Narcolepsy Type 1 as an Autoimmune Disorder: Evidence, and Implications for Pharmacological Treatment

CNS Drugs

Volumn 31, Issue 10, 2017, Pages 821-834

  Barateau, Lucie ^a,b,c   Liblau, Roland ^d   Peyron, Christelle ^e   Dauvilliers, Yves ^a,b,c  

^a GUI DE CHAULIAC HOSPITAL   (France)

^b Sleep Disorders Center   (France)

^c INSERM U1061   (France)

^d University of Toulouse III   (France)

^e UNIVERSITÉ LYON 1   (France)

Author keywords

[No Author keywords available]

Indexed keywords

AUTOANTIBODY; CYTOKINE; IMMUNOMODULATING AGENT; IMMUNOSUPPRESSIVE AGENT; OREXIN; OREXIN RECEPTOR; HLA A ANTIGEN;

ANIMAL MODEL; ARTICLE; AUTOIMMUNE DISEASE; AUTOPSY; BLOOD BRAIN BARRIER; CEREBROSPINAL FLUID; CLINICAL FEATURE; ENVIRONMENTAL EXPOSURE; GENETIC RISK; GENETIC SUSCEPTIBILITY; HLA SYSTEM; HUMAN; IMMUNOTHERAPY; INFLAMMATION; NARCOLEPSY; NARCOLEPSY TYPE 1; NONHUMAN; PRIORITY JOURNAL; REGULATOR GENE; SUBSTITUTION THERAPY; ANIMAL; CAUSALITY; COMPLICATION; DISEASE MODEL; GENETICS;

ANIMALS; AUTOIMMUNE DISEASES; CAUSALITY; DISEASE MODELS, ANIMAL; ENVIRONMENTAL EXPOSURE; HLA-A ANTIGENS; HUMANS; NARCOLEPSY;

EID: 85029767481     PISSN: 11727047     EISSN: 11791934     Source Type: Journal    
DOI: 10.1007/s40263-017-0464-6     Document Type: Article

References (128)

1. AASM: American Academy of Sleep Medicine. ICSD-3: International Classification of Sleep Disorders. 3rd ed. Darien, IL; 2014.
2. Ohayon MM, Priest RG, Zulley J, Smirne S, Paiva T. Prevalence of narcolepsy symptomatology and diagnosis in the European general population. Neurology. 2002;58:1826–33.
3. Dauvilliers Y, Arnulf I, Mignot E. Narcolepsy with cataplexy. Lancet. 2007;369:499–511.
4. Scammell TE. Narcolepsy. N Engl J Med. 2015;373:2654–62.
5. Peyron C, Faraco J, Rogers W, Ripley B, Overeem S, Charnay Y, et al. A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains. Nat Med. 2000;6:991–7.
6. Mignot E, Lammers GJ, Ripley B, Okun M, Nevsimalova S, Overeem S, et al. The role of cerebrospinal fluid hypocretin measurement in the diagnosis of narcolepsy and other hypersomnias. Arch Neurol. 2002;59:1553–62.
7. Dauvilliers Y, Baumann CR, Carlander B, Bischof M, Blatter T, Lecendreux M, et al. CSF hypocretin-1 levels in narcolepsy, Kleine-Levin syndrome, and other hypersomnias and neurological conditions. J Neurol Neurosurg Psychiatry. 2003;74:1667–73.
8. Li S-B, Jones JR, de Lecea L. Hypocretins, neural systems, physiology, and psychiatric disorders. Curr Psychiatry Rep. 2016;18:7.
9. Chemelli RM, Willie JT, Sinton CM, Elmquist JK, Scammell T, Lee C, et al. Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation. Cell. 1999;98:437–51.
10. Liblau RS, Vassalli A, Seifinejad A, Tafti M. Hypocretin (orexin) biology and the pathophysiology of narcolepsy with cataplexy. Lancet Neurol. 2015;14:318–28.
11. Partinen M, Kornum BR, Plazzi G, Jennum P, Julkunen I, Vaarala O. Narcolepsy as an autoimmune disease: the role of H1N1 infection and vaccination. Lancet Neurol. 2014;13:600–13.
12. Kornum BR, Knudsen S, Ollila HM, Pizza F, Jennum PJ, Dauvilliers Y, et al. Narcolepsy. Nat Rev Dis Primer. 2017;3:16100.
13. Rose NR, Bona C. Defining criteria for autoimmune diseases (Witebsky’s postulates revisited). Immunol Today. 1993;14:426–30.
14. Damoiseaux JGMC, Tervaert JWC. The definition of autoimmune disease: are Koch’s postulates applicable? Neth J Med. 2002;60:266–8.
15. Dauvilliers Y, Montplaisir J, Molinari N, Carlander B, Ondze B, Besset A, et al. Age at onset of narcolepsy in two large populations of patients in France and Quebec. Neurology. 2001;57:2029–33.
16. Dauvilliers Y, Maret S, Bassetti C, Carlander B, Billiard M, Touchon J, et al. A monozygotic twin pair discordant for narcolepsy and CSF hypocretin-1. Neurology. 2004;62:2137–8.
17. Jennum PJ, Kornum BR, Issa NM, Gammeltoft S, Tommerup N, Morling N, et al. Monozygotic twins discordant for narcolepsy type 1 and multiple sclerosis. Neurol Neuroimmunol Neuroinflamm. 2016;3:e249.
18. Chabas D, Taheri S, Renier C, Mignot E. The genetics of narcolepsy. Annu Rev Genom Hum Genet. 2003;4:459–83.
19. Silber MH, Krahn LE, Olson EJ, Pankratz VS. The epidemiology of narcolepsy in Olmsted County, Minnesota: a population-based study. Sleep. 2002;25:197–202.
20. Quintero OL, Amador-Patarroyo MJ, Montoya-Ortiz G, Rojas-Villarraga A, Anaya J-M. Autoimmune disease and gender: plausible mechanisms for the female predominance of autoimmunity. J Autoimmun. 2012;38:J109–19.
21. Barateau L, Lopez R, Arnulf I, Lecendreux M, Franco P, Drouot X, et al. Comorbidity between central disorders of hypersomnolence and immune-based disorders. Neurology. 2017;88(1):93–100.
22. Dauvilliers Y, Abril B, Mas E, Michel F, Tafti M. Normalization of hypocretin-1 in narcolepsy after intravenous immunoglobulin treatment. Neurology. 2009;73:1333–4.
23. Lecendreux M, Berthier J, Corny J, Bourdon O, Dossier C, Delclaux C. Intravenous immunoglobulin therapy in pediatric narcolepsy: a nonrandomized, open-label, controlled, longitudinal observational study. J Clin Sleep Med. 2017;13(3):441–53.
24. Juji T, Satake M, Honda Y, Doi Y. HLA antigens in Japanese patients with narcolepsy. All the patients were DR2 positive. Tissue Antigens. 1984;24:316–9.
25. Mignot E. Complex HLA-DR and -DQ interactions confer risk of narcolepsy-cataplexy in three ethnic groups. Am J Hum Genet. 2001;68:686–99.
26. Han F, Lin L, Schormair B, Pizza F, Plazzi G, Ollila HM, et al. HLA DQB1*06:02 negative narcolepsy with hypocretin/orexin deficiency. Sleep. 2014;37:1601–8.
27. Tafti M, Hor H, Dauvilliers Y, Lammers GJ, Overeem S, Mayer G, et al. DQB1 locus alone explains most of the risk and protection in narcolepsy with cataplexy in Europe. Sleep. 2014;37:19–25.
28. Hor H, Kutalik Z, Dauvilliers Y, Valsesia A, Lammers GJ, Donjacour CEHM, et al. Genome-wide association study identifies new HLA class II haplotypes strongly protective against narcolepsy. Nat Genet. 2010;42:786–9.
29. Ollila HM, Ravel J-M, Han F, Faraco J, Lin L, Zheng X, et al. HLA-DPB1 and HLA class I confer risk of and protection from narcolepsy. Am J Hum Genet. 2015;96:136–46.
30. Tafti M, Lammers GJ, Dauvilliers Y, Overeem S, Mayer G, Nowak J, et al. Narcolepsy-associated HLA class I alleles implicate cell-mediated cytotoxicity. Sleep. 2016;39(3):581–7.
31. Hallmayer J. Narcolepsy is strongly associated with the T-cell receptor alpha locus. Nat Genet. 2009;41:708–11.
32. Miyagawa T, Honda M, Kawashima M, Shimada M, Tanaka S, Honda Y, et al. Polymorphism located in TCRA locus confers susceptibility to essential hypersomnia with HLA-DRB1*1501-DQB1*0602 haplotype. J Hum Genet. 2010;55:63–5.
33. Kornum BR, Kawashima M, Faraco J, Lin L, Rico TJ, Hesselson S, et al. Common variants in P2RY11 are associated with narcolepsy. Nat Genet. 2011;43:66–71.
34. Degn M, Dauvilliers Y, Dreisig K, Lopez R, Pfister C, Pradervand S, et al. Rare missense mutations in P2RY11 in narcolepsy with cataplexy. Neurol: Brain J; 2017.
35. Han F, Faraco J, Dong XS, Ollila HM, Lin L, Li J, et al. Genome wide analysis of narcolepsy in China implicates novel immune loci and reveals changes in association prior to versus after the 2009 H1N1 influenza pandemic. PLoS Genet. 2013;9:e1003880.
36. Toyoda H, Miyagawa T, Koike A, Kanbayashi T, Imanishi A, Sagawa Y, et al. A polymorphism in CCR1/CCR3 is associated with narcolepsy. Brain Behav Immun. 2015;49:148–55.
37. Faraco J, Lin L, Kornum BR, Kenny EE, Trynka G, Einen M, et al. ImmunoChip study implicates antigen presentation to T cells in narcolepsy. PLoS Genet. 2013;9:e1003270.
38. Degn M, Kornum BR. Type 1 narcolepsy: a CD8(+) T cell-mediated disease? Ann N Y Acad Sci. 2015;1351:80–8.
39. Partinen M, Kornum BR, Plazzi G, Jennum P, Julkunen I, Vaarala O. Does autoreactivity have a role in narcolepsy? Lancet Neurol. 2014;13:1072–3.
40. Hor H, Bartesaghi L, Kutalik Z, Vicário JL, de Andrés C, Pfister C, et al. A missense mutation in myelin oligodendrocyte glycoprotein as a cause of familial narcolepsy with cataplexy. Am J Hum Genet. 2011;89:474–9.
41. Han F, Lin L, Warby SC, Faraco J, Li J, Dong SX, et al. Narcolepsy onset is seasonal and increased following the 2009 H1N1 pandemic in China. Ann Neurol. 2011;70:410–7.
42. Orellana C, Villemin E, Tafti M, Carlander B, Besset A, Billiard M. Life events in the year preceding the onset of narcolepsy. Sleep. 1994;17:S50–3.
43. Picchioni D, Hope CR, Harsh JR. A case-control study of the environmental risk factors for narcolepsy. Neuroepidemiology. 2007;29:185–92.
44. Dauvilliers Y, Arnulf I, Lecendreux M, Monaca Charley C, Franco P, Drouot X, et al. Increased risk of narcolepsy in children and adults after pandemic H1N1 vaccination in France. Brain J Neurol. 2013;136:2486–96.
45. Partinen M, Saarenpää-Heikkilä O, Ilveskoski I, Hublin C, Linna M, Olsén P, et al. Increased incidence and clinical picture of childhood narcolepsy following the 2009 H1N1 pandemic vaccination campaign in Finland. PLoS One. 2012;7:e33723.
46. Heier MS, Gautvik KM, Wannag E, Bronder KH, Midtlyng E, Kamaleri Y, et al. Incidence of narcolepsy in Norwegian children and adolescents after vaccination against H1N1 influenza A. Sleep Med. 2013;14:867–71.
47. Miller E, Andrews N, Stellitano L, Stowe J, Winstone AM, Shneerson J, et al. Risk of narcolepsy in children and young people receiving AS03 adjuvanted pandemic A/H1N1 2009 influenza vaccine: retrospective analysis. BMJ. 2013;346:f794.
48. Montplaisir J, Petit D, Quinn M-J, Ouakki M, Deceuninck G, Desautels A, et al. Risk of narcolepsy associated with inactivated adjuvanted (AS03) A/H1N1 (2009) pandemic influenza vaccine in Quebec. PLoS One. 2014;9:e108489.
49. Vaarala O, Vuorela A, Partinen M, Baumann M, Freitag TL, Meri S, et al. Antigenic differences between AS03 adjuvanted influenza A (H1N1) pandemic vaccines: implications for pandemrix-associated narcolepsy risk. PLoS One. 2014;9:e114361.
50. Ahmed SS, Volkmuth W, Duca J, Corti L, Pallaoro M, Pezzicoli A, et al. Antibodies to influenza nucleoprotein cross-react with human hypocretin receptor 2. Sci Transl Med. 2015;7:294ra105.
51. Aran A, Lin L, Nevsimalova S, Plazzi G, Hong SC, Weiner K, et al. Elevated anti-streptococcal antibodies in patients with recent narcolepsy onset. Sleep. 2009;32:979–83.
52. Pizza F, Franceschini C, Peltola H, Vandi S, Finotti E, Ingravallo F, et al. Clinical and polysomnographic course of childhood narcolepsy with cataplexy. Brain J Neurol. 2013;136:3787–95.
53. Ambati A, Poiret T, Svahn B-M, Valentini D, Khademi M, Kockum I, et al. Increased β-haemolytic group A streptococcal M6 serotype and streptodornase B-specific cellular immune responses in Swedish narcolepsy cases. J Intern Med. 2015;278:264–76.
54. Carlander B, Puech-Cathala AM, Jaussent I, Scholz S, Bayard S, Cochen V, et al. Low vitamin D in narcolepsy with cataplexy. PLoS One. 2011;6:e20433.
55. Dauvilliers Y, Evangelista E, Lopez R, Barateau L, Scholz S, Crastes de Paulet B, et al. Vitamin D deficiency in type 1 narcolepsy: a reappraisal. Sleep Med. 2017;29:1–6.
56. Smith AJF, Jackson MW, Neufing P, McEvoy RD, Gordon TP. A functional autoantibody in narcolepsy. Lancet Lond Engl. 2004;364:2122–4.
57. Bergman P, Adori C, Vas S, Kai-Larsen Y, Sarkanen T, Cederlund A, et al. Narcolepsy patients have antibodies that stain distinct cell populations in rat brain and influence sleep patterns. Proc Natl Acad Sci USA. 2014;111:E3735–44.
58. Toyoda H, Tanaka S, Miyagawa T, Honda Y, Tokunaga K, Honda M. Anti-Tribbles homolog 2 autoantibodies in Japanese patients with narcolepsy. Sleep. 2010;33:875–8.
59. Kawashima M, Lin L, Tanaka S, Jennum P, Knudsen S, Nevsimalova S, et al. Anti-Tribbles homolog 2 (TRIB2) autoantibodies in narcolepsy are associated with recent onset of cataplexy. Sleep. 2010;33:869–74.
60. Cvetkovic-Lopes V. Elevated Tribbles homolog 2 specific antibody levels in narcolepsy patients. J Clin Investig. 2010;120:713–9.
61. Katzav A, Arango MT, Kivity S, Tanaka S, Givaty G, Agmon-Levin N, et al. Passive transfer of narcolepsy: anti-TRIB2 autoantibody positive patient IgG causes hypothalamic orexin neuron loss and sleep attacks in mice. J Autoimmun. 2013;45:24–30.
62. Tanaka S, Honda Y, Honda M, Yamada H, Honda K, Kodama T. Anti-tribbles pseudokinase 2 (TRIB2)-immunization modulates hypocretin/orexin neuronal functions. Sleep. 2017;40(1):zsw036.
63. Saariaho A-H, Vuorela A, Freitag TL, Pizza F, Plazzi G, Partinen M, et al. Autoantibodies against ganglioside GM3 are associated with narcolepsy-cataplexy developing after Pandemrix vaccination against 2009 pandemic H1N1 type influenza virus. J Autoimmun. 2015;63:68–75.
64. Giannoccaro MP, Waters P, Pizza F, Liguori R, Plazzi G, Vincent A. Antibodies against hypocretin receptor 2 are rare in narcolepsy. Sleep. 2017;40(2):zsw056.
65. Black JL, Krahn LE, Pankratz VS, Silber M. Search for neuron-specific and nonneuron-specific antibodies in narcoleptic patients with and without HLA DQB1*0602. Sleep. 2002;25:719–23.
66. Black JL, Silber MH, Krahn LE, Fredrickson PA, Pankratz VS, Avula R, et al. Analysis of hypocretin (orexin) antibodies in patients with narcolepsy. Sleep. 2005;28:427–31.
67. Overeem S, Verschuuren JJ, Fronczek R, Schreurs L, den Hertog H, Hegeman-Kleinn IM, et al. Immunohistochemical screening for autoantibodies against lateral hypothalamic neurons in human narcolepsy. J Neuroimmunol. 2006;174:187–91.
68. Tanaka S, Honda Y, Inoue Y, Honda M. Detection of autoantibodies against hypocretin, hcrtrl, and hcrtr2 in narcolepsy: anti-Hcrt system antibody in narcolepsy. Sleep. 2006;29:633–8.
69. Knudsen S, Mikkelsen JD, Jennum P. Antibodies in narcolepsy-cataplexy patient serum bind to rat hypocretin neurons. NeuroReport. 2007;18:77–9.
70. Deloumeau A, Bayard S, Coquerel Q, Déchelotte P, Bole-Feysot C, Carlander B, et al. Increased immune complexes of hypocretin autoantibodies in narcolepsy. PLoS One. 2010;5:e13320.
71. van der Heide A, Hegeman-Kleinn IM, Peeters E, Lammers GJ, Fronczek R. Immunohistochemical screening for antibodies in recent onset type 1 narcolepsy and after H1N1 vaccination. J Neuroimmunol. 2015;283:58–62.
72. Ramberger M, Högl B, Stefani A, Mitterling T, Reindl M, Lutterotti A. CD4+ T-cell reactivity to orexin/hypocretin in patients with narcolepsy type 1. Sleep. 2017;40(3).
73. Thannickal TC. Reduced number of hypocretin neurons in human narcolepsy. Neuron. 2000;27:469–74.
74. Dauvilliers Y, Bauer J, Rigau V, Lalloyer N, Labauge P, Carlander B, et al. Hypothalamic immunopathology in anti-Ma-associated diencephalitis with narcolepsy-cataplexy. JAMA Neurol. 2013;70:1305–10.
75. Bernard-Valnet R, Yshii L, Quériault C, Nguyen X-H, Arthaud S, Rodrigues M, et al. CD8 T cell-mediated killing of orexinergic neurons induces a narcolepsy-like phenotype in mice. Proc Natl Acad Sci USA. 2016;113:10956–61.
76. Tabuchi S, Tsunematsu T, Black SW, Tominaga M, Maruyama M, Takagi K, et al. Conditional ablation of orexin/hypocretin neurons: a new mouse model for the study of narcolepsy and orexin system function. J Neurosci Off J Soc Neurosci. 2014;34:6495–509.
77. Morrish E, King MA, Smith IE, Shneerson JM. Factors associated with a delay in the diagnosis of narcolepsy. Sleep Med. 2004;5:37–41.
78. Hartmann FJ, Bernard-Valnet R, Quériault C, Mrdjen D, Weber LM, Galli E, et al. High-dimensional single-cell analysis reveals the immune signature of narcolepsy. Med: J Exp; 2016.
79. Overeem S, Dalmau J, Bataller L, Nishino S, Mignot E, Verschuuren J, et al. Hypocretin-1 CSF levels in anti-Ma2 associated encephalitis. Neurology. 2004;62:138–40.
80. Okun ML, Giese S, Lin L, Einen M, Mignot E, Coussons-Read ME. Exploring the cytokine and endocrine involvement in narcolepsy. Brain Behav Immun. 2004;18:326–32.
81. Himmerich H, Beitinger PA, Fulda S, Wehrle R, Linseisen J, Wolfram G, et al. Plasma levels of tumor necrosis factor alpha and soluble tumor necrosis factor receptors in patients with narcolepsy. Arch Intern Med. 2006;166:1739–43.
82. Tanaka S, Honda M, Toyoda H, Kodama T. Increased plasma IL-6, IL-8, TNF-alpha, and G-CSF in Japanese narcolepsy. Hum Immunol. 2014;75:940–4.
83. Dauvilliers Y, Jaussent I, Lecendreux M, Scholz S, Bayard S, Cristol JP, et al. Cerebrospinal fluid and serum cytokine profiles in narcolepsy with cataplexy: a case-control study. Brain Behav Immun. 2014;37:260–6.
84. Lecendreux M, Libri V, Jaussent I, Mottez E, Lopez R, Lavault S, et al. Impact of cytokine in type 1 narcolepsy: role of pandemic H1N1 vaccination? J Autoimmun. 2015;60:20–31.
85. Kornum BR, Pizza F, Knudsen S, Plazzi G, Jennum P, Mignot E. Cerebrospinal fluid cytokine levels in type 1 narcolepsy patients very close to onset. Brain Behav Immun. 2015;49:54–8.
86. Tesoriero C, Codita A, Zhang M-D, Cherninsky A, Karlsson H, Grassi-Zucconi G, et al. H1N1 influenza virus induces narcolepsy-like sleep disruption and targets sleep-wake regulatory neurons in mice. Proc Natl Acad Sci USA. 2016;113:E368–77.
87. Barateau L, Lopez R, Dauvilliers Y. Treatment options for narcolepsy. CNS Drugs. 2016;30:369–79.
88. Roth T, Dauvilliers Y, Guinta D, Alvarez-Horine S, Dynin E, Black J. Effect of sodium oxybate on disrupted nighttime sleep in patients with narcolepsy. J Sleep Res. 2017;26(4):407–14.
89. Szakacs Z, Dauvilliers Y, Mikhaylov V, Poverennova I, Krylov S, Jankovic S, et al. Safety and efficacy of pitolisant on cataplexy in patients with narcolepsy: a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2017;16(3):200–7.
90. Hasan S, Pradervand S, Ahnaou A, Drinkenburg W, Tafti M, Franken P. How to keep the brain awake? The complex molecular pharmacogenetics of wake promotion. Neuropsychopharmacol Off Publ Am Coll Neuropsychopharmacol. 2009;34:1625–40.
91. Bogan RK, Feldman N, Emsellem HA, Rosenberg R, Lu Y, Bream G, et al. Effect of oral JZP-110 (ADX-N05) treatment on wakefulness and sleepiness in adults with narcolepsy. Sleep Med. 2015;16:1102–8.
92. Liu X, Petit J-M, Ezan P, Gyger J, Magistretti P, Giaume C. The psychostimulant modafinil enhances gap junctional communication in cortical astrocytes. Neuropharmacology. 2013;75:533–8.
93. Hecht M, Lin L, Kushida CA, Umetsu DT, Taheri S, Einen M, et al. Report of a case of immunosuppression with prednisone in an 8-year-old boy with an acute onset of hypocretin-deficiency narcolepsy. Sleep. 2003;26:809–10.
94. Lünemann JD, Quast I, Dalakas MC. Efficacy of intravenous immunoglobulin in neurological diseases. Neurother J Am Soc Exp Neurother. 2016;13:34–46.
95. Lecendreux M, Maret S, Bassetti C, Mouren M-C, Tafti M. Clinical efficacy of high-dose intravenous immunoglobulins near the onset of narcolepsy in a 10-year-old boy. J Sleep Res. 2003;12:347–8.
96. Dauvilliers Y, Carlander B, Rivier F, Touchon J, Tafti M. Successful management of cataplexy with intravenous immunoglobulins at narcolepsy onset. Ann Neurol. 2004;56:905–8.
97. Chen W, Black J, Call P, Mignot E. Late-onset narcolepsy presenting as rapidly progressing muscle weakness: response to plasmapheresis. Ann Neurol. 2005;58:489–90.
98. Dauvilliers Y. Follow-up of four narcolepsy patients treated with intravenous immunoglobulins. Ann Neurol. 2006;60:153.
99. Fronczek R, Verschuuren J, Lammers GJ. Response to intravenous immunoglobulins and placebo in a patient with narcolepsy with cataplexy. J Neurol. 2007;254:1607–8.
100. Plazzi G, Poli F, Franceschini C, Parmeggiani A, Pirazzoli P, Bernardi F, et al. Intravenous high-dose immunoglobulin treatment in recent onset childhood narcolepsy with cataplexy. J Neurol. 2008;255:1549–54.
101. Valko PO, Khatami R, Baumann CR, Bassetti CL. No persistent effect of intravenous immunoglobulins in patients with narcolepsy with cataplexy. J Neurol. 2008;255:1900–3.
102. Knudsen S, Biering-Sørensen B, Kornum BR, Petersen ER, Ibsen JD, Gammeltoft S, et al. Early IVIg treatment has no effect on post-H1N1 narcolepsy phenotype or hypocretin deficiency. Neurology. 2012;79:102–3.
103. Cossburn M, Pace AA, Jones J, Ali R, Ingram G, Baker K, et al. Autoimmune disease after alemtuzumab treatment for multiple sclerosis in a multicenter cohort. Neurology. 2011;77:573–9.
104. Hersh CM, Cohen JA. Alemtuzumab for the treatment of relapsing-remitting multiple sclerosis. Immunotherapy. 2014;6:249–59.
105. Donjacour CEHM, Lammers GJ. A remarkable effect of alemtuzumab in a patient suffering from narcolepsy with cataplexy. J Sleep Res. 2012;21:479–80.
106. Sarkanen T, Alén R, Partinen M. Transient impact of rituximab in H1N1 vaccination-associated narcolepsy with severe psychiatric symptoms. Neurologist. 2016;21:85–6.
107. Luca G, Haba-Rubio J, Dauvilliers Y, Lammers G-J, Overeem S, Donjacour CE, et al. Clinical, polysomnographic and genome-wide association analyses of narcolepsy with cataplexy: a European Narcolepsy Network study. J Sleep Res. 2013;22:482–95.
108. Thorpy MJ, Krieger AC. Delayed diagnosis of narcolepsy: characterization and impact. Sleep Med. 2014;15:502–7.
109. Lopez R, Barateau L, Evangelista E, Chenini S, Robert P, Jaussent I, et al. Temporal changes in the cerebrospinal fluid level of hypocretin-1 and histamine in narcolepsy. Sleep. 2016.
110. Rice GPA, Hartung H-P, Calabresi PA. Anti-alpha4 integrin therapy for multiple sclerosis: mechanisms and rationale. Neurology. 2005;64:1336–42.
111. Ntranos A, Hall O, Robinson DP, Grishkan IV, Schott JT, Tosi DM, et al. FTY720 impairs CD8 T-cell function independently of the sphingosine-1-phosphate pathway. J Neuroimmunol. 2014;270:13–21.
112. Ruperto N, Lovell DJ, Quartier P, Paz E, Rubio-Pérez N, Silva CA, et al. Abatacept in children with juvenile idiopathic arthritis: a randomised, double-blind, placebo-controlled withdrawal trial. Lancet Lond Engl. 2008;372:383–91.
113. Browne SK. Anticytokine autoantibody-associated immunodeficiency. Annu Rev Immunol. 2014;32:635–57.
114. Ahlmann M, Hempel G. The effect of cyclophosphamide on the immune system: implications for clinical cancer therapy. Cancer Chemother Pharmacol. 2016;78:661–71.
115. Pizza F, Vandi S, Liguori R, Parchi P, Avoni P, Mignot E, et al. Primary progressive narcolepsy type 1: the other side of the coin. Neurology. 2014;83:2189–90.
116. Konya C, Goronzy JJ, Weyand CM. Treating autoimmune disease by targeting CD8(+) T suppressor cells. Expert Opin Biol Ther. 2009;9:951–65.
117. MacLeod MKL, Anderton SM. Antigen-based immunotherapy (AIT) for autoimmune and allergic disease. Curr Opin Pharmacol. 2015;23:11–6.
118. Lutterotti A, Martin R. Antigen-specific tolerization approaches in multiple sclerosis. Expert Opin Investig Drugs. 2014;23:9–20.
119. Harrison LC, Wentworth JM, Zhang Y, Bandala-Sanchez E, Böhmer RM, Neale AM, et al. Antigen-based vaccination and prevention of type 1 diabetes. Curr Diabet Rep. 2013;13:616–23.
120. Zandian A, Forsström B, Häggmark-Månberg A, Schwenk JM, Uhlén M, Nilsson P, et al. Whole-proteome peptide microarrays for profiling autoantibody repertoires within multiple sclerosis and narcolepsy. J Proteome Res. 2017;16:1300–14.
121. Kantor S, Mochizuki T, Lops SN, Ko B, Clain E, Clark E, et al. Orexin gene therapy restores the timing and maintenance of wakefulness in narcoleptic mice. Sleep. 2013;36:1129–38.
122. Mieda M, Willie JT, Hara J, Sinton CM, Sakurai T, Yanagisawa M. Orexin peptides prevent cataplexy and improve wakefulness in an orexin neuron-ablated model of narcolepsy in mice. Proc Natl Acad Sci USA. 2004;101:4649–54.
123. Dauvilliers Y, Siegel JM, Lopez R, Torontali ZA, Peever JH. Cataplexy–clinical aspects, pathophysiology and management strategy. Nat Rev Neurol. 2014;10:386–95.
124. Deadwyler SA, Porrino L, Siegel JM, Hampson RE. Systemic and nasal delivery of orexin-A (hypocretin-1) reduces the effects of sleep deprivation on cognitive performance in nonhuman primates. J Neurosci Off J Soc Neurosci. 2007;27:14239–47.
125. Weinhold SL, Seeck-Hirschner M, Nowak A, Hallschmid M, Göder R, Baier PC. The effect of intranasal orexin-A (hypocretin-1) on sleep, wakefulness and attention in narcolepsy with cataplexy. Behav Brain Res. 2014;262:8–13.
126. Nagahara T, Saitoh T, Kutsumura N, Irukayama-Tomobe Y, Ogawa Y, Kuroda D, et al. Design and synthesis of non-peptide, selective orexin receptor 2 agonists. J Med Chem. 2015;58:7931–7.
127. Irukayama-Tomobe Y, Ogawa Y, Tominaga H, Ishikawa Y, Hosokawa N, Ambai S, et al. Nonpeptide orexin type-2 receptor agonist ameliorates narcolepsy-cataplexy symptoms in mouse models. Proc Natl Acad Sci USA. 2017;114:5731–6.
128. Hasegawa E, Yanagisawa M, Sakurai T, Mieda M. Orexin neurons suppress narcolepsy via 2 distinct efferent pathways. J Clin Investig. 2014;124:604–16.