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Nature. 2018 Oct;562(7725):63-68. doi: 10.1038/s41586-018-0540-1. Epub 2018 Sep 19.

T cells in patients with narcolepsy target self-antigens of hypocretin neurons.

Author information

1
Institute for Research in Biomedicine, Faculty of Biomedical Sciences, Università della Svizzera italiana, Bellinzona, Switzerland.
2
Institute of Microbiology, ETH Zurich, Zurich, Switzerland.
3
Department of Neurology, University Hospital, Bern, Switzerland.
4
Institute of Immunology, University of Witten/Herdecke, Witten, Germany.
5
Swiss Institute of Bioinformatics, Lausanne, Switzerland.
6
Sleep and Epilepsy Center, Neurocenter of Southern Switzerland, Lugano, Switzerland.
7
Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland.
8
Center for Sleep Research and Sleep Medicine, Clinic Barmelweid, Barmelweid, Switzerland.
9
Department of Physiology, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland.
10
Department of Neurology, University Hospital, Bern, Switzerland. claudio.bassetti@insel.ch.
11
Institute for Research in Biomedicine, Faculty of Biomedical Sciences, Università della Svizzera italiana, Bellinzona, Switzerland. federica.sallusto@irb.usi.ch.
12
Institute of Microbiology, ETH Zurich, Zurich, Switzerland. federica.sallusto@irb.usi.ch.

Abstract

Narcolepsy is a chronic sleep disorder caused by the loss of neurons that produce hypocretin. The close association with HLA-DQB1*06:02, evidence for immune dysregulation and increased incidence upon influenza vaccination together suggest that this disorder has an autoimmune origin. However, there is little evidence of autoreactive lymphocytes in patients with narcolepsy. Here we used sensitive cellular screens and detected hypocretin-specific CD4+ T cells in all 19 patients that we tested; T cells specific for tribbles homologue 2-another self-antigen of hypocretin neurons-were found in 8 out of 13 patients. Autoreactive CD4+ T cells were polyclonal, targeted multiple epitopes, were restricted primarily by HLA-DR and did not cross-react with influenza antigens. Hypocretin-specific CD8+ T cells were also detected in the blood and cerebrospinal fluid of several patients with narcolepsy. Autoreactive clonotypes were serially detected in the blood of the same-and even of different-patients, but not in healthy control individuals. These findings solidify the autoimmune aetiology of narcolepsy and provide a basis for rapid diagnosis and treatment of this disease.

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PMID:
30232458
DOI:
10.1038/s41586-018-0540-1

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