The adjuvant component α-tocopherol triggers via modulation of Nrf2 the expression and turnover of hypocretin in vitro and its implication to the development of narcolepsy

Abstract

Background: After the H1N1 swine flu vaccination campaign an increased number of narcolepsy cases in children and adolescents was observed in Scandinavian and later in further European countries that correlated with the vaccination by an AS03-adjuvanted influenza vaccine (Pandemrix). Narcolepsy is a chronic sleep disorder characterized by the loss of hypocretin in the cerebrospinal fluid due to selective destruction of hypocretin-producing neurons in the perifornical hypothalamus. In >99% of the cases narcolepsy is associated with the HLA-subtype DQB1*602 giving the link to an autoimmune process. In contrast to other squalene-based adjuvants, for which no association with narcolepsy was reported so far, ASO3 contains in addition α-tocopherol. It could be observed recently that α-tocopherol activates the transcription factor Nrf2. Nrf2 triggers the expression of cytoprotective genes, i.e. the catalytic active subunits of the constitutive proteasome, by binding to the antioxidant response element (ARE). It was hypothesized that α-tocopherol via activation of Nrf2 affects expression and turnover of hypocretin, leading to an increased amount of hypocretinα-specific fragments that bind to DQB1*602.

Results: α-Tocopherol activates Nrf2 in neuronal cells in vitro. Promoter analysis revealed an ARE sequence in the hypocretin promoter. Indeed, α-tocopherol increases by activation of Nrf2 the expression of hypocretin. In parallel, α-tocopherol -dependent induction of Nrf2 augments expression of catalytic subunits of the proteasome leading to increased degradation of hypocretin. Moreover, elevated activation of Nrf2 is associated with a decreased activity of NF-κB that results in an increased sensitivity to apoptotic stimuli.

Conclusion: In case of a genetic predisposition (DQB1*602) α-tocopherol could confer to development of narcolepsy by activation of Nrf2 that finally leads to an elevated formation of longer hypocretin-derived fragments that can be presented by HLA-subtype DQB1*602. These cells are recognized by the immune system and due to their increased sensitivity to apoptotic stimuli they can be destroyed, finally leading to a lack of hypocretin.

Keywords: ASO3; Adjuvant; Hypocretin; NF-κB; Nrf2; α-Tocopherol.