Page 120 - The autoimmune hypothesis of narcolepsy and its unexplored clinical features M.S. Schinkelshoek

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Future perspectives
The remaining question that this thesis does not touch upon, however, is whether we are searching for an autoimmune response to the right antigen. Thus far, hypocretin has always been regarded as the sole candidate antigen targeted in the autoimmune response in the development of NT1. This seems logical, since hypocretin is not produced in other neurons in the hypothalamus and hypocretin deficiency is strongly linked to the phenotype of the disorder (Lin et al., 1999, Nishino et al., 2000a, Peyron et al., 2000). However, whether other proteins or peptides exist that are relatively specific for hypocretin- producing neurons is largely unknown. Several studies have suggested genes that are relatively specific for hypocretin-producing neurons. However, this data is mostly derived from mouse studies (Liu et al., 2015, Romanov et al., 2017, Cvetkovic-Lopes et al., 2010, Dalal et al., 2013, Mickelsen et al., 2017, Seifinejad et al., 2019). Only one study uses posterior hypothalamus transcriptome data from human post-mortem brains (Honda et al 2010). Further information on the human expression levels of these genes in the hypocretin-producing neurons, or even in the hypothalamus, is lacking. The recent study in which hypocretin- specific CD8+ T cells were identified in healthy controls and NT1 patients was the first to compile data of these studies attempting to identify alternative candidate antigens and also perform experiments to assess reactivity to those antigens (Pedersen et al., 2019). Even though they did not find convincing evidence for autoreactivity, this approach seems promising. However, more reliable data on proteins being produced in hypocretin-producing neurons in humans is a prerequisite for designing experiments assessing immune responses to alternative candidate antigens other than hypocretin in NT1 patients. With the emergence of open access single cell RNA sequencing datasets and in silico data analysis methods becoming more and more advanced, identifying these alternative candidate antigens becomes feasible.
Frequently neglected symptoms of NT1
The second part of this thesis focuses on clinical symptoms of NT1. The assumed strong causal and temporal association between the destruction of hypocretin-producing neurons and the appearance of symptoms of NT1 is reinforced in Chapter 1. In this Chapter, we describe a case that shows that the relation between the development of hypocretin deficiency and the appearance of NT1 symptoms is causal and can be a process of only weeks. The case is