Page 13 - The autoimmune hypothesis of narcolepsy and its unexplored clinical features M.S. Schinkelshoek

Pathophysiology
Discovery of hypocretin and its deficiency in narcolepsy
In 1998, the discovery of a novel peptide signaling system led to the unravelling of the cause of narcolepsy. Two groups separately, but simultaneously, identified two new peptide hormones. The one group called them orexins (Sakurai et al., 1998) after the Greek word for appetite, ὄρεξις, based on the role the hormones supposedly played in the regulation of appetite and metabolism based on their location in the hypothalamus); the other called them hypocretins based on their amino acid sequence that somewhat resembles that of the gut hormone secretin (de Lecea et al., 1998). Hypocretin-1 and hypocretin-2 are peptides that are derived from a common precursor protein called preprohypocretin that is produced solely in a group of around 80,000 neurons that are located in the lateral and posterior hypothalamus, henceforth in this thesis called hypocretin-producing neurons. One year later, in 1999, it was discovered that a mutation in one of the receptors for these hormones, the hypocretin receptor 2, was the cause of narcolepsy in narcoleptic dogs (Lin et al., 1999). Subsequently, the selective loss of hypocretin-producing neurons in the hypothalamus of narcolepsy patients was found to be the cause of narcolepsy in humans (Nishino et al., 2001, Peyron et al., 2000). This discovery directed research in narcolepsy to the question what causes the selective loss of these hypocretin-producing neurons. In addition, the discovery of the hypocretins allowed for using the concentration of hypocretin-1 in the cerebrospinal fluid as a biomarker for narcolepsy (Ripley et al., 2001, Mignot et al., 2002). Chapter 1 highlights a case that underscores the role of the development of hypocretin deficiency as the cause of NT1 symptoms.
HLA
As mentioned, in the early 1980s, it was found that Japanese narcolepsy patients all carried the HLA class I subtype DR2 (Juji et al., 1984), that is used by antigen-presenting cells of the immune system to present antigens to CD4+ T cells. This strong association was reproduced and it was found that the HLA- DQ subtype DQB1*06:02 is the most frequent subtype in narcolepsy across all ethnic groups (Mignot et al., 1994). This HLA-DQ subtype forms a haplotype with HLA-DQA1*01:02. It was reported that 85-95% of all NT1 patients carry this specific haplotype, compared to a frequency in the general population of
General introduction
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