Page 15 - The autoimmune hypothesis of narcolepsy and its unexplored clinical features M.S. Schinkelshoek

studies have sparked the discussion whether different immunological mechanisms may be involved in post-H1N1 NT1 cases (Juvodden et al., 2019a, Lind et al., 2019). These results would test the hypothesis that sporadic and post-H1N1 NT1 should be regarded as separate entities based on different immunological mechanisms leading to the disease. Chapter 2 adds new information to this discussion.
Association of NT1 with other infections
Also other infections are associated with the development of NT1. Most notably, the finding of elevated anti-streptococcal antibody titres in recent-onset NT1 patients suggested an association with other upper airway infections than only H1N1 influenza, particularly β-hemolytic streptococcal infections (Aran et al., 2009). Several other studies report associations of NT1 with streptococcal infections (Lopes et al., 2015, Natarajan et al., 2013), flu or other respiratory tract infections (Picchioni et al., 2007), tick-borne encephalitis virus vaccination (Hidalgo et al., 2016) or proxies of infections in the patient, such as month of diagnosis (Han et al., 2011). In Chapter 1, we describe a case that developed NT1 shortly after a gastrointestinal infection. The exact role of infections other than H1N1 influenza remains to be elucidated. This is partly due to the fact that NT1 is a rare disease, but also because documentation on the presence of especially viral infections is poor, because many people do not consult a doctor for these infections.
The autoimmune hypothesis of narcolepsy
Figure 1 provides an overview of the autoimmune hypothesis of narcolepsy. The hypothesis is that antigens from outside the body (e.g. H1N1 influenza, Streptococcus species, vaccines) trigger the immune system. In people susceptible for developing NT1, these antigens are presented to CD4+ T cells by HLA- DQB1*06:02 on antigen-presenting cells. In these people, cross-reactive CD4+ T cells are present that are able to mount an immune response to both the foreign peptide and the hypocretin peptide which closely resembles this foreign peptide. When activated, these cross-reactive CD4+ T cells elicit an autoimmune response that via multiple suggested pathways (e.g. hypocretin peptide-specific cytotoxic CD8+ T cells or autoantibodies targeting hypocretin- producing neurons) eventually lead to the destruction of hypocretin-producing neurons in the lateral hypothalamus.
General introduction
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