Narcolepsy is a neurological disorder characterized by excessive daytime sleepiness, cataplexy, hypnagonic hallucinations, sleep paralysis, and disturbed nocturnal sleep patterns. This disease is secondary to the specific loss of hypothalamic hypocretin (orexin)-producing neurons in the lateral hypothalamus. An autoimmune basis for the disease has long been suspected based on its strong association with the genetic marker DQB1*06:02, and current studies greatly support this hypothesis. Narcolepsy with hypocretin deficiency is associated with human leukocyte antigen (HLA) and T cell receptor (TCR) polymorphisms, suggesting that an autoimmune process targets a peptide unique to hypocretin-producing neurons via specific HLA-peptide-TCR interactions. This concept has gained a lot of notoriety after the increase of childhood narcolepsy in 2010 following the 2009 H1N1 pandemic (pH1N1) in China and vaccination with Pandemrix, an adjuvanted H1N1 vaccine that was used in Scandinavia. The surge of narcolepsy cases subsequent to influenza A H1N1 infection and H1N1 vaccination suggests that processes such as molecular mimicry or bystander activation might be crucial for disease development. 1. Introduction Narcolepsy with hypocretin deficiency is a common sleep disorder that affects approximately 0.02% of the population worldwide and causes disability in 24% of the affected subjects. It is clinically characterized by excessive daytime sleepiness and abnormal sleep-wake patterns. These patients also suffer from cataplexy, a sudden loss of muscle tone triggered by strong emotions such as laughter, and are considered to be fragments of Rapid Eye Movement (REM) sleep that intrude into wakefulness, such as hypnagogic (dream-like) hallucinations as they drift off to sleep, as well as cataplexy (sudden loss of muscle tone triggered by strong emotions). All narcoleptic subjects present chronic sleepiness, but the intensity varies across the day and between individuals. This sleepiness is most troublesome during periods of inactivity, though it is often improved temporarily by a brief nap. As a consequence of sleepiness, patients may report inattention, poor memory, blurry vision, diplopia, and automatic behaviors such as driving without awareness [1–3]. 2. The Hypocretin System The disorder is caused by the specific loss of hypothalamic neurons producing two hypocretin peptides with high homology with each other, namely, hypocretin-1 and hypocretin-2 (also called orexin A and B), which are comprised of 33 and 28 amino acids, respectively [4–6]. These are produced by
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