Update on autoantibodies to modified proteins.

Abstract

This article provides an update on the recent findings on autoantibodies to modified proteins in rheumatoid arthritis (RA). In the past few years, the knowledge on the autoantibodies to citrullinated antigens has expanded considerably. More specifically, it is now clear that many different citrullinated protein antigens present in the synovial compartment can be recognized by anticitrullinated protein antibody (ACPA). This is most likely a consequence of the cross-reactivity the ACPA response displays to citrullinated proteins. It is now also clear that the isotype usage and the citrullinated epitope repertoire recognized by ACPA expands before the manifestation of full-blown RA and that this goes hand in hand with a rise in ACPA level. Next to ACPA, several other autoantibody systems directed against other posttranslationally modified proteins, such as proteins containing a homocitrulline residue resulting from protein carbamylation, have been identified. On the whole, the evolution of these autoantibody systems in time mimics the evolution of the ACPA response, indicating that the break of tolerance underlying different autoimmune responses present in RA occurs before disease onset, with a further maturation of these responses shortly before or concurrent with the manifestation of clinical symptoms. Since the discovery of rheumatoid factor over 65 years ago, our knowledge on autoantibodies and their relevance for rheumatic disease has expanded enormously. Especially, the realization that next to rheumatoid factor, also other autoantibodies recognizing posttranslationally modified proteins are present in RA patients has contributed significantly to the understanding of disease. In the past few years, several new autoantibody systems to differentially modified proteins have been identified and their relation to clinical outcome has been scrutinized. Here, we provide an update on the recent developments in our knowledge on the presence and consequences of autoantibodies to modified proteins in RA.