Abstract
BackgroundBesides anti-citrullinated protein antibodies (ACPA), rheumatoid arthritis patients (RA) often display autoantibody reactivities against other post-translationally modified (PTM) proteins, more specifically carbamylated and acetylated proteins. Immunizing mice with one particular PTM results in an anti-modified protein antibody (AMPA) response recognizing different PTM-antigens. Furthermore, human AMPA, isolated based on their reactivity to one PTM, cross-react with other PTMs. However, it is unclear whether the AMPA-reactivity profile is “fixed” in time or whether consecutive exposure to different PTMs can shape the evolving AMPA response towards a particular PTM.MethodsLongitudinally collected serum samples of 8 human individuals at risk of RA and 5 with early RA were tested with ELISA, and titers were analyzed to investigate the evolution of the AMPA responses over time. Mice (13 per immunization group in total) were immunized with acetylated (or carbamylated) protein (ovalbumin) twice or cross-immunized with an acetylated and then a carbamylated protein (or vice versa) and their serum was analyzed for AMPA responses.ResultsHuman data illustrated dynamic changes in AMPA-reactivity profiles in both individuals at risk of RA and in early RA patients. Mice immunized with either solely acetylated or carbamylated ovalbumin (AcOVA or CaOVA) developed reactivity against both acetylated and carbamylated antigens. Irrespective of the PTM-antigen used for the first immunization, a booster immunization with an antigen bearing the other PTM resulted in increased titers to the second/booster PTM. Furthermore, cross-immunization skewed the overall AMPA-response profile towards a relatively higher reactivity against the “booster” PTM.ConclusionsThe relationship between different reactivities within the AMPA response is dynamic. The initial exposure to a PTM-antigen induces cross-reactive responses that can be boosted by an antigen bearing this or other PTMs, indicating the formation of cross-reactive immunological memory. Upon subsequent exposure to an antigen bearing another type of PTM, the overall reactivity pattern can be skewed towards better recognition of the later encountered PTM. These data might explain temporal differences in the AMPA-response profile and point to the possibility that the PTM responsible for the initiation of the AMPA response may differ from the PTM predominantly recognized later in time.
Highlights
Besides anti-citrullinated protein antibodies (ACPA), rheumatoid arthritis patients (RA) often display autoantibody reactivities against other post-translationally modified (PTM) proteins, carbamylated and acetylated proteins
Dynamic changes of anti-modified protein antibody (AMPA)‐reactivity titers in humans Previously, it has been shown that AMPA levels can fluctuate over time [20, 23]; these levels were measured in arbitrary units at a fixed dilution, and different AMPA reactivities were determined using different antigen backbones
No consistent changes were observed in absolute or relative specific AMPA-levels in individuals at risk for RA, these data show that the AMPA-response to a given PTM is not stable and that these can fluctuate in time
Summary
Besides anti-citrullinated protein antibodies (ACPA), rheumatoid arthritis patients (RA) often display autoantibody reactivities against other post-translationally modified (PTM) proteins, carbamylated and acetylated proteins. Immunizing mice with one particular PTM results in an anti-modified protein antibody (AMPA) response recognizing different PTM-antigens. In the last few decades, many insights have been gained about the role of autoantibody responses in the pathophysiology of rheumatoid arthritis (RA). The exact role of the ACPA response in disease development is not yet clear, considerable insights have been obtained about the nature of this response and its evolution before and after disease onset. The ACPA response may undergo another change, as active treatment with disease-modifying anti-rheumatic drugs (DMARDs) can lead to a decrease of autoantibody levels, rarely results in autoantibody serum levels turning negative [6, 7]. The evolution of the ACPA response before and throughout the disease appears to be a complex phenomenon, as its immunological underpinnings remains to be understood
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