Page 63 - The autoimmune hypothesis of narcolepsy and its unexplored clinical features M.S. Schinkelshoek

Introduction
Narcolepsy type 1 (NT1) is a sleep-wake disorder characterized by a pentad of core symptoms: excessive daytime sleepiness, cataplexy, hypnagogic hallucinations, sleep paralysis and disturbed nocturnal sleep. Diagnosis is based on the third edition of the International Classification of Sleep Disorders (ICSD, 2014). Estimations of its prevalence are between 20-50 per 100,000 individuals (Wijnans et al., 2013). NT1 is caused by the destruction of most hypocretin- producing neurons in the lateral hypothalamus, leading to a hypocretin deficiency that can be measured in the cerebrospinal fluid (Peyron et al., 2000, Thannickal et al., 2000). The destruction of the hypocretin-producing neurons is hypothesized to be the result of an autoimmune response. Two discoveries have reinforced this hypothesis. Firstly, it was described that 95% of NT1 patients carry the HLA-DQA1*01:02 / DQB1*06:02 haplotype that encodes HLA-DQ6, an HLA-class II molecule on human antigen-presenting cells (Juji et al., 1984, Mignot et al., 1997, Tafti et al., 2014). Genome-wide association studies added to this finding by showing associations of NT1 with variants within immune- related genes in NT1 patients (Faraco et al., 2013, Han et al., 2013, Hor et al., 2010). Additionally, the 2009 H1N1 influenza pandemic and the subsequent vaccination campaign was followed by an increase in the incidence of NT1 in several European countries and China (Dauvilliers et al., 2013, Feltelius et al., 2015, Lind et al., 2014, Partinen et al., 2012, Han et al., 2011). These findings shifted the focus of further research on candidate immune cell types driving the autoimmune response leading to the disappearance of hypocretin-producing neurons in NT1.
Studies on the role of B cells failed to detect autoreactive B cells or autoantibodies to hypocretin or its receptors (Black et al., 2005, Overeem et al., 2006, Tanaka et al., 2006, van der Heide et al., 2015a). Studies focusing on the role of autoreactive CD4+ T cells targeting hypocretin show conflicting results. HLA-DQ- restricted (Luo et al., 2018) or HLA-DR-restricted hypocretin-specific CD4+ T cell responses (Latorre et al., 2018) were demonstrated by two groups, while others found HLA-DQ-restricted hypocretin-specific CD4+ T cell responses in both NT1 patients and healthy controls (Jiang et al., 2019, Pedersen et al., 2019). Previously, our group did not show any HLA-DQ-restricted hypocretin- specific CD4+ T cells responses in NT1 patients (Schinkelshoek et al., 2019).
Immune cell composition in peripheral blood
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