Narcolepsy patients have antibodies that stain distinct cell populations in rat brain and influence sleep patterns

Peter Bergman, Csaba Adori, Szilvia Vas, Ylva Kai-Larsen, Tomi Sarkanen, Andreas Cederlund, Birgitta Agerberth, Ilkka Julkunen, Beata Horvath, Diana Kostyalik, Lajos Kalmár, Gyorgy Bagdy, Anne Huutoniemi, Markku Partinen, Tomas Hökfelt

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54 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)E3735-E3744
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number35
DOIs
Publication statusPublished - Sep 2 2014

Keywords

  • Autoantigen
  • H1N1 vaccination
  • Neurotransmitter
  • POMC neurons

ASJC Scopus subject areas

  • General

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    Bergman, P., Adori, C., Vas, S., Kai-Larsen, Y., Sarkanen, T., Cederlund, A., Agerberth, B., Julkunen, I., Horvath, B., Kostyalik, D., Kalmár, L., Bagdy, G., Huutoniemi, A., Partinen, M., & Hökfelt, T. (2014). Narcolepsy patients have antibodies that stain distinct cell populations in rat brain and influence sleep patterns. Proceedings of the National Academy of Sciences of the United States of America, 111(35), E3735-E3744. https://doi.org/10.1073/pnas.1412189111