Significance: The production of antibodies to posttranslationally modified antigens is a hallmark in rheumatoid arthritis (RA). In particular, the presence of citrullination-associated antibodies, targeting both citrullinating enzymes (the peptidylarginine deiminases [PADs]) and citrullinated antigens (anticitrullinated protein antibodies [ACPAs]), has suggested that dysregulated citrullination is relevant for disease pathogenesis. Antibodies to other protein modifications with physicochemical similarities to citrulline, such as carbamylated-lysine and acetylated-lysine, have also gained interest in RA, but their mechanistic relation to ACPAs remains unclear. Recent Advances: Recent studies using RA-derived monoclonal antibodies have found that ACPAs are cross-reactive to carbamylated and acetylated peptides, challenging our understanding of the implications of such cross-reactivity. Critical Issues: Analogous to the classic antibody response to chemically modified proteins, we examine the possibility that antibodies to modified proteins in RA are more likely to resemble antihapten antibodies rather than autoantibodies. This potential shift in the autoantibody paradigm in RA offers the opportunity to explore new mechanisms involved in the origin and cross-reactivity of pathogenic antibodies in RA. In contrast to citrullination, carbamylation is a chemical modification associated with oxidative stress, it is highly immunogenic, and is considered in the group of posttranslational modification-derived products. We discuss the possibility that carbamylated proteins are antigenic drivers of cross-reacting antihapten antibodies that further create the ACPA response, and that ACPAs may direct the production of antibodies to PAD enzymes. Future Directions: Understanding the complexity of autoantibodies in RA is critical to develop tools to clearly define their origin, identify drivers of disease propagation, and develop novel therapeutics. Antioxid. Redox Signal. 36, 389-409.
Keywords: ACPA; PAD; acetylation; carbamylation; citrullination; rheumatoid arthritis.