Elevated Tribbles homolog 2-specific antibody levels in narcolepsy patients.
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.
Cvetkovic-Lopes
Vesna
V
Département de Neurosciences Fondamentales, Centre Médical Universitaire, Genève, Switzerland.
Bayer
Laurence
L
Dorsaz
Stéphane
S
Maret
Stéphanie
S
Pradervand
Sylvain
S
Dauvilliers
Yves
Y
Lecendreux
Michel
M
Lammers
Gert-Jan
GJ
Donjacour
Claire E H M
CE
Du Pasquier
Renaud A
RA
Pfister
Corinne
C
Petit
Brice
B
Hor
Hyun
H
Mühlethaler
Michel
M
Tafti
Mehdi
M
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
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