Objectives Anti-citrullinated protein antibodies (ACPA) are highly specific for rheumatoid arthritis (RA) and have been implicated in disease pathogenesis. Recent ongoing evidence indicates that the ACPA response broadens before precipitation of full-blown RA, as indicated by a more extensive isotype usage and an increased citrullinated epitope recognition profile. Nonetheless, the evolution of the ACPA response is still poorly understood and might intrinsically differ from the protective responses against pathogens.
Methods The avidity and the avidity maturation of ACPA in relation to the avidity of antibodies against recall antigens were analysed.
Results The avidity of ACPA was significantly lower than the avidity of antibodies to the recall antigens tetanus toxoid and diptheria toxoid. Moreover, ACPA did not show avidity maturation during longitudinal follow-up and ACPA avidity was also relatively low in patients who displayed extensive isotype switching.
Conclusions These observations indicate that the natural evolution of ACPA differs from the development of antibodies against recall antigens. These data also indicate that ACPA avidity maturation and isotype switching are disconnected, whereby extensive isotype switching occurs in the setting of restricted avidity maturation. Intrinsic differences between the RA-specific autoantibody system and protective antibody responses against pathogens could be of relevance for designing novel B cell-targeted therapies for RA.
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Funding PS receives a grant from Ramathibodi Hospital, Mahidol University, Thailand. LAT is a recipient of a NWO-VENI grant. DvdW is supported by the Dutch Organization for Scientific Research (AGIKO grant). REMT is a recipient of a NWO-VICI grant. This study was supported by the European Union (Sixth Framework Programme integrated project Autocure and Seventh Framework Programme integrated project Masterswitch number 223404) and also by national funding from the Netherlands Genomics Initiative (NGI) as part of the Netherlands Proteomics Center (NPC) and the Center for Medical Systems Biology (CMSB).
Ethical approval The collection and use of patient samples was approved by the local medical ethics committee in compliance with the Declaration of Helsinki.
Competing interests None.
Provenance and peer review Not commissioned; externally peer reviewed