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Research Article

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, and Tomas Hökfelt
  1. aDepartment of Laboratory Medicine, Division of Clinical Microbiology, Karolinska Institutet and Karolinska University Hospital, 14186 Stockholm, Sweden;
  2. bDepartment of Medicine, Center for Infectious Medicine (CIM), Karolinska Institutet and Karolinska University Hospital, 14186 Stockholm, Sweden;
  3. cDepartment of Neuroscience, Karolinska Institutet, 1711 Stockholm, Sweden;
  4. dDepartment of Pharmacodynamics, Semmelweis University, 1089, Budapest, Hungary;
  5. eHungarian Academy of Sciences (MTA)--Semmelweis University (SE) Neuropsychopharmacology and Neurochemistry Research Group, 1089 Budapest, Hungary;
  6. fDepartment of Neurology, Central Finland Hospital, 40620 Jyväskylä, Finland;
  7. gHelsinki Sleep Clinic, Vitalmed Research Centre, 00420 Helsinki, Finland;
  8. hDepartment of Medical Biochemistry and Biophysics, Karolinska Institutet, 17177 Stockholm, Sweden;
  9. iDepartment of Virology, University of Turku, 20520 Turku, Finland;
  10. jVirology Unit, National Institute for Health and Welfare (THL), 00300 Helsinki, Finland;
  11. kInstitute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, 1117 Budapest, Hungary; and
  12. lDepartment of Clinical Neurosciences, University of Helsinki, 00014 Helsinki, Finland

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PNAS September 2, 2014 111 (35) E3735-E3744; first published August 18, 2014; https://doi.org/10.1073/pnas.1412189111
Peter Bergman
aDepartment of Laboratory Medicine, Division of Clinical Microbiology, Karolinska Institutet and Karolinska University Hospital, 14186 Stockholm, Sweden;
bDepartment of Medicine, Center for Infectious Medicine (CIM), Karolinska Institutet and Karolinska University Hospital, 14186 Stockholm, Sweden;
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  • For correspondence: peter.bergman@ki.se adorics@gmail.com tomas.hokfelt@ki.se
Csaba Adori
cDepartment of Neuroscience, Karolinska Institutet, 1711 Stockholm, Sweden;
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  • For correspondence: peter.bergman@ki.se adorics@gmail.com tomas.hokfelt@ki.se
Szilvia Vas
dDepartment of Pharmacodynamics, Semmelweis University, 1089, Budapest, Hungary;
eHungarian Academy of Sciences (MTA)--Semmelweis University (SE) Neuropsychopharmacology and Neurochemistry Research Group, 1089 Budapest, Hungary;
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Ylva Kai-Larsen
aDepartment of Laboratory Medicine, Division of Clinical Microbiology, Karolinska Institutet and Karolinska University Hospital, 14186 Stockholm, Sweden;
cDepartment of Neuroscience, Karolinska Institutet, 1711 Stockholm, Sweden;
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Tomi Sarkanen
fDepartment of Neurology, Central Finland Hospital, 40620 Jyväskylä, Finland;
gHelsinki Sleep Clinic, Vitalmed Research Centre, 00420 Helsinki, Finland;
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Andreas Cederlund
hDepartment of Medical Biochemistry and Biophysics, Karolinska Institutet, 17177 Stockholm, Sweden;
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Birgitta Agerberth
aDepartment of Laboratory Medicine, Division of Clinical Microbiology, Karolinska Institutet and Karolinska University Hospital, 14186 Stockholm, Sweden;
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Ilkka Julkunen
iDepartment of Virology, University of Turku, 20520 Turku, Finland;
jVirology Unit, National Institute for Health and Welfare (THL), 00300 Helsinki, Finland;
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Beata Horvath
dDepartment of Pharmacodynamics, Semmelweis University, 1089, Budapest, Hungary;
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Diana Kostyalik
dDepartment of Pharmacodynamics, Semmelweis University, 1089, Budapest, Hungary;
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Lajos Kalmár
kInstitute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, 1117 Budapest, Hungary; and
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Gyorgy Bagdy
dDepartment of Pharmacodynamics, Semmelweis University, 1089, Budapest, Hungary;
eHungarian Academy of Sciences (MTA)--Semmelweis University (SE) Neuropsychopharmacology and Neurochemistry Research Group, 1089 Budapest, Hungary;
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Anne Huutoniemi
gHelsinki Sleep Clinic, Vitalmed Research Centre, 00420 Helsinki, Finland;
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Markku Partinen
gHelsinki Sleep Clinic, Vitalmed Research Centre, 00420 Helsinki, Finland;
lDepartment of Clinical Neurosciences, University of Helsinki, 00014 Helsinki, Finland
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Tomas Hökfelt
cDepartment of Neuroscience, Karolinska Institutet, 1711 Stockholm, Sweden;
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  • For correspondence: peter.bergman@ki.se adorics@gmail.com tomas.hokfelt@ki.se
  1. Contributed by Tomas G. M. Hökfelt, July 7, 2014 (sent for review December 18, 2013; reviewed by Clifford B. Saper, Jeffrey M. Friedman, and Thomas S. Kilduff)

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Significance

Narcolepsy is a chronic sleep disease with autoimmune origin. We explored occurrence of autoantibodies in narcolepsy and other sleep-related disorders (OSRDs) by screening human sera with immunohistochemistry on rat brains. Hypocretin/orexinergic neurons were not stained, but a prominent immunostaining pattern of hypothalamic melanin-concentrating hormone (MCH) and proopiomelanocortin (POMC) neurons was overrepresented in cases of narcolepsy and OSRD patients. The autoantigen was identified as the common C-terminal epitope of neuropeptide glutamic acid-isoleucine/α–melanocyte-stimulating hormone (NEI/αMSH). Purified IgGs from a patient with MCH/POMC staining injected intracerebroventricularly to rats caused disturbed sleep patterns. Also, GABAergic cortical interneurons were stained with other narcolepsy and OSRD sera. Thus, autoantibodies are frequent in patients with sleep disorders, and NEI/αMSH may be a previously unidentified autoantigen involved in pathomechanism(s). These findings indicate possible diagnostic/therapeutic targets.

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.

  • H1N1 vaccination
  • POMC neurons
  • autoantigen
  • neurotransmitter

Footnotes

  • ↵1To whom correspondence may be addressed. Email: peter.bergman{at}ki.se, adorics{at}gmail.com, or tomas.hokfelt{at}ki.se.
  • ↵2P.B. and C.A. contributed equally to this work.

  • Author contributions: P.B., C.A., B.A., A.H., M.P., and T.H. designed research; P.B., C.A., S.V., Y.K.-L., T.S., B.H., D.K., and L.K. performed research; T.S., A.C., I.J., B.H., D.K., L.K., G.B., A.H., and M.P. contributed new reagents/analytic tools; P.B., C.A., S.V., Y.K.-L., T.S., B.A., I.J., G.B., A.H., M.P., and T.H. analyzed data; and P.B., C.A., S.V., Y.K.-L., A.H., M.P., and T.H. wrote the paper.

  • Reviewers: C.B.S., Harvard Medical School, Beth Israel Deaconess Medical Center; J.M.F., The Rockefeller University; T.S.K., SRI International.

  • The authors declare no conflict of interest.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1412189111/-/DCSupplemental.

Freely available online through the PNAS open access option.

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Autoantibodies in narcolepsy
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
Proceedings of the National Academy of Sciences Sep 2014, 111 (35) E3735-E3744; DOI: 10.1073/pnas.1412189111

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Autoantibodies in narcolepsy
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
Proceedings of the National Academy of Sciences Sep 2014, 111 (35) E3735-E3744; DOI: 10.1073/pnas.1412189111
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