Page 31 - The autoimmune hypothesis of narcolepsy and its unexplored clinical features M.S. Schinkelshoek

Introduction
Narcolepsy type 1 (NT1) is a rare disorder of the regulation of sleep and wakefulness with an incidence of 1 per 100,000 person years and prevalence ranging between 20 and 50 per 100,000 individuals (Wijnans et al., 2013). NT1 is characterised by five core symptoms: excessive daytime sleepiness, cataplexy, hypnagogic hallucinations, sleep paralysis and disturbed nocturnal sleep. These symptoms arise as a result of the presumed destruction of over 90 percent of hypocretin (Hcrt)-producing neurons in the lateral hypothalamus hypothesized as being caused by an autoimmune response (Bassetti et al., 2019, Kornum et al., 2017b).
95% of NT1 patients carry the HLA-DQA1*01:02 / DQB1*06:02 haplotype encoding HLA-DQB1*06:02, an HLA-class II molecule expressed on antigen presenting cells (Tafti et al., 2014). HLA-DQB1*06:02 is also present in about 20% of the general European population. As a result, HLA-DQB1*06:02 has been considered as a genetic factor necessary but not sufficient for development of NT1. Apart from the well-known association with HLA- DQB1*06:02, there are positive and negative associations between other HLA- DQB1 alleles and NT1: the frequency of HLA-DQB1*03:01 (HLA-DQ7) was found to be increased, whereas HLA-DQB1*02:01 (HLA-DQ2), HLA- DQB1*05:01, HLA-DQB1*06:01, HLA-DQB1*06:03 and HLA-DQB1*06:09 were decreased in NT1 patients compared with healthy controls (Hong et al., 2007, Ollila et al., 2015, Tafti et al., 2014).
An increase in the incidence of NT1 has been observed in several European countries since the 2009 influenza A(H1N1) pdm09 pandemic, and the subsequent vaccination campaign (Dauvilliers et al., 2013, Feltelius et al., 2015, Lind et al., 2014, Partinen et al., 2012). Recent studies have identified autoreactive T cells against hypocretin peptides (Latorre et al., 2018, Pedersen et al., 2019), but their reactivity was not HLA-DQB1*06:02 restricted. Reports on T cells recognizing both H1N1 and hypocretin peptides show conflicting results (Luo et al., 2018, Schinkelshoek et al., 2019), with detected T cell cross- reactivity in the first study not being replicated in the second.
Following these epidemiological and laboratory reports, a discussion on the existence of a post-H1N1 NT1 variant has arisen, with specifically Scandinavian countries making the distinction between sporadic and post-H1N1 NT1. Several recent Scandinavian studies report HLA-DQ-haplotypes associated specifically with post-H1N1 NT1 (HLA-DQ2, HLA-DQ7) (Juvodden et al.,
HLA associations after 2009 H1N1 pandemic
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