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- Title
Elevated Tribbles homolog 2-specific antibody levels in narcolepsy patients.
- Authors
Cvetkovic-Lopes, Vesna; Bayer, Laurence; Dorsaz, Stéphane; Maret, Stéphanie; Pradervand, Sylvain; Dauvilliers, Yves; Lecendreux, Michel; Lammers, Gert-Jan; Donjacour, Claire E. H. M.; Du Pasquier, Renaud A.; Pfister, Corinne; Petit, Brice; Hor, Hyun; Mühlethaler, Michel; Tafti7, Mehdi; Dorsaz, Stéphane; Maret, Stéphanie; Mühlethaler, Michel; Tafti, Mehdi
- 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.
- Subjects
AUTOIMMUNE diseases; NARCOLEPSY; OREXINS; LABORATORY mice; PEPTIDES; ENZYME-linked immunosorbent assay; ANTIBODY titer
- Publication
Journal of Clinical Investigation, 2010, Vol 120, Issue 3, p713
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI41366