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  • Review Article
  • Published:

Mechanisms leading from systemic autoimmunity to joint-specific disease in rheumatoid arthritis

Nature Reviews Rheumatology volume 13, pages 79–86 (2017)Cite this article

Subjects

Key Points

  • Anti-citrullinated protein antibodies (ACPAs) bind specifically to osteoclasts and osteoclast precursors in the normal bone and joint compartment; such binding promotes osteoclast differentiation and osteolytic function in vitro

  • Osteoclast differentiation is dependent on the citrullination of proteins by protein-arginine deiminases

  • Both Fc-dependent and Fc-independent mechanisms are involved in ACPA-mediated osteoclast activation

  • Binding of ACPAs to osteoclasts induces the production of the chemokine IL-8

  • Infusion of ACPAs into mice causes IL-8-dependent bone loss and IL-8-mediated pain behaviour

  • The unique role of citrullination in osteoclast differentiation and ACPA-induced osteoclast activation might explain important features of the gradual development of rheumatoid arthritis, including why the joints are targeted

Abstract

A key unanswered question in the pathophysiology of rheumatoid arthritis (RA) is how systemic autoimmunity progresses to joint-specific inflammation. In patients with seropositive RA (that is, characterized by the presence of autoantibodies) evidence is accumulating that immunity against post-translationally modified (such as citrullinated) autoantigens might be triggered in mucosal organs, such as the lung, long before the first signs of inflammation are seen in the joints. However, the mechanism by which systemic autoimmunity specifically homes to the joint and bone compartment, thereby triggering inflammation, remains elusive. This Review summarizes potential pathways involved in this joint-homing mechanism, focusing particularly on osteoclasts as the primary targets of anti-citrullinated protein antibodies (ACPAs) in the bone and joint compartment. Osteoclasts are dependent on citrullinating enzymes for their normal differentiation and are unique in displaying citrullinated antigens on their cell surface in a non-inflamed state. The binding of ACPAs to osteoclasts releases the chemokine IL-8, leading to bone erosion and pain. This process initiates a chain of events that could lead to attraction and activation of neutrophils, resulting in a complex series of proinflammatory processes in the synovium, eventually leading to RA.

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Figure 1: Anti-citrullinated protein antibodies induce activation of osteoclasts.
Figure 2: Anti-citrullinated protein antibodies induce pain behaviour.
Figure 3: Stages in the development of seropositive rheumatoid arthritis.

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Acknowledgements

The authors' research is supported by grants from the Swedish Research Council; the European Union 7th Framework Programme (FP7) project FP7-HEALTH-2012 INNOVATION-1 Euro-TEAM (305549–2); the Initial Training Network 7th Framework Osteoimmune Programme (289150); the Innovative Medicine Initiative, Be The Cure (115142–2); and the Swedish Foundation for Strategic Research (all to A.I.C. and L.K.); and from the German Research Council Priority Programme, SPP 1468 - Immunobone (CRC1181) and the German Federal Ministry of Education and Research (BMBF) project METARTHROS (to G.S.).

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Authors and Affiliations

  1. Department of Medicine (Solna), Rheumatology Unit, Karolinska Institute and Karolinska University Hospital, Stockholm, 171 76, Sweden

    Anca I. Catrina, Vivianne Malmström & Lars Klareskog

  2. Department of Physiology and Pharmacology, Molecular Pain Research Group, Karolinska Institute, von Eulers väg 8, Stockholm, 171 65, Sweden

    Camilla I. Svensson

  3. Department of Internal Medicine 3, Rheumatology and Immunology, University of Erlangen-Nuremberg, Ulmenweg 18, Erlangen, 91054, Germany

    Georg Schett

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  3. Vivianne Malmström
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  4. Georg Schett
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  5. Lars Klareskog
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Contributions

All authors researched data for the article, contributed substantially to discussions of its content and wrote the manuscript. A.I.C. and L.K. contributed equally to review and/or editing of the article before submission.

Corresponding authors

Correspondence to Anca I. Catrina or Lars Klareskog.

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The authors declare no competing financial interests.

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Catrina, A., Svensson, C., Malmström, V. et al. Mechanisms leading from systemic autoimmunity to joint-specific disease in rheumatoid arthritis. Nat Rev Rheumatol 13, 79–86 (2017). https://doi.org/10.1038/nrrheum.2016.200

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