Antibodies and B cells recognising citrullinated proteins display a broad cross-reactivity towards other post-translational modifications
- 1 April 2020
- journal article
- research article
- Published by BMJ in Annals Of The Rheumatic Diseases
- Vol. 79 (4), 472-480
- https://doi.org/10.1136/annrheumdis-2019-216499
Abstract
Objective Autoantibodies against antigens carrying distinct post-translational modifications (PTMs), such as citrulline, homocitrulline or acetyllysine, are hallmarks of rheumatoid arthritis (RA). The relation between these anti-modified protein antibody (AMPA)-classes is poorly understood as is the ability of different PTM-antigens to activate B-cell receptors (BCRs) directed against citrullinated proteins (CP). Insights into the nature of PTMs able to activate such B cells are pivotal to understand the 'evolution' of the autoimmune response conceivable underlying the disease. Here, we investigated the cross-reactivity of monoclonal AMPA and the ability of different types of PTM-antigens to activate CP-reactive BCRs. Methods BCR sequences from B cells isolated using citrullinated or acetylated antigens were used to produce monoclonal antibodies (mAb) followed by a detailed analysis of their cross-reactivity towards PTM-antigens. Ramos B-cell transfectants expressing CP-reactive IgG BCRs were generated and their activation on stimulation with PTM-antigens investigated. Results Most mAbs were highly cross-reactive towards multiple PTMs, while no reactivity was observed to the unmodified controls. B cells carrying CP-reactive BCRs showed activation on stimulation with various types of PTM-antigens. Conclusions Our study illustrates that AMPA exhibit a high cross-reactivity towards at least two PTMs indicating that their recognition pattern is not confined to one type of modification. Furthermore, our data show that CP-reactive B cells are not only activated by citrullinated, but also by carbamylated and/or acetylated antigens. These data are vital for the understanding of the breach of B-cell tolerance against PTM-antigens and the possible contribution of these antigens to RA-pathogenesis.Funding Information
- ZonMw (435002030, 90714509, 91116004, 91214031, 91617107)
- Deutsche Forschungsgemeinschaft (A031503, TRR130-P02)
- RTCure (777357)
- Excellence Initiative of the German federal and state governments (EXC 294)
- ReumaNederland (15-2-402, 17-1-402, 18-1-205)
- Target-to-B (LSHM18055-SGF)
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