Page 17 - The autoimmune hypothesis of narcolepsy and its unexplored clinical features M.S. Schinkelshoek

results of this study have been disputed by another group claiming that the OX2 receptor is not present on the surface of hypocretin-producing neurons and is therefore not a plausible target antigen for the autoimmune response leading to the development of NT1 (Vassalli et al., 2015).
Reports on T cells recognizing both H1N1 and hypocretin peptides have been published (De la Herran-Arita et al., 2013, Luo et al., 2018), but the first of these studies has subsequently been retracted (De la Herran-Arita and Garcia-Garcia, 2014). In Chapter 3, our experiments on cross-reactive T cells are presented. Recent studies have identified autoreactive T cells against hypocretin peptides (Latorre et al., 2018, Pedersen et al., 2019), but these cells were not HLA- DQB1*06:02 restricted. One study showed HLA-DQB1*06:02-restricted autoreactive T cells against hypocretin peptides, but they were found both in NT1 patients and in healthy controls (Jiang et al., 2019).
Genetics
As mentioned before, NT1 is strongly associated with the gene encoding HLA- DQB1*06:02 and other HLA type II genes. Also HLA type I genes, of which the gene product present antigens to cytotoxic CD8+ T cells, are associated with NT1, albeit these associations are considerably weaker than those with HLA type II genes (Ollila et al., 2015, Tafti et al., 2016). In addition to these HLA-associations, genome-wide association and gene sequencing studies have identified several other genes involved in the immune system that are associated with NT1: CTSH, that encodes pro-cathepsin H; P2RY11, that encodes a modulator of the autoimmune response to infection, p2Y purinoreceptor 11; and TNFSF4, that encodes tumor necrosis factor ligand superfamily member 4 (Faraco et al., 2013, Kornum et al., 2011, Tafti et al., 2014, Han et al., 2013). A recent study was the first to RNA sequence hypocretin-producing neurons in late embryonic mice, identifying the transcription of genes that distinguish hypocretin-producing neurons from adjacent melanin-concentrating hormone- producing neurons (Seifinejad et al., 2019). This could be a first step to identifying genes that, like hypocretin, are transcribed only in the hypocretin-producing neurons, and are therefore a plausible alternative target for an autoimmune response leading to the destruction of hypocretin-producing neurons leading to NT1.
General introduction
15