title: Impact of cytokine in type 1 narcolepsy: Role of pandemic H1N1 vaccination ?
abstract: Recent advances in the identification of susceptibility genes and environmental exposures (pandemic influenza 2009 vaccination) provide strong support that narcolepsy type 1 is an immune-mediated disease. Considering the limited knowledge regarding the immune mechanisms involved in narcolepsy whether related to flu vaccination or not and the recent progresses in cytokine measurement technology, we assessed 30 cytokines, chemokines and growth factors using the Luminex technology in either peripheral (serum) or central (CSF) compartments in a large population of 90 children and adult patients with narcolepsy type 1 in comparison to 58 non-hypocretin deficient hypersomniacs and 41 healthy controls. Furthermore, we compared their levels in patients with narcolepsy whether exposed to pandemic flu vaccine or not, and analyzed the effect of age, duration of disease and symptom severity. Comparison for sera biomarkers between narcolepsy (n = 84, 54 males, median age: 15.5 years old) and healthy controls (n = 41, 13 males, median age: 20 years old) revealed an increased stimulation of the immune system with high release of several pro- and anti-inflammatory serum cytokines and growth factors with interferon-γ, CCL11, epidermal growth factor, and interleukin-2 receptor being independently associated with narcolepsy. Increased levels of interferon-γ, CCL11, and interleukin-12 were found when close to narcolepsy onset. After several adjustments, only one CSF biomarker differed between narcolepsy (n = 44, 26 males, median age: 15 years old) and non-hypocretin deficient hypersomnias (n = 57, 24 males, median age: 36 years old) with higher CCL 3 levels found in narcolepsy. Comparison for sera biomarkers between patients with narcolepsy who developed the disease post-pandemic flu vaccination (n = 36) to those without vaccination (n = 48) revealed an increased stimulation of the immune system with high release of three cytokines, regulated upon activation normal T-cell expressed and secreted, CXCL10, and CXCL9, being independently and significantly increased in the group exposed to the vaccine. No significant differences were found between narcoleptics whether exposed to flu vaccination or not for CSF biomarkers except for a lower CXCL10 level found in the exposed group. To conclude, we highlighted the role of sera cytokine with pro-inflammatory properties and especially interferon-γ being independently associated with narcolepsy close to disease onset. The activity of the interferon-γ network was also increased in the context of narcolepsy after the pandemic flu vaccination being a potential key player in the immune mechanism that triggers narcolepsy and that coordinates the immune response necessary for resolving vaccination assaults.
authors.affiliation: AP-HP, Pediatric Sleep Center, CHU Robert-Debré, Paris, France; National Reference Centre for Orphan Diseases, Narcolepsy, Idiopathic Hypersomnia and Kleine-Levin Syndrome (CNR narcolepsie-hypersomnie), France.
authors.forename: Michel
authors.initials: M
authors.lastname: Lecendreux
authors.affiliation: Inserm UMS20, Centre d'Immunologie Humaine (CIH) Institut Pasteur, France.
authors.forename: Valentina
authors.initials: V
authors.lastname: Libri
authors.affiliation: Inserm U1061, Montpellier, France; Université Montpellier 1, Montpellier, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Jaussent
authors.affiliation: Inserm UMS20, Centre d'Immunologie Humaine (CIH) Institut Pasteur, France.
authors.forename: Estelle
authors.initials: E
authors.lastname: Mottez
authors.affiliation: National Reference Centre for Orphan Diseases, Narcolepsy, Idiopathic Hypersomnia and Kleine-Levin Syndrome (CNR narcolepsie-hypersomnie), France; Inserm U1061, Montpellier, France; Université Montpellier 1, Montpellier, France; Sleep Disorders Center, Department of Neurology, Gui-de-Chauliac Hospital, CHU Montpellier, France.
authors.forename: Régis
authors.initials: R
authors.lastname: Lopez
authors.affiliation: National Reference Centre for Orphan Diseases, Narcolepsy, Idiopathic Hypersomnia and Kleine-Levin Syndrome (CNR narcolepsie-hypersomnie), France; Sleep Disorders Unit, Pitié-Salpêtrière University Hospital, AP-HP, France; Brain Research Institute (CRICM-UPMC-Paris6; Inserm UMR_S 975; CNRS UMR 7225), Sorbonne Universities, UPMC Univ Paris 06, Paris, F-75005, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Lavault
authors.affiliation: Aviesan/Institut Multi-Organismes Immunologie, Hématologie et Pneumologie (ITMO IHP), France.
authors.forename: Armelle
authors.initials: A
authors.lastname: Regnault
authors.affiliation: National Reference Centre for Orphan Diseases, Narcolepsy, Idiopathic Hypersomnia and Kleine-Levin Syndrome (CNR narcolepsie-hypersomnie), France; Sleep Disorders Unit, Pitié-Salpêtrière University Hospital, AP-HP, France; Brain Research Institute (CRICM-UPMC-Paris6; Inserm UMR_S 975; CNRS UMR 7225), Sorbonne Universities, UPMC Univ Paris 06, Paris, F-75005, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Arnulf
authors.affiliation: National Reference Centre for Orphan Diseases, Narcolepsy, Idiopathic Hypersomnia and Kleine-Levin Syndrome (CNR narcolepsie-hypersomnie), France; Inserm U1061, Montpellier, France; Université Montpellier 1, Montpellier, France; Sleep Disorders Center, Department of Neurology, Gui-de-Chauliac Hospital, CHU Montpellier, France. Electronic address: ydauvilliers@yahoo.fr.
authors.forename: Yves
authors.initials: Y
authors.lastname: Dauvilliers
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000097:blood / Q000134:cerebrospinal fluid; D002648:Child; D016207:Cytokines / Q000097:blood* / Q000134:cerebrospinal fluid* / Q000276:immunology; D005260:Female; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology*; D007252:Influenza Vaccines / Q000276:immunology*; D007251:Influenza, Human / Q000276:immunology / Q000821:virology; D007371:Interferon-gamma / Q000097:blood / Q000134:cerebrospinal fluid / Q000276:immunology; D008297:Male; D008875:Middle Aged; D009290:Narcolepsy / Q000276:immunology*; D014611:Vaccination; D055815:Young Adult
chemical_list: D015415:Biomarkers; D016207:Cytokines; D007252:Influenza Vaccines; D007371:Interferon-gamma
keywords: Autoimmunity; Cytokine; Flu vaccination; H1N1; Hypocretin/Orexin; Interferon gamma; Narcolepsy