Autoantibodies against peptidylarginine deiminases (PADs) may worsen rheumatoid arthritis by increasing the sensitivity of these enzymes for calcium (Sci. Trans. Med. 5, 186ra65).

Credit: Moredun / Science Source

PADs convert peptidylarginine to citrulline. As citrullinated proteins are effective autoantigens, PADs have been implicated in autoimmune disease. In the case of rheumatoid arthritis, PAD4 is of particular interest, as it is found in synovial fluid. However, PAD4 requires high concentrations of calcium, much higher than those found at the synovium, to work.

Studying samples from patients with rheumatoid arthritis, Erika Darrah et al. identified autoantibodies that recognize both PAD3 and PAD4 and that markedly increase the activity of PAD4. By measuring enzyme kinetics, the authors found that the antibodies increased PAD4's sensitivity for calcium by an order of magnitude. People with arthritis with these autoantibodies had worse disease than those who were negative for them.

Although it remains to be seen whether this mechanism is active in vivo, the results of this study disclose an intriguing new mechanism for the generation of citrullinated autoantigens and for the pathogenesis of rheumatoid arthritis.