Protective and Pathogenic Antibodies to Citrullinated Antigens

Autoimmune diseases start years before clinical onset. In rheumatoid arthritis (RA), autoantibodies to citrullinated proteins (ACPA) and to modified IgG (rheumatoid factors, RF) can be detected many years before the inflammatory attack on cartilaginous joints. It has been assumed that these antibodies are pathogenic. We show here that many of the antibodies produced before disease onset are protective although there are likely also pathogenic clones directed to cartilaginous joints. To determine the function of these antibodies, it is crucial to analyze them in vivo, which is only possible in mouse models. To ease the translation, we have genetically humanized models which will now allow a more accurate analysis of autoimmune mechanisms in human disease. In this review, we will also discuss what we know today regarding the targeted epitopes and the role of pathogenic and protective antibodies. With this knowledge as the basis, we have developed new types of serologic tests for RA.