T-helper 17 cells expand in multiple sclerosis and are inhibited by interferon-β

Authors

  • Luca Durelli MD,

    1. Department of Clinical and Biological Sciences, Division of Neurology, San Luigi Gonzaga School of Medicine, Orbassano (Torino), Turin, Italy
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    • L.D. and L.C. contributed equally to this work.

  • Laura Conti PhD,

    1. Center for Experimental Research and Medical Studies, San Giovanni Battista University Hospital, Turin, Italy
    2. Department of Medicine and Experimental Oncology, Section of Pathology, University of Turin, Turin, Italy
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    • L.D. and L.C. contributed equally to this work.

  • Marinella Clerico MD,

    1. Department of Clinical and Biological Sciences, Division of Neurology, San Luigi Gonzaga School of Medicine, Orbassano (Torino), Turin, Italy
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  • Daniela Boselli PhD,

    1. Center for Experimental Research and Medical Studies, San Giovanni Battista University Hospital, Turin, Italy
    2. Department of Medicine and Experimental Oncology, Section of Pathology, University of Turin, Turin, Italy
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  • Giulia Contessa MD,

    1. Department of Clinical and Biological Sciences, Division of Neurology, San Luigi Gonzaga School of Medicine, Orbassano (Torino), Turin, Italy
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  • Paolo Ripellino MD,

    1. Department of Clinical and Biological Sciences, Division of Neurology, San Luigi Gonzaga School of Medicine, Orbassano (Torino), Turin, Italy
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  • Bruno Ferrero MD,

    1. Department of Clinical and Biological Sciences, Division of Neurology, San Luigi Gonzaga School of Medicine, Orbassano (Torino), Turin, Italy
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  • Pierre Eid PhD,

    1. Institut National de la Santé et de la Recherche Médicale U.542, Université Paris-Sud 11, Villejuif, France
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  • Francesco Novelli PhD

    Corresponding author
    1. Center for Experimental Research and Medical Studies, San Giovanni Battista University Hospital, Turin, Italy
    2. Department of Medicine and Experimental Oncology, Section of Pathology, University of Turin, Turin, Italy
    • Center for Experimental Research and Medical Studies, San Giovanni Battista Hospital, Via Cherasco n 15, 10127 Torino, Italy
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  • Potential conflict of interest: L.D. received honoraria for speaking and for consultancy from Industria Farmaceutica Serono, Italy; Bayer Schering Pharma AG (formerly Schering AG), Berlin, Germany; and Dompe' Biotec, Italy. M.C. received honoraria for speaking from Bayer Schering Pharma AG (formerly Schering AG), Berlin, Germany. In both cases, these honoraria were not in excess of $10,000/year. The other authors reported no conflicts of interest.

Abstract

Objective

T-helper 1 (Th1) and Th17 lymphocytes are involved in experimental autoimmune encephalomyelitis, the model of multiple sclerosis (MS). We characterized the Th1/Th17 cell populations in peripheral blood (PB), their interferon (IFN) receptor expression sensitivity to IFN-β in MS patients.

Methods

In 30 untreated patients with active MS (AMS) and 32 with inactive MS (IMS), and in 22 healthy subjects, we measured intracellular cytokine expression, interleukin-17–producing myelin basic protein–stimulated PB lymphocytes, surface IFN type I receptor chain1 (IFN-αR1) expression, IFN-β-dependent signal transducer and activator of transcription 1 (STAT1) phosphorylation, and apoptosis of anti-CD3 monoclonal antibody–stimulated PB lymphocytes.

Results

Th17 cell percentage increased around sevenfold in AMS compared with IMS or healthy subjects, but there was no change in Th1 cells. Th17 cells in AMS were myelin basic protein specific. The longitudinal follow-up of 18 MS patients shifting between AMS and IMS showed that the percentage of Th17 but not Th1 cells always increased in AMS. IFN-αR1 expression, IFN-β–induced STAT1 activation, and apoptosis were significantly greater in Th17 than Th1 cells. IFN-αR1 expression and IFN-β–dependent STAT1 activation progressively increased in vitro with a highly significant positive correlation only in developing Th17 but not in Th0 or Th1 cells.

Interpretation

Evidence that an expansion of peripheral Th17 cells, a Th subset that can infiltrate brain parenchyma and damage cells, is associated with disease activity in MS. The greater IFN-αR1 level expressed by Th17 compared with Th1 cells might make them a selective target for IFN-β therapy. Ann Neurol 2009;65:499–509

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