334 Chapter 11 type 1 and reported inconsistent presence of cross-reactive T-cells against hypocretin and type A H1N1 influenza peptides [69, 71, 178, 413]. Involvement of CD4+ T cells seems apparent but insufficient as the generally HLA class II-restricted signalling nature of CD4+ T cells implies an inability to directly harm hypocretin neurons and necessitates additional involvement of HLA class I-mediated effector cells to induce hypocretin deficiency. Higher frequencies of autoreactive effector CD8+ T cells have been found in narcolepsy type 1 blood samples compared to controls [68, 75] and human postmortem hypothalamic CD8+ T-cell infiltration and gliosis was reported in a donor with secondary narcolepsy type 1 by Ma2 antibody encephalitis [73]. These results suggest involvement of T cells in the pathogenesis of narcolepsy type 1. Indirect bystander activation of effector immune cells has been suggested in other autoimmune conditions [414] and warrants exploration in the context of narcolepsy type 1. This entails the activation of T cells or B cells triggered by local inflammation in the absence of specific antigen recognition. Transferring autoantibodies [407, 415] and immunization experiments with autoantigens [416, 417] have so far not resulted in induction of the typical narcolepsy type 1 phenotype with hypocretin deficiency in animal studies. Multiple human immunotherapy studies have additionally tested corticosteroids [418-422], plasmapheresis [423] and intravenous immunoglobulins (IVIG) [420, 422, 424-426] in different narcolepsy type 1 disease stages. Despite sporadic initial clinical improvements, no curing nor lasting clinical effects have been documented after administration of corticosteroids. Plasmapheresis and IVIG also provided transient improvement of excessive daytime sleepiness and/ or cataplexy when administered within months of narcolepsy type 1 onset in multiple case reports, case series and a non-randomized trial [420, 422427]. One case even showed temporary normalization of their cerebrospinal fluid hypocretin levels during IVIG treatment with deterioration of narcolepsy symptoms within months after discontinuation [425], which suggests that interference in the immunological process underlying hypocretin deficiency is possible. Absence of control groups in these studies could have introduced possible placebo effects, and the sole clinical trial had disease severity group differences at baseline [420]. Converging evidence strongly points towards an autoimmune origin of narcolepsy type 1. Officially, the criteria for autoimmune disorders are still incompletely fulfilled, as only the first criterion is currently satisfied [395]. Numerous aspects of the immunological cascade underlying narcolepsy type 1 remain unclear and necessitate additional research. This includes elucidating the effector mechanisms responsible for hypocretin deficiency
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