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OPINION

The structure, specificity and function of anti-citrullinated protein antibodies

Nature Reviews Rheumatology volume 15, pages 503–508 (2019)Cite this article

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Abstract

In this Perspectives article, we outline a proposed model for understanding the specificity and function of anti-citrullinated protein antibodies (ACPAs). We suggest that ACPAs vary in specificity between two extremes: some are ‘promiscuous’ in that they are highly specific for the citrulline side chain, but cross-react with a range of citrullinated peptides, whereas others are ‘private’ in that their recognition of citrulline as well as proximal amino acid side chains enables protein-specific interactions. Promiscuous ACPAs tend to dominate in the sera both before and after the onset of rheumatoid arthritis, but their functional role has not been clarified. No firm evidence exists that these ACPAs are pathogenic. By contrast, private ACPAs encompass antibodies that specifically recognize citrullinated epitopes on joint proteins or that cross-react with joint proteins, thereby opening up the possibility that these private ACPAs are arthritogenic. These joint-reactive antibodies are more likely to target joints by binding to joint tissues and to promote the formation of local immune complexes leading to bone erosions, pain and arthritis.

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Fig. 1: Examples of different types of ACPAs and joint-reactive autoantibodies in RA.
Fig. 2: The three stages of the development of RA.

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Acknowledgements

The work of the authors is supported by grants from the Knut and Alice Wallenberg Foundation, the Swedish Association against Rheumatism, the Swedish Medical Research Council, the Swedish Foundation for Strategic Research and the EU-funded IMI project BeTheCure. We thank C. Svensson, Karolinska Institute, for critical reading and corrections.

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  1. Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden

    Changrong Ge & Rikard Holmdahl

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  1. Changrong Ge
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Both authors researched data for the article, contributed to the discussion of content, wrote, and reviewed/edited the manuscript before submission.

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Correspondence to Rikard Holmdahl.

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The authors are listed as inventors on a patent application describing the protective effects of ACPA (Holmdahl R, Rispens T, Xu B, Ge C. Antibodies to citrullinated proteins. European Patent office PCT/EP2018/082236)

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Ge, C., Holmdahl, R. The structure, specificity and function of anti-citrullinated protein antibodies. Nat Rev Rheumatol 15, 503–508 (2019). https://doi.org/10.1038/s41584-019-0244-4

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