatory diseases are associated with increased levels of citrullinated proteins.

There is growing interest in examining the role citrullinated proteins play in RA. Antibodies to these proteins may appear in the blood many years before symptoms of RA emerge. In addition, studies have shown that:

- Citrullination makes certain proteins more prone to bind to SE gene–containing molecules

- Citrullination of a collagen protein causes the protein to be capable of triggering arthritis in mice

- Citrullinated proteins are found on many cells collected from the airways (lungs) of smokers but not on cells from the airways of nonsmokers

A group of Swedish researchers put this information together to propose a theory of how smoking might trigger RA in a person with a genetically altered immune system. According to this theory, prolonged exposure to cigarette smoke causes formation of a large number of citrullinated proteins that, in the presence of altered immunity, trigger an autoimmune response (antibody formation) that ultimately targets the joints and other tissues for autoimmune attack.

This theory has led researchers to propose further theories, one of which is that initial steps in RA development may occur in the lungs, and that smoking may be part of a trigger mechanism. A research team at University of Colorado in Denver is investigating this theory.

Kristen Demoruelle, MD, a second-year rheumatology fellow on the Denver research team, describes the group’s work as “preclinical” because it involves studying people who have not developed symptoms of RA but are considered at high risk for the disease because they have a family member with RA and test positive for ACPAs or for two or more versions of the rheumatoid factor antibody. In previous studies by the group, the presence of these high-risk autoantibodies predicted the future development of RA. The team is trying to understand how and why these autoantibodies appear before RA starts.