Autoantibodies that target PAD4, an enzyme involved in citrullination, have been identified in individuals with rheumatoid arthritis (RA) and are associated with severe joint disease. Despite the discovery of these autoantibodies and their association with disease, their role in the pathogenesis of RA is unclear. Now, a study in Arthritis Rheumatology provides the first in vivo findings that directly implicate anti-PAD4 autoantibodies in the pathogenesis of RA.

To test the function of anti-PAD4 antibodies in vivo and in vitro, the researchers cloned five monoclonal anti-PAD4 antibodies that were derived from individuals with RA. They generated a chimeric antibody from the clone with the highest binding affinity and injected this into mice with collagen-induced arthritis (CIA). Mice injected with the anti-PAD4 antibody had exacerbated disease, more-severe synovial fibroblast hyperplasia and higher innate and adaptive immune cell infiltrates (including monocytes, neutrophils and T cells) in the joints than control animals.