title: Elevated Tribbles homolog 2-specific antibody levels in narcolepsy patients.
abstract: Narcolepsy is a sleep disorder characterized by excessive daytime sleepiness and attacks of muscle atonia triggered by strong emotions (cataplexy). Narcolepsy is caused by hypocretin (orexin) deficiency, paralleled by a dramatic loss in hypothalamic hypocretin-producing neurons. It is believed that narcolepsy is an autoimmune disorder, although definitive proof of this, such as the presence of autoantibodies, is still lacking. We engineered a transgenic mouse model to identify peptides enriched within hypocretin-producing neurons that could serve as potential autoimmune targets. Initial analysis indicated that the transcript encoding Tribbles homolog 2 (Trib2), previously identified as an autoantigen in autoimmune uveitis, was enriched in hypocretin neurons in these mice. ELISA analysis showed that sera from narcolepsy patients with cataplexy had higher Trib2-specific antibody titers compared with either normal controls or patients with idiopathic hypersomnia, multiple sclerosis, or other inflammatory neurological disorders. Trib2-specific antibody titers were highest early after narcolepsy onset, sharply decreased within 2-3 years, and then stabilized at levels substantially higher than that of controls for up to 30 years. High Trib2-specific antibody titers correlated with the severity of cataplexy. Serum of a patient showed specific immunoreactivity with over 86% of hypocretin neurons in the mouse hypothalamus. Thus, we have identified reactive autoantibodies in human narcolepsy, providing evidence that narcolepsy is an autoimmune disorder.
authors.affiliation: Département de Neurosciences Fondamentales, Centre Médical Universitaire, Genève, Switzerland.
authors.forename: Vesna
authors.initials: V
authors.lastname: Cvetkovic-Lopes
authors.forename: Laurence
authors.initials: L
authors.lastname: Bayer
authors.forename: Stéphane
authors.initials: S
authors.lastname: Dorsaz
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Maret
authors.forename: Sylvain
authors.initials: S
authors.lastname: Pradervand
authors.forename: Yves
authors.initials: Y
authors.lastname: Dauvilliers
authors.forename: Michel
authors.initials: M
authors.lastname: Lecendreux
authors.forename: Gert-Jan
authors.initials: GJ
authors.lastname: Lammers
authors.forename: Claire E H M
authors.initials: CE
authors.lastname: Donjacour
authors.forename: Renaud A
authors.initials: RA
authors.lastname: Du Pasquier
authors.forename: Corinne
authors.initials: C
authors.lastname: Pfister
authors.forename: Brice
authors.initials: B
authors.lastname: Petit
authors.forename: Hyun
authors.initials: H
authors.lastname: Hor
authors.forename: Michel
authors.initials: M
authors.lastname: Mühlethaler
authors.forename: Mehdi
authors.initials: M
authors.lastname: Tafti
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000097:blood* / Q000276:immunology; D001324:Autoantigens / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D001327:Autoimmune Diseases / Q000097:blood* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D005260:Female; D006801:Humans; D007031:Hypothalamus / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009290:Narcolepsy / Q000097:blood* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D009474:Neurons / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D009479:Neuropeptides / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000068797:Orexins; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000037:antagonists & inhibitors; D012720:Severity of Illness Index; D007319:Sleep Initiation and Maintenance Disorders / Q000097:blood / Q000235:genetics / Q000276:immunology / Q000473:pathology; D013997:Time Factors
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D000068797:Orexins; C515847:tribbles 2 protein, mouse; D017346:Protein Serine-Threonine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C489044:TRIB2 protein, human