title: Narcolepsy patients have antibodies that stain distinct cell populations in rat brain and influence sleep patterns.
abstract: Narcolepsy is a chronic sleep disorder, likely with an autoimmune component. During 2009 and 2010, a link between A(H1N1)pdm09 Pandemrix vaccination and onset of narcolepsy was suggested in Scandinavia. In this study, we searched for autoantibodies related to narcolepsy using a neuroanatomical array: rat brain sections were processed for immunohistochemistry/double labeling using patient sera/cerebrospinal fluid as primary antibodies. Sera from 89 narcoleptic patients, 52 patients with other sleep-related disorders (OSRDs), and 137 healthy controls were examined. Three distinct patterns of immunoreactivity were of particular interest: pattern A, hypothalamic melanin-concentrating hormone and proopiomelanocortin but not hypocretin/orexin neurons; pattern B, GABAergic cortical interneurons; and pattern C, mainly globus pallidus neurons. Altogether, 24 of 89 (27%) narcoleptics exhibited pattern A or B or C. None of the patterns were exclusive for narcolepsy but were also detected in the OSRD group at significantly lower numbers. Also, some healthy controls exhibited these patterns. The antigen of pattern A autoantibodies was identified as the common C-terminal epitope of neuropeptide glutamic acid-isoleucine/α-melanocyte-stimulating hormone (NEI/αMSH) peptides. Passive transfer experiments on rat showed significant effects of pattern A human IgGs on rapid eye movement and slow-wave sleep time parameters in the inactive phase and EEG θ-power in the active phase. We suggest that NEI/αMSH autoantibodies may interfere with the fine regulation of sleep, contributing to the complex pathogenesis of narcolepsy and OSRDs. Also, patterns B and C are potentially interesting, because recent data suggest a relevance of those brain regions/neuron populations in the regulation of sleep/arousal.
authors.affiliation: Department of Laboratory Medicine, Division of Clinical Microbiology, Karolinska Institutet and Karolinska University Hospital, 14186 Stockholm, Sweden; Department of Medicine, Center for Infectious Medicine (CIM), Karolinska Institutet and Karolinska University Hospital, 14186 Stockholm, Sweden; peter.bergman@ki.se adorics@gmail.com tomas.hokfelt@ki.se.
authors.forename: Peter
authors.initials: P
authors.lastname: Bergman
authors.affiliation: Department of Neuroscience, Karolinska Institutet, 1711 Stockholm, Sweden; peter.bergman@ki.se adorics@gmail.com tomas.hokfelt@ki.se.
authors.forename: Csaba
authors.initials: C
authors.lastname: Adori
authors.affiliation: Department of Pharmacodynamics, Semmelweis University, 1089, Budapest, Hungary; Hungarian Academy of Sciences (MTA)--Semmelweis University (SE) Neuropsychopharmacology and Neurochemistry Research Group, 1089 Budapest, Hungary;
authors.forename: Szilvia
authors.initials: S
authors.lastname: Vas
authors.affiliation: Department of Laboratory Medicine, Division of Clinical Microbiology, Karolinska Institutet and Karolinska University Hospital, 14186 Stockholm, Sweden; Department of Neuroscience, Karolinska Institutet, 1711 Stockholm, Sweden;
authors.forename: Ylva
authors.initials: Y
authors.lastname: Kai-Larsen
authors.affiliation: Department of Neurology, Central Finland Hospital, 40620 Jyväskylä, Finland; Helsinki Sleep Clinic, Vitalmed Research Centre, 00420 Helsinki, Finland;
authors.forename: Tomi
authors.initials: T
authors.lastname: Sarkanen
authors.affiliation: Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17177 Stockholm, Sweden;
authors.forename: Andreas
authors.initials: A
authors.lastname: Cederlund
authors.affiliation: Department of Laboratory Medicine, Division of Clinical Microbiology, Karolinska Institutet and Karolinska University Hospital, 14186 Stockholm, Sweden;
authors.forename: Birgitta
authors.initials: B
authors.lastname: Agerberth
authors.affiliation: Department of Virology, University of Turku, 20520 Turku, Finland; Virology Unit, National Institute for Health and Welfare (THL), 00300 Helsinki, Finland;
authors.forename: Ilkka
authors.initials: I
authors.lastname: Julkunen
authors.affiliation: Department of Pharmacodynamics, Semmelweis University, 1089, Budapest, Hungary;
authors.forename: Beata
authors.initials: B
authors.lastname: Horvath
authors.affiliation: Department of Pharmacodynamics, Semmelweis University, 1089, Budapest, Hungary;
authors.forename: Diana
authors.initials: D
authors.lastname: Kostyalik
authors.affiliation: Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, 1117 Budapest, Hungary; and.
authors.forename: Lajos
authors.initials: L
authors.lastname: Kalmár
authors.affiliation: Department of Pharmacodynamics, Semmelweis University, 1089, Budapest, Hungary; Hungarian Academy of Sciences (MTA)--Semmelweis University (SE) Neuropsychopharmacology and Neurochemistry Research Group, 1089 Budapest, Hungary;
authors.forename: Gyorgy
authors.initials: G
authors.lastname: Bagdy
authors.affiliation: Helsinki Sleep Clinic, Vitalmed Research Centre, 00420 Helsinki, Finland;
authors.forename: Anne
authors.initials: A
authors.lastname: Huutoniemi
authors.affiliation: Helsinki Sleep Clinic, Vitalmed Research Centre, 00420 Helsinki, Finland; Department of Clinical Neurosciences, University of Helsinki, 00014 Helsinki, Finland.
authors.forename: Markku
authors.initials: M
authors.lastname: Partinen
authors.affiliation: Department of Neuroscience, Karolinska Institutet, 1711 Stockholm, Sweden; peter.bergman@ki.se adorics@gmail.com tomas.hokfelt@ki.se.
authors.forename: Tomas
authors.initials: T
authors.lastname: Hökfelt
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D001323:Autoantibodies / Q000097:blood* / Q000276:immunology; D001921:Brain / Q000276:immunology* / Q000473:pathology*; D003078:Colchicine / Q000031:analogs & derivatives / Q000494:pharmacology; D004569:Electroencephalography; D005917:Globus Pallidus / Q000276:immunology / Q000473:pathology; D006624:Hippocampus / Q000276:immunology / Q000473:pathology; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D007395:Interneurons / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009290:Narcolepsy / Q000276:immunology* / Q000473:pathology*; D019579:Neocortex / Q000276:immunology / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009830:Olfactory Bulb / Q000276:immunology / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D012890:Sleep / Q000502:physiology*; D055815:Young Adult
chemical_list: D001323:Autoantibodies; D007074:Immunoglobulin G; D009419:Nerve Tissue Proteins; C402064:colchicone; D003078:Colchicine
keywords: H1N1 vaccination; POMC neurons; autoantigen; neurotransmitter