Among the autoantibodies detected in patients with rheumatoid arthritis, none indicate the disease as reliably as those that bind to citrullinated proteins. On page 449, Uysal et al. now suggest that these popular biomarkers not only signal the presence of disease, but help to induce it.

The inflamed cartilage and soft tissue in arthritic patients' joints consist mainly of type II collagen. Previous studies showed that those collagenous proteins are partially citrullinated—in other words, some of their arginine residues have been replaced by citrulline. The presence of antibodies targeting citrullinated proteins diagnoses arthritis with 99% accuracy. And because they are often detected before arthritic symptoms set in, Uysal et al. suspected that they might help generate joint destruction.

The authors now confirm the disease-inducing role of antibodies targeting citrullinated collagen epitopes. Injecting these antibodies into normal mice resulted in disease, and injecting them into arthritic mice worsened disease. According to Uysal et al., disease induction relates to how these antibodies bind their target.

By assessing the crystal structure of one antibody-citrullinated protein complex, the authors show that the antibody recognizes citrulline, rather than some other part of the modified protein. This direct binding suggests that the antibodies might cross-react with other proteins known to be citrullinated in arthritic joints, such as fibrinogen and fillagrin, thus exacerbating inflammation.

The numbers of citrulline-specific antibodies may soar soon after citrullinated proteins evoke an immune response. Mixed in with these antibodies are others that react to noncitrullinated collagen epitopes. The authors speculate that the latter antibodies might present collagen epitopes to T cells. And in turn, collagen-specific T cells could provide help for B cells that recognize either modified or unmodified collagen, creating a vicious cycle that culminates in collagen attack and cartilage destruction.

Why citrulline triggers an immune response in the first place and why that reaction is joint-specific in arthritis remain key questions. Because citrullinated proteins lurk behind several other human diseases, such as psoriasis and multiple sclerosis, understanding how these antibodies interact with their targets may help unravel the pathenogenicity of multiple maladies.