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Glycobiology of rheumatic diseases

Nature Reviews Rheumatology volume 19, pages 28–43 (2023)Cite this article

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An Author Correction to this article was published on 23 February 2023

This article has been updated

Abstract

Glycosylation has a profound influence on protein activity and cell biology through a variety of mechanisms, such as protein stability, receptor interactions and signal transduction. In many rheumatic diseases, a shift in protein glycosylation occurs, and is associated with inflammatory processes and disease progression. For example, the Fc-glycan composition on (auto)antibodies is associated with disease activity, and the presence of additional glycans in the antigen-binding domains of some autoreactive B cell receptors can affect B cell activation. In addition, changes in synovial fibroblast cell-surface glycosylation can alter the synovial microenvironment and are associated with an altered inflammatory state and disease activity in rheumatoid arthritis. The development of our understanding of the role of glycosylation of plasma proteins (particularly (auto)antibodies), cells and tissues in rheumatic pathological conditions suggests that glycosylation-based interventions could be used in the treatment of these diseases.

Key points

  • Autoantigen-specific IgG in patients with rheumatic diseases has a distinct N-glycosylation signature in the fragment crystallizable (Fc) domain, characterized by fucosylation without sialylation or galactosylation.

  • In rheumatoid arthritis (RA) and anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, autoantigen-specific IgG, as well as autoreactive B cell receptors, are extensively N-glycosylated in the fragment antigen-binding (Fab) domain.

  • Specific Fc and Fab IgG glycan signatures are associated with RA disease activity and remission.

  • Mechanistic evidence is lacking on how fucosylated, agalactosylated IgG Fc glycans possibly cause a pro-inflammatory phenotype in humans.

  • RA is associated with reduction of cell-surface sialylation of synovial fibroblasts, affecting their interactions with galectin-3 and resulting in a cytokine-induced switch towards a pro-inflammatory phenotype.

  • Glycan-based therapies could intervene in inflammatory processes by alteration of glycosylation, or by specific targeting and depletion of autoreactive B cells and autoantibodies.

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Fig. 1: Biosynthesis of protein glycans and the IgG-specific glycan signatures in rheumatoid arthritis.
Fig. 2: Functional effects of disease-specific Fc and Fab glycosylation in humans.
Fig. 3: Disease-specific tissue glycosylation.
Fig. 4: Therapeutic potential of glycosylation.

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Authors and Affiliations

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

    Theresa Kissel, René E. M. Toes & Thomas W. J. Huizinga

  2. Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, Netherlands

    Manfred Wuhrer

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The authors contributed equally to all aspects of the article.

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R.E.M.T. and T.W.J.H. are mentioned inventors on a patent application on ACPA-IgG V-domain glycosylation. The remaining authors declare no competing interests.

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Kissel, T., Toes, R.E.M., Huizinga, T.W.J. et al. Glycobiology of rheumatic diseases. Nat Rev Rheumatol 19, 28–43 (2023). https://doi.org/10.1038/s41584-022-00867-4

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