Page 14 - The autoimmune hypothesis of narcolepsy and its unexplored clinical features M.S. Schinkelshoek

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20-30%. In recent studies, the reported association with HLA-DQB1*06:02 in NT1 was found to be closer to an almost perfect association with close to 100% of NT1 patients expressing the HLA-DQB1*06:02 allele (Tafti et al., 2014, van der Heide et al., 2015b). In addition, homozygosity for the HLA- DQB1*06:02 subtype was reported to constitute an even higher risk for the development of NT1 than the presence of one HLA-DQB1*06:02 already does (Pelin et al., 1998). As a result, HLA-DQB1*06:02 has been considered as a genetic factor that is necessary but not sufficient to develop NT1. Apart from the strong association with HLA- DQB1*06:02, there are both positive and negative associations between HLA-DQB1 alleles and NT1: the frequency of HLA-DQB1*03:01 was found to be increased, whereas HLA-DQB1*02:01 (HLA-DQ2), HLA-DQB1*05:01, HLA-DQB1*06:01, HLA-DQB1*06:03 and HLA-DQB1*06:09 were decreased in NT1 patients as compared with healthy controls (Hong et al., 2007, Ollila et al., 2015, Tafti et al., 2014). Apart from HLA-DQ, also positive and negative associations with other HLA subtypes, both HLA class I and class II, such as HLA-DR, HLA-A, HLA-B and HLA-C are described in NT1 (Juvodden et al., 2019b, Lind et al., 2019) albeit not nearly as strong as the association with HLA-DQB1*06:02.
2009 H1N1 influenza A pandemic
The 2009 H1N1 influenza A pandemic brought about a new surge in interest in the autoimmune hypothesis of NT1. This influenza strain, also called Mexican or swine flu, infected and killed many people around the world. The emergence of the pandemic was shortly followed by vaccination programs that had to be established in a shorter time and on a bigger scale than ever before. One year later, an increase in the incidence of NT1 was observed. In several (Northern) European countries, but also in China, a steep increase in narcolepsy incidence compared to the decade before the pandemic was described (Dauvilliers et al., 2013, Feltelius et al., 2015, Lind et al., 2014, Partinen et al., 2012, Han et al., 2011). The role that influenza vaccines played in this increased incidence of NT1 was discussed and investigated widely. Only Pandemrix, a vaccine predominantly used in Scandinavian countries, was suggested to constitute a small, but significant, risk factor for the development of NT1 in these countries (Sarkanen et al., 2018).
Following these epidemiological and laboratory reports, a discussion on the existence of a post-H1N1 NT1 variant has arisen. Several recent Scandinavian