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  • Review Article
  • Published:

Beyond citrullination: other post-translational protein modifications in rheumatoid arthritis

Key Points

  • As well as citrullination, several other post-translational protein modifications are targeted by autoantibodies in rheumatoid arthritis (RA)

  • Anti-hinge antibodies might restore the lost capacity to trigger Fc effector functions of IgG cleaved in the hinge region by proteases expressed in the synovial compartment

  • Anti-modified protein antibodies (AMPAs) are mainly found in anti-citrullinated protein antibody (ACPA)-positive patients

  • Anti-carbamylated protein (anti-CarP) antibodies and ACPAs are only partially crossreactive despite recognizing two rather similar modifications

  • T cell help for AMPA-producing B cells does not have to target the post-translationally modified protein owing to the crossreactive nature of AMPAs

  • Post-translationally modified matrix proteins could be relevant targets for AMPAs in RA because these immobile proteins are difficult to clear and hence are exposed in a durable manner

Abstract

The presence of autoantibodies is one of the hallmarks of rheumatoid arthritis (RA). In the past few decades, rheumatoid factors (autoantibodies that recognize the Fc-tail of immunoglobulins) as well as anti-citrullinated protein antibodies (ACPAs) have been studied intensively. ACPAs recognize post-translationally modified proteins in which the amino acid arginine has been converted into a citrulline. More recently, other autoantibody systems recognizing post-translationally modified proteins have also gained attention, including autoantibodies recognizing fragmented immunoglobulin (anti-hinge antibodies), autoantibodies recognizing acetylated proteins and autoantibodies recognizing proteins that are modified by adducts formed under oxidative stress. In particular, detailed insights have been obtained on the presence and properties of autoantibodies recognizing carbamylated proteins, commonly called anti-carbamylated protein (anti-CarP) antibodies. In this Review, we summarize the current knowledge relating to these emerging autoantibodies that recognize post-translationally modified proteins identified in RA, with an emphasis on anti-CarP antibodies.

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Figure 1: Post-translational modifications of plasma proteins versus matrix proteins.
Figure 2: Possible mechanisms of T cell help provided to AMPA-producing B cells.
Figure 3: Limited proteolysis results in the formation of IgG fragments.
Figure 4: Post-translational modifications on arginine and lysine.

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Acknowledgements

The authors wish to acknowledge the support of the Innovative Medicines Initiative Joint Undertaking (IMI JU)-funded project BeTheCure (contract no. 115142–2), the Molecular Diagnostics in Rheumatoid Arthritis (MODIRA) project (40-43600-98-14001) and the Dutch Arthritis Foundation. L.A.T. is financially supported by a VIDI grant from the Netherlands Organisation for Scientific Research. R.E.M.T. is financially supported by a VICI grant from the Netherlands Organisation for Scientific Research.

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Correspondence to Rene E. M. Toes.

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L.A.T. and R.E.M.T are listed as inventors on a patent for a method related to the detection of anti-CarP antibodies in arthritis (EP2671078B1).

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Trouw, L., Rispens, T. & Toes, R. Beyond citrullination: other post-translational protein modifications in rheumatoid arthritis. Nat Rev Rheumatol 13, 331–339 (2017). https://doi.org/10.1038/nrrheum.2017.15

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