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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The data presented in this manuscript are included in the paper and its Supplementary Information. TCR sequences from samples listed in Supplementary Table 2 are available as a .txt file. The sequences have also been deposited in the ImmunoAccess database (http://clients.adaptivebiotech.com/pub/Latorre-2018-nature; https://www.doi.org/10.21417/B73H0P).
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We thank all patients and their families for their participation in the study. We thank A. Sette and C. Lindestam Arlehamn (La Jolla Institute for Allergy and Immunology) for providing the human cytomegalovirus and Epstein–Barr virus peptide pools, G. Nepom and W. Kwok (University of Washington) and R. Martin and M. Sospedra (University Hospital Zurich) for providing DR2a- and DR2b-transfected B cell lines, the Servizio Tipizzazione of the Policlinico San Matteo, University of Pavia, for HLA typing, H. Hidalgo for logistical support and L. Sallusto for discussions and support. This work was supported by the European Research Council grant (no. 323183, PREDICT, to F.S.) and the Swiss National Science Foundation grants (no. 149475 and no. CRSII3_154483 to F.S.). F.S. and the Institute for Research in Biomedicine are supported by the Helmut Horten Foundation.
Nature thanks B. Kornum, E. Unanue and the other anonymous reviewer(s) for their contribution to the peer review of this work.