Insights into the origin of ACPAs in RA

PROJECT SUMMARY/ABSTRACT Citrullination is a physiologic post-translational modification found across multiple normal human tissues. Why this modification is the most important target of antibodies in rheumatoid arthritis (RA) is unknown. While the pathogenic role of anti-citrullinated protein antibodies (ACPAs) remains uncertain, the striking association between ACPAs and RA has raised the possibility that understanding the origin of these antibodies may shed light on the cause of RA. Interestingly, our preliminary studies provide evidence that ACPAs may originate from a distinct antibody targeting a different but structurally similar modification, known as carbamylation. Our overarching hypothesis is that ACPAs can arise during affinity maturation of germline encoded antibodies to carbamylated proteins. In this proposal, we will use RA-derived monoclonal ACPAs to support or discard this novel hypothesis. If the proposal is successful, this work may uncover a mechanism for why citrullinated proteins become immunogenic and potentially to support germline encoded antibodies to carbamylated proteins as initial players in the development of RA.