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Lungs, joints and immunity against citrullinated proteins in rheumatoid arthritis

Key Points

  • Autoantibodies against post-translational modified citrullinated proteins, so-called anti-citrullinated protein antibodies (ACPAs), define a distinct clinical RA phenotype; this phenotype is characterized by an increased frequency of early inflammatory lung changes

  • The presence of ACPAs before signs of inflammation in joints suggests that immunity against citrullinated proteins is initiated outside the joint

  • Changes in the lung and enrichment of ACPAs in the lungs (bronchoalveolar lavage fluid) occur in both individuals at risk of developing RA as well as patients with early RA

  • The lung, therefore, might be a site of initiation of immunity to citrullinated proteins

  • Early targeting of the immune reactions in the lung might be a new approach to modulate disease

Abstract

Rheumatoid arthritis (RA) is a prototype for a criterion-defined inflammatory disease, for which the aetiology and initial molecular pathogenesis has been elusive for a long time. We describe in this Review how studies on the interplay between specific immunity, alongside genetic and environmental predisposing factors, provide new tools to understand the molecular basis of distinct subsets of the disease. A particular emphasis is on the possibility that pathogenic immune reactions might be initiated at other sites than the joints, and that the lungs could harbour such sites. New data strengthen this concept, showing that local immunity towards citrullinated proteins and accompanying inflammation might be present in the lungs early during disease development. This progress makes RA an interesting case for the future development of therapies that might be directed against disease-inducing immunity even before inflammation and destruction of joints has begun.

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Figure 1: A schematic model of initiation of RA-associated immunity against citrullinated proteins in the lungs.
Figure 2: Summary of the pathogenic roles of ACPAs in RA.

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Acknowledgements

A.I.C. acknowledges support from the Swedish Foundation for Strategic Research, the Initial Training Networks 7th framework programme Osteoimmune (289150), the European 7th framework programme (FP7/2007–2013) Euro-TEAM (305549), the Innovative Medicine Initiative Be The Cure (115142-2) and the Swedish Research Council. A.J.Y. acknowledges grant support from the Swedish Foundation for Strategic Research. L.K. acknowledges support from the Swedish Foundation for Strategic Research, the European 7th framework programme (FP7/2007–2013) Euro-TEAM (305549), the Innovative Medicine Initiative Be The Cure (115142-2) and the Swedish Research Council.

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All authors made substantial contributions to researching data for the article and made substantial contributions to discussions of content and writing the article. A.I.C. and L.K. had the main responsibility for reviewing and/or editing of the article before submission.

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Correspondence to Anca I. Catrina.

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Catrina, A., Ytterberg, A., Reynisdottir, G. et al. Lungs, joints and immunity against citrullinated proteins in rheumatoid arthritis. Nat Rev Rheumatol 10, 645–653 (2014). https://doi.org/10.1038/nrrheum.2014.115

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