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Narcolepsy-Associated HLA Class I Alleles Implicate Cell-Mediated Cytotoxicity

Tafti, Mehdi ; Lammers, Gert J. ; Dauvilliers, Yves ; Overeem, Sebastiaan ; Mayer, Geert ; Nowak, Jacek ; Pfister, Corinne ; Dubois, Valérie ; Eliaou, Jean-François ; Eberhard, Hans-Peter ; Liblau, Roland ; Wierzbicka, Aleksandra ; Geisler, Peter ; Bassetti, Claudio L. ; Mathis, Johannes ; Lecendreux, Michel ; Khatami, Ramin ; Heinzer, Raphaël ; Haba-Rubio, José ; Feketeova, Eva ; Baumann, Christian R. ; Kutalik, Zoltán ; Tiercy, Jean-Marie

In: Sleep, 2016, vol. 39, no. 3, p. 581-587

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    Titel
    • Narcolepsy-Associated HLA Class I Alleles Implicate Cell-Mediated Cytotoxicity
    Autor
    • Tafti, Mehdi. Center for Integrative Genomics (CIG) University of Lausanne, Lausanne, Switzerland
    • Lammers, Gert J.. Department of Neurology, Leiden University Medical Centre, Leiden, the Netherlands
    • Dauvilliers, Yves. INSERM-1061, Montpellier, France
    • Overeem, Sebastiaan. Sleep Medicine Center ‘Kempenhaeghe', Heeze, the Netherlands
    • Mayer, Geert. Hephata-Clinic for Neurology, Schwalmstadt-Treysa, Germany
    • Nowak, Jacek. Department of Immunogenetics, Institute of Hematology and Transfusion Medicine, Warsaw, Poland
    • Pfister, Corinne. Center for Integrative Genomics (CIG) University of Lausanne, Lausanne, Switzerland
    • Dubois, Valérie. HLA Laboratory, Etablissement Français du Sang, Lyon, France
    • Eliaou, Jean-François. Department of Immunology, CHRU of Montpellier, University of Montpellier, France
    • Eberhard, Hans-Peter. German National Bone Marrow Donor Registry, Ulm, Germany
    • Liblau, Roland. INSERM-UMR1043, CNRS-U5282, Université de Toulouse, Centre de Physiopathologie Toulouse Purpan (CPTP), Toulouse, France
    • Wierzbicka, Aleksandra. Institute of Psychiatry and Neurology, Department of Clinical Neurophysiology and Sleep Disorders Center, Warsaw, Poland
    • Geisler, Peter. Sleep Disorders and Research Center, Department of Psychiatry and Psychotherapy, University Hospital Regensburg, Regensburg, Germany
    • Bassetti, Claudio L.. Department of Neurology, Inselspital, Bern University Hospital and University of Bern, Switzerland
    • Mathis, Johannes. Department of Neurology, Inselspital, Bern University Hospital and University of Bern, Switzerland
    • Lecendreux, Michel. Pediatric Sleep Center, National Reference Network for Orphan Diseases (Narcolepsy and Idiopathic Hypersomnia), Department of Child and Adolescent Psychopathology, Robert Debré Hospital, Paris VII University, Paris, France
    • Khatami, Ramin. Sleep Medicine, Barmelweid Clinic, Switzerland
    • Heinzer, Raphaël. Center for Investigation and Research in Sleep (CIRS), Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland
    • Haba-Rubio, José. Center for Investigation and Research in Sleep (CIRS), Centre Hospitalier Universitaire Vaudois (CHUV), Lausanne, Switzerland
    • Feketeova, Eva. Department of Neurology, Faculty of Medicine, Safarikiensis University and Louis Pasteur Faculty Hospital Kosice, Kosice, Slovakia
    • Baumann, Christian R.. Department of Neurology, University Hospital Zurich, Switzerland
    • Kutalik, Zoltán. Swiss Institute of Bioinformatics, Lausanne, Switzerland
    • Tiercy, Jean-Marie. National Reference Laboratory for Histocompatibility, Transplantation Immunology Unit, Department of Genetics and Laboratory Medicine, University Hospital Geneva, Geneva, Switzerland
    Dokumententyp
    • Postprint
    Sprache
    • Englisch
    Veröffentlicht in
    • Sleep, 2016, vol. 39, no. 3, p. 581-587. Oxford University Press
    Andere elektronische Ausgabe
    OAI-PMH-ID
    • oai:doc.rero.ch:332624
    Summary
    Abstract Study Objectives: Narcolepsy with cataplexy is tightly associated with the HLA class II allele DQB1*06:02. Evidence indicates a complex contribution of HLA class II genes to narcolepsy susceptibility with a recent independent association with HLA-DPB1. The cause of narcolepsy is supposed be an autoimmune attack against hypocretin-producing neurons. Despite the strong association with HLA class II, there is no evidence for CD4+ T-cell-mediated mechanism in narcolepsy. Since neurons express class I and not class II molecules, the final effector immune cells involved might include class I-restricted CD8+ T-cells. Methods: HLA class I (A, B, and C) and II (DQB1) genotypes were analyzed in 944 European narcolepsy with cataplexy patients and in 4,043 control subjects matched by country of origin. All patients and controls were DQB1*06:02 positive and class I associations were conditioned on DQB1 alleles. Results: HLA-A*11:01 (OR = 1.49 [1.18-1.87] P = 7.0*10−4), C*04:01 (OR = 1.34 [1.10-1.63] P = 3.23*10−3), and B*35:01 (OR = 1.46 [1.13-1.89] P = 3.64*10−3) were associated with susceptibility to narcolepsy. Analysis of polymorphic class I amino-acids revealed even stronger associations with key antigen-binding residues HLA-A-Tyr9 (OR = 1.32 [1.15-1.52] P = 6.95*10−5) and HLA-C-Ser11 (OR = 1.34 [1.15-1.57] P = 2.43*10−4). Conclusions: Our findings provide a genetic basis for increased susceptibility to infectious factors or an immune cytotoxic mechanism in narcolepsy, potentially targeting hypocretin neurons. Significance Although evidence strongly indicates that immune-related mechanisms are involved in the pathogenesis of narcolepsy with hypocretin deficiency, functional data are missing. The strong association with HLA class II genes is not corroborated by any CD4+ T Cell implication and inflammation. Additionally, these genes are not normally expressed in the brain. Here, we show that several HLA class I variants are associated with narcolepsy. Since these molecules are expressed in the brain, our results suggest that a cytotoxic (CD8+ T Cell or NK cell) mechanism might be the final step in the disease, leading to hypocretin neuronal destruction.