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Title

Elevated Tribbles homolog 2-specific antibody levels in narcolepsy patients

Authors
Cvetkovic-Lopes, Vesna
Dorsaz, Stephane
Maret, Stephanie
Pradervand, Sylvain
Dauvilliers, Yves
Lecendreux, Michel
Lammers, G. J.
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Published in Journal of Clinical Investigation. 2010, vol. 120, no. 3, p. 713-719
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.
Keywords AnimalsAutoantibodies/*blood/immunologyAutoantigens/genetics/immunology/*metabolismAutoimmune Diseases/*blood/genetics/immunology/pathologyFemaleHumansHypothalamus/immunology/metabolism/pathologyIntracellular Signaling Peptides andProteins/genetics/immunology/*metabolismMaleMiceMice, TransgenicNarcolepsy/*blood/genetics/immunology/pathologyNeurons/immunology/metabolism/pathologyNeuropeptides/genetics/immunology/metabolismProtein-Serine-Threonine Kinases/genetics/immunology/*metabolismSeverity of Illness IndexSleep Initiation and MaintenanceDisorders/blood/genetics/immunology/pathologyTime Factors
Stable URL http://archive-ouverte.unige.ch/unige:10220
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PMID: 20160349
Structures
Research group Mécanismes impliqués dans la régulation des états de veille et de sommeil (213)
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