333 Discussion Is narcolepsy type 1 an autoimmune disorder? Many questions about the potential triggers of narcolepsy type 1 and the underlying immunological processes remain unanswered. It is important to present our Section A findings in light of recent fundamental studies investigating the underlying immunological mechanisms in narcolepsy type 1. Criteria have been composed to define autoimmune disorders, of which at least two should be fulfilled to qualify [395-397]: (1) a specific adaptive immune response directed towards the affected organ or tissue, (2) autoreactive T cells and/or autoantibodies are present in the affected organ or tissue, (3) autoreactive T cells and/or autoantibodies can transfer the disease to healthy individuals or animals, (4) immunization with the autoantigen induces the disease in animal models, and (5) elimination or suppression of the autoimmune response prevents disease progression or even improve the clinical manifestation. The underlying immunological processes causing hypocretin deficiency in narcolepsy type 1 are likely of autoimmune origin [395] and the growing evidence for this will be briefly presented. The current hypothesis is that external antibodies presented by HLADQB1*0602 on antigen-presenting cells activate CD4+ T cells that induce an immunological reaction targeting hypocretin [4]. Multiple studies have identified autoantibodies against hypocretin in people with narcolepsy type 1 [398-403], especially anti-Tribbles homolog 2 (TRIB2) [404-406], neuropeptide glutamic acid-isoleucine/α-melanocyte-stimulating hormone (NEI/αMSH) [407], the hypocretin receptor 2 (HCRTR2) [408], neurexin-1-alpha (NRXN1) [409] and prostaglandin receptor D2 [410]. The studies reported inconsistent presence of these autoantibodies, but similar detection in sera from control groups and autoreactivity often lacked exclusive cross-reactivity to hypocretin [411]. Increased reactivity against type A H1N1 influenza [69, 74, 412, 413] and streptococcus pyogenes [10, 64-67] have also been reported in narcolepsy type 1, with structural analogies and hereby possible molecular mimicry between the influenza haemagglutinin protein in type A H1N1 influenza and hypocretin [413]. Our association with type B Victoria influenza and the interindividual differences in self-reported triggers prior to onset of central disorders of hypersomnolence could explain inconsistencies between studies and underlines the need for future studies incorporating personalised immunoassays with additional autoantibodies that could potentially target the hypocretin system. CD4+ T cells cross-reactive to hypocretin peptides have been identified in narcolepsy type 1. These cells were not HLA-DQB1*0602 restricted, however, and also seen in individuals with narcolepsy type 2 [68]. Following reports focussed on HLA-DQB1*0602-restricted CD4+ T cell populations in narcolepsy 11
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