en
Scientific article
English

Elevated Tribbles homolog 2-specific antibody levels in narcolepsy patients

Published inThe Journal of clinical investigation, vol. 120, no. 3, p. 713-719
Publication date2010
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
  • Animals
  • Autoantibodies/*blood/immunology
  • Autoantigens/genetics/immunology/*metabolism
  • Autoimmune Diseases/*blood/genetics/immunology/pathology
  • Female
  • Humans
  • Hypothalamus/immunology/metabolism/pathology
  • Intracellular Signaling Peptides and
  • Proteins/genetics/immunology/*metabolism
  • Male
  • Mice
  • Mice, Transgenic
  • Narcolepsy/*blood/genetics/immunology/pathology
  • Neurons/immunology/metabolism/pathology
  • Neuropeptides/genetics/immunology/metabolism
  • Protein-Serine-Threonine Kinases/genetics/immunology/*metabolism
  • Severity of Illness Index
  • Sleep Initiation and Maintenance
  • Disorders/blood/genetics/immunology/pathology
  • Time Factors
Citation (ISO format)
CVETKOVIC-LOPES, Vesna et al. Elevated Tribbles homolog 2-specific antibody levels in narcolepsy patients. In: The Journal of clinical investigation, 2010, vol. 120, n° 3, p. 713–719. doi: 10.1172/JCI41366
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accessLevelRestricted
Identifiers
ISSN of the journal0021-9738
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