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From risk to chronicity: evolution of autoreactive B cell and antibody responses in rheumatoid arthritis

Nature Reviews Rheumatology volume 18, pages 371–383 (2022)Cite this article

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Abstract

The presence of disease-specific autoantibody responses and the efficacy of B cell-targeting therapies in rheumatoid arthritis (RA) indicate a pivotal role for B cells in disease pathogenesis. Important advances have shaped our understanding of the involvement of autoantibodies and autoreactive B cells in the disease process. In RA, autoantibodies target antigens with a variety of post-translational modifications such as carbamylation, acetylation and citrullination. B cell responses against citrullinated antigens generate anti-citrullinated protein antibodies (ACPAs), which are themselves modified in the variable domains by abundant N-linked glycans. Insights into the induction of autoreactive B cells against antigens with post-translational modifications and the development of autoantibody features such as isotype usage, epitope recognition, avidity and glycosylation reveal their relationship to particular RA risk factors and clinical phenotypes. Glycosylation of the ACPA variable domain, for example, seems to predict RA onset in ACPA+ healthy individuals, possibly because it affects B cell receptor signalling. Moreover, ACPA-expressing B cells show dynamic phenotypic changes and develop a continuously proliferative and activated phenotype that can persist in patients who are in drug-induced clinical remission. Together, these findings can be integrated into a conceptual framework of immunological autoreactivity in RA, delineating how it develops and persists and why disease activity recurs when therapy is tapered or stopped.

Key points

  • Anti-modified-protein antibodies exhibit broad cross-reactivity towards multiple post-translational modifications.

  • Compared with other antibodies, anti-citrullinated protein antibodies (ACPAs) are characterized by the presence of high numbers of N-linked glycans in the variable domain.

  • Generation of the amino acid sequences that are required for N-linked glycosylation is mediated by somatic hypermutation and associated with the presence of HLA-shared epitope alleles.

  • Generation of glycosylation sites occurs prior to the development of rheumatoid arthritis and likely provides a selective advantage to ACPA-expressing B cells.

  • ACPA-expressing B cells, unlike B cells directed against recall antigens, display an activated and proliferative phenotype in rheumatoid arthritis, suggesting that they undergo continuous antigenic triggering.

  • Even in patients in drug-induced clinical remission, ACPA-expressing B cells still display an activated, proliferative phenotype, indicating a lack of induction of immunological remission.

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Fig. 1: Post-translational modifications and autoantibody cross-reactivity.
Fig. 2: Peripheral checkpoints controlling B cell activation.
Fig. 3: Potential induction of autoreactive B cells at mucosal sites and their possible contribution to rheumatoid arthritis.
Fig. 4: Development and structural features of ACPA V-domain glycosylation.
Fig. 5: Conceptual framework for autoreactive B cell activation and the maintenance of disease chronicity.

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Authors and Affiliations

  1. Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands

    Hans Ulrich Scherer, Diane van der Woude & Rene E. M. Toes

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H.U.S. and R.E.M.T. are mentioned inventors on a patent application relating to ACPA-IgG V-domain glycosylation. D.v.d.W. declares no competing interests.

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Scherer, H.U., van der Woude, D. & Toes, R.E.M. From risk to chronicity: evolution of autoreactive B cell and antibody responses in rheumatoid arthritis. Nat Rev Rheumatol 18, 371–383 (2022). https://doi.org/10.1038/s41584-022-00786-4

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