Review Article | Published:

The B cell response to citrullinated antigens in the development of rheumatoid arthritis

Nature Reviews Rheumatology volume 14, pages 157169 (2018) | Download Citation


The immune response to citrullinated antigens is found almost exclusively in patients with rheumatoid arthritis (RA). It is a dynamic response that expands before the onset of disease and generates antibodies (anti-citrullinated protein antibodies (ACPAs)) that are extensively glycosylated in the variable domain. This feature of ACPAs is remarkable and warrants detailed investigation, as it can offer insights into the earliest immunologic mechanisms that lead up to the development of RA. The acquisition of variable domain glycans, in fact, could enable ACPA-expressing B cells to breach tolerance. Although the underlying mechanisms are still elusive, data to support this concept are emerging, owing to the reliable identification and isolation of citrullinated antigen-directed B cells from patients with RA. This technological proficiency also allows for the generation of an increasing number of well-defined monoclonal ACPAs, and provides the opportunity to test and define the mechanisms by which the citrullinated antigen-directed B cell response contributes to the onset and persistence of inflammation. Together with a revised perception of the HLA-risk effect and novel insights into how T cells can govern antibody effector functions, these developments shape an increasingly clear picture of the B cell response to citrullinated antigens in the development of RA.

Key points

  • The anti-citrullinated protein antibody (ACPA) response dynamically evolves before the onset of rheumatoid arthritis (RA)

  • HLA-shared epitope alleles and T cells are suggested to be involved in driving the expansion of the ACPA response in the pre-arthritis phase of RA

  • ACPA-IgG molecules are extensively glycosylated in the variable domain because of N-glycosylation sites generated by somatic hypermutation

  • The extensive presence of ACPA-IgG variable domain glycans points to mechanisms by which ACPA-expressing B cells could escape tolerance checkpoints

  • ACPA Fc-glycans potentially function as modulators of inflammation and, via IL-23 and T helper 17 cells, could be involved in the transition from asymptomatic autoimmunity to inflammatory arthritis

  • The frequency and phenotype of ACPA-expressing B cells in the circulation suggest a continuously active B cell immune response that is insufficiently targeted by current therapeutic interventions

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The authors thank Lise Hafkenscheid for help with preparing the molecular model depicted in the figure in Box 2. H.U.S, R.E.M.T. and T.H.U. acknowledge support from the Dutch Arthritis Foundation, the Netherlands Organisation for Scientific Research (NWO), and European Union Innovative Medicines Initiative and 7th Framework Program (FP7) grants. G.S. acknowledges support from the German Research Council (DFG) through projects SPP1468, SPP1937 and CRC1181 as well as the Innovative Medicines Initiative-funded project BTCure.

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  1. Department of Rheumatology, Leiden University Medical Center, PO Box 9600, 2300RC Leiden, The Netherlands.

    • Hans Ulrich Scherer
    • , Tom W. J. Huizinga
    •  & Rene E. M. Toes
  2. Department of Internal Medicine 3, Rheumatology and Immunology, Friedrich Alexander University Erlangen-Nürnberg (FAU) and Universitätsklinikum, Ulmenweg 18, 91054 Erlangen, Germany.

    • Gerhard Krönke
    •  & Georg Schett


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All authors wrote the article, provided substantial contributions to discussions of its content, and undertook review and/or editing of the manuscript before submission.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Rene E. M. Toes.


Immunoglobulin isotypes

Different immunoglobulin variants, defined by the isotype of the immunoglobulin heavy chains (α, δ, γ, ε, μ).


In antibodies, describes the cumulative binding strength of more than one receptor–ligand interaction; the binding strength of multiple, polyclonal antibodies (each of which potentially exhibits a different affinity for a particular antigen) can be described based on their avidity.

HLA shared epitope

(HLA-SE). A group of genes encoding HLA alleles that share a common amino acid sequence (the 'shared epitope') in the antigen-binding region of the HLA molecule; carriers of these alleles are at an increased risk of developing anti-citrullinated protein antibody (ACPA)-positive RA.


The post-translational, covalent linkage of glycan residues (carbohydrates) to an asparagine (N) residue in a given protein.

Somatic hypermutation

A process that introduces point mutations in genes that encode variable regions of antibodies; part of affinity maturation that occurs primarily in germinal centres.

Affinity maturation

The process that generates B cell receptors with increased affinity for their cognate antigen, in which B cells with the highest avidity are positively selected; this process requires somatic hypermutation in B cells and occurs mainly in germinal centres.

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