Page 118 - The autoimmune hypothesis of narcolepsy and its unexplored clinical features M.S. Schinkelshoek
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patients and 19 HLA-matched healthy controls. In none of our proliferation experiments with T cell lines stimulated with both peptides, we found any proliferative response to the two hypocretin peptides used. Additionally, we isolated H1N1-HA275–287-specific T cell clones (157 T cell clones from 12 patients, shown in Table 3.3 in Chapter 3) in which we have not been able to detect any reactivity to both hypocretin peptides.
Thirdly, Mignot et al. state that the depth of our TCR sequencing is too low to be able to find any sequences common for NT1. We agree with them on this point, but this was not the primary focus of our project, we elaborate on this limitation of our study in the Discussion section of Chapter 3.
Important unsolved issues in studies showing autoreactivity to hypocretin are the identification of hypocretin-specific CD4+ and CD8+ T cells in healthy controls (Jiang et al., 2019, Pedersen et al., 2019) and the finding of HLA-DR- restricted instead of HLA-DQB1*06:02-restricted hypocretin-specific T cells (Latorre et al., 2018), as would have been expected based on the autoimmune hypothesis.
To conclude, the discussed studies add complementary information to the autoimmune hypothesis of narcolepsy. It seems more and more probable that the H1N1 influenza pandemic has a direct link with the development of narcolepsy type 1, but direct evidence of T cells being implicated in the autoimmune destruction of hypocretin-producing neurons is still missing.
 • Hypocretin and H1N1-hemagglutinin peptides that are bound to HLA-DQ6 show structural homology
• H1N1-hemagglutinin-specific CD4+ T cells are detected in NT1 patients and controls
• Cross-reactivity between H1N1-hemagglutinin and hypocretin peptides is not observed
• H1N1-hemagglutinin-specific CD4+ T cell reactivity is HLA- DQ6-restricted
• There is no biased expression in the H1N1-hemagglutinin- specific T cell receptor repertoire
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