Project 176103

Rheumatoid Arthritis (RA) is a common, chronic and crippling disease that destroys cartilage and bone in the joints. The cause of RA is not known but it has been shown that a molecule called the shared epitope (SE) which is genetically influenced is frequent in those with RA. In addition to the SE, those with RA have antibodies against proteins that have been altered by citrulline (we'll call these anti-citrulline antibodies). These antibodies: 1) are very specific indicators for RA and 2) often occur before RA starts and thus, can be used to predict who is at risk to develop RA. Those with RA who have high amounts of these antibodies have more severe disease. These findings suggest that anti-citrulline antibodies participate in, or even directly cause, RA. This possibility is further strengthened by the fact that anti-citrulline antibodies attack citrullinated proteins which are found in RA joints. Our research group developed a new mouse model that mimics human RA. This mouse is called DR4 transgenic (DR4 tg) mouse. It was genetically engineered to have the SE found in human RA. We were able to induce anti-citrulline antibodies and arthritis in these mice. The proposed studies will examine directly whether, when and how anti-citrulline antibodies and/or cells involved in their production cause arthritis. To answer these questions we will isolate anti-citrulline antibodies and cells from arthritic DR4 tg mice and from RA patients at various stages of the disease. We will inject these anti-citrulline antibodies or cells into healthy mice and determine whether the injected mice develop arthritis. These studies should provide new insight into the cause of RA and allow the design of new forms of therapy or specific treatment directed at blocking the production of anti-citrulline antibodies and/or their citrullinated protein targets in the joints.