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  • Review Article
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Coeliac disease and rheumatoid arthritis: similar mechanisms, different antigens

Nature Reviews Rheumatology volume 11, pages 450–461 (2015)Cite this article

Subjects

Key Points

  • Coeliac disease and rheumatoid arthritis are multifactorial HLA-associated diseases

  • Immune responses to enzymatically modified protein antigens are a hallmark of both these diseases

  • Environmental insults are probably key to breaking of immune tolerance to enzymatically modified protein antigens

  • B-cell to T-cell presentation of target enzymatically modified protein antigens provides a powerful amplification loop sustaining the autoimmune disease process

  • This paradigm provides multiple targets for specific interventions aimed at reinstating immune tolerance to enzymatically modified protein antigens

Abstract

Rheumatoid arthritis (RA) and coeliac disease are inflammatory diseases that both have a strong association with class II HLAs: individuals carrying HLA-DQ2.5 and/or HLA-DQ8 alleles have an increased risk of developing coeliac disease, whereas those carrying HLA-DR shared epitope alleles exhibit an increased risk of developing RA. Although the molecular basis of the association with specific HLA molecules in RA remains poorly defined, an immune response against post-translationally modified protein antigens is a hallmark of each disease. In RA, understanding of the pathogenetic role of B-cell responses to citrullinated antigens, including vimentin, fibrinogen and α-enolase, is rapidly growing. Moreover, insight into the role of HLAs in the pathogenesis of coeliac disease has been considerably advanced by the identification of T-cell responses to deamidated gluten antigens presented in conjunction with predisposing HLA-DQ2.5 molecules. This article briefly reviews these advances and draws parallels between the immune mechanisms leading to RA and coeliac disease, which point to a crucial role for T-cell–B-cell cooperation in the development of full-blown disease. Finally, the ways in which these novel insights are being exploited therapeutically to re-establish tolerance in patients with RA and coeliac disease are described.

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Figure 1: Binding of modified peptides to MHC class II molecules and their interactions with T cells in coeliac disease and RA.
Figure 2: Recognition of HLA-DQ2.5–α2-gliadin complexes by the S16 TCR, which consists of TCR α-chain V (TRAV) 26-1 and TCR β-chain V (TRBV) 7-2 subunits.
Figure 3: A two-hit model for the development of ACPA-positive RA.
Figure 4: T cells and B cells in coeliac disease and RA.

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Acknowledgements

The authors' research work is supported by the Australian Research Council, the National Health and Medical Research Council (NHMRC) of Australia and the Dutch Arthritis foundation. R.T. is supported by an NHMRC Research fellowship and Arthritis Queensland, J.R. by an NHMRC Australia Fellowship, and R.E.T. by a Vici fellowship from Nederlandse Organizatie voor Wetenschappelijk Onderzoek (NWO). The authors thank Jan Petersen for help with the drafting of the original figures.

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Authors and Affiliations

  1. Department of Immunohaematology and Blood Transfusion, Leiden University Medical Centre, Albinusdreef 2, Leiden, 2333, ZA, Netherlands

    Frits Koning

  2. Department of Rheumatology, Leiden University Medical Centre, Albinusdreef 2, Leiden, 2333, ZA, Netherlands

    Rene E. Toes

  3. The University of Queensland Diamantina Institute, Level 6, Translational Research Institute, Princess Alexandra Hospital, 37 Kent Street, Woolloongabba, 4102, QLD, Australia

    Ranjeny Thomas

  4. Australian Research Council Centre of Excellence in Advanced Molecular Imaging and Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, Monash University, Clayton, 3800, VIC, Australia

    Jamie Rossjohn

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  4. Rene E. Toes
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The authors contributed equally to all aspects of the manuscript: researching data for the article, discussions of its content, writing and review or editing of the manuscript before submission.

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Correspondence to Frits Koning.

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Competing interests

R.T. has filed patent applications (PCT/AU2007/001555: Compositions and methods for modulating immune responses, USA; PCT/AU2013/000303: Citrullinated aggrecan peptides for immunotherapy in rheumatoid arthritis, USA) related to technology for targeting dendritic cells to achieve antigen-specific tolerance, and is a director of Dendright, a spin-off company developing commercial vaccines that target dendritic cells to suppress autoimmune diseases. The other authors declare no competing interests.

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Koning, F., Thomas, R., Rossjohn, J. et al. Coeliac disease and rheumatoid arthritis: similar mechanisms, different antigens. Nat Rev Rheumatol 11, 450–461 (2015). https://doi.org/10.1038/nrrheum.2015.59

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