Anti-citrullinated protein antibodies (ACPAs) are a hallmark of rheumatoid arthritis (RA) and have long been considered to contribute to pathogenesis. In this study, we sequenced the plasmablast antibody repertoires of RA patients and functionally characterized their encoded ACPAs. Recombinantly expressed monoclonal ACPAs bound citrullinated autoantigens, as well as autocitrullinated peptidylarginine deiminase 4 (PAD4). Using the collagen antibody induced arthritis (CAIA) mouse model, we demonstrated that the recombinant ACPAs significantly reduced paw thickness and arthritis severity as compared to isotype-matched control antibodies. Treatment with recombinant ACPAs also significantly reduced bone erosions, synovitis, and cartilage damage in histologic analysis of paws. This amelioration was observed for all the ACPAs tested and was independent of citrullinated antigen specificities. Furthermore, disease amelioration was more prominent when ACPAs were injected at earlier stages of CAIA than at later phases of the model, implying that ACPAs’ anti-inflammatory effects were more preventative than therapeutic. This study highlights a potential protective role for ACPAs in RA.
