Interleukin-21 modulates Th1 and Th17 responses in giant cell arteritis

Authors

  • Benjamin Terrier,

    1. Université Pierre et Marie Curie, Paris 6, CNRS UMR 7211, and INSERM UMRS 959, Paris, France
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    • Drs. Terrier and Geri contributed equally to this work;

  • Guillaume Geri,

    1. Université Pierre et Marie Curie, Paris 6, CNRS UMR 7211, and INSERM UMRS 959, Paris, France
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    • Drs. Terrier and Geri contributed equally to this work;

  • Wahiba Chaara,

    1. Université Pierre et Marie Curie, Paris 6, CNRS UMR 7211, INSERM UMRS 959, and Groupe Hospitalier Pitié-Salpetrière, Paris, France
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    • Drs. Chaara and Allenbach contributed equally to this work;

  • Yves Allenbach,

    1. Université Pierre et Marie Curie, Paris 6, CNRS UMR 7211, INSERM UMRS 959, and Groupe Hospitalier Pitié-Salpetrière, Paris, France
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    • Drs. Chaara and Allenbach contributed equally to this work;

  • Michelle Rosenzwajg,

    1. Université Pierre et Marie Curie, Paris 6, CNRS UMR 7211, INSERM UMRS 959, and Groupe Hospitalier Pitié-Salpetrière, Paris, France
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  • Nathalie Costedoat-Chalumeau,

    1. Université Pierre et Marie Curie, Paris 6, CNRS UMR 7211, INSERM UMRS 959, and Groupe Hospitalier Pitié-Salpetrière, Paris, France
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  • Pierre Fouret,

    1. Université Pierre et Marie Curie, Paris 6 and Groupe Hospitalier Pitié-Salpetrière, Paris, France
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  • Lucile Musset,

    1. Université Pierre et Marie Curie, Paris 6 and Groupe Hospitalier Pitié-Salpetrière, Paris, France
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  • Olivier Benveniste,

    1. Université Pierre et Marie Curie, Paris 6, CNRS UMR 7211, INSERM UMRS 959, and Groupe Hospitalier Pitié-Salpetrière, Paris, France
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  • Adrien Six,

    1. Université Pierre et Marie Curie, Paris 6, CNRS UMR 7211, and INSERM UMRS 959, Paris, France
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  • David Klatzmann,

    1. Université Pierre et Marie Curie, Paris 6, CNRS UMR 7211, INSERM UMRS 959, and Groupe Hospitalier Pitié-Salpetrière, Paris, France
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  • David Saadoun,

    Corresponding author
    1. Université Pierre et Marie Curie, Paris 6, CNRS UMR 7211, INSERM UMRS 959, and Groupe Hospitalier Pitié-Salpetrière, Paris, France
    • Department of Internal Medicine, UMR 7211 (CNRS/UPMC), INSERM U959, Hôpital Pitié-Salpétrière, 47-83 Boulevard de l'Hôpital, 75013 Paris, France
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    • Drs. Saadoun and Cacoub contributed equally to this work.

  • Patrice Cacoub

    Corresponding author
    1. Université Pierre et Marie Curie, Paris 6, CNRS UMR 7211, INSERM UMRS 959, and Groupe Hospitalier Pitié-Salpetrière, Paris, France
    • Department of Internal Medicine, UMR 7211 (CNRS/UPMC), INSERM U959, Hôpital Pitié-Salpétrière, 47-83 Boulevard de l'Hôpital, 75013 Paris, France
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    • Drs. Saadoun and Cacoub contributed equally to this work.


Abstract

Objective

Giant cell arteritis (GCA) is a large-vessel vasculitis of unknown origin. Recent findings indicate that at least 2 separate lineages of CD4+ T cells, Th1 and Th17 cells, participate in vascular inflammation. The pathways driving these T cell differentiations are incompletely understood, but may provide novel therapeutic targets. This study was undertaken to identify cytokines involved in the pathogenesis of GCA.

Methods

Thirty GCA patients fulfilling the American College of Rheumatology criteria, with active disease or disease in remission, and 30 age-matched controls were included. Levels of 27 cytokines were determined in culture supernatants, and flow cytometric analysis of peripheral blood mononuclear cells (PBMCs) and immunohistochemical analysis of temporal artery samples were performed.

Results

Multiparametric analysis of cytokines produced by PBMCs associated with GCA disease activity identified a signature involving interleukin-2 receptor (IL-2R), IL-12, interferon-γ (IFNγ), IL-17A, IL-21, and granulocyte–macrophage colony-stimulating factor (GM-CSF). An expansion of Th1 and Th17 cells and a decrease in Treg cells were observed in the peripheral blood of patients with active GCA. An expansion of IL-21–producing CD4+ T cells was also observed in patients with active GCA and correlated positively with Th17 and Th1 cell expansion. Immunohistochemical analysis revealed IFNγ, IL-17A, and IL-21 expression within inflammatory infiltrates. Stimulation of purified CD4+ T cells with IL-21 increased Th1 and Th17 cell frequencies and decreased FoxP3 expression. In contrast, blockade of IL-21 using IL-21R-Fc markedly decreased the production of IL-17A and IFNγ and increased FoxP3 expression.

Conclusion

Our findings indicate that IL-21 plays a critical role in modulating Th1 and Th17 responses and Treg cells in GCA, and might represent a potential target for novel therapy.

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