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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 imnmnoreactivity 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.
Introduction
Hypocretin (orexin) neurons play a critical role in the don of sleep and wakefulness, and disturbances of the cretin system have been directly linked to narcolepsy in and humans (1-6). Human narcolepsy is believed to be by a selective hypocretin neuronal loss (2, 3). Current eses suggest an autoimmune process targeting these Attempts to characterize immune-related processes have so far. Narcolepsy is tightly associated with the HLA system, 95% of narcolepsy patients with cataplexy carrying the HLADQB 1*0602 allele and having undetectable hypocretin levels their cerebrospinal fluid (CSF) (7, 8). A recent genome-wide ciation study found a strong association between narcolepsy a T cell receptor a gene variant, corroborating the hypothesis (9). Moreover, using a model of spontaneous migrating motor complex, the presence of functional autoantibodies in sera of narcolepsy patients could be demonstrated 11). However, peripheral or central immune abnormalities in narcolepsy, even in patients diagnosed shortly after the disease onset; could not be demonstrated thus far (12). One hypothesis...