Page 43 - 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 a prevalence ranging between 20-50 per 100,000 individuals (Ohayon et al., 2002, Wijnans et al., 2013). The disorder 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 destruction of over 90 percent of hypocretin (Hcrt)-producing neurons in the lateral hypothalamus (Peyron et al., 2000, Thannickal et al., 2000). Unfortunately, causal treatment of the disorder is not yet available.
In pursuit of the disease mechanism, two findings have shifted the focus of narcolepsy research to the hypothesis that the destruction of Hcrt-producing neurons is caused by an autoimmune process. First, 95% of NT1 patients carry the HLA-DQA1*01:02 / DQB1*06:02 haplotype encoding HLA-DQ6, an HLA-class II molecule expressed on antigen-presenting cells (Juji et al., 1984, Mignot et al., 1997, Tafti et al., 2014), which was later complemented by genome-wide association studies that showed variants within immune system- regulating genes in NT1 patients (Faraco et al., 2013, Han et al., 2013, Hor et al., 2010). Second, an increase in the incidence of NT1 has been observed in several European countries after the 2009 H1N1 influenza pandemic, and the subsequent vaccination campaign (Dauvilliers et al., 2013, Feltelius et al., 2015, Lind et al., 2014, Partinen et al., 2012). Even though there was no wide-spread vaccination campaign in Asian countries, an increased incidence has also been reported in China (Han et al., 2011). This suggests that NT1 might develop as the result of a cross-reactive anti-viral immune response that leads to the destruction of Hcrt-producing neurons. More insight in this reaction could pave the way for causal treatment development in NT1 and potentially also prevention of the disease by identifying individuals at-risk.
Research on the autoimmune reaction has focused on two candidate immune cell types that could drive this reaction leading to NT1: cross-reactive B cells and cross- or autoreactive CD4+ T cells. Four studies (Black et al., 2005, Overeem et al., 2006, Tanaka et al., 2006, van der Heide et al., 2015a) failed to detect autoreactive B cells or autoantibodies to Hcrt or Hcrt-receptors. Another group claimed to have identified autoreactive CD4+ T cells specific for Hcrt (De la Herran-Arita et al., 2013, De la Herran-Arita et al., 2014), but the article was subsequently retracted. While HLA-DR-restricted Hcrt-specific
H1N1 reactivity in CD4+ T cells
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