The role of the adjuvant component α-tocopherol in the development of narcolepsy
Bibliographic record
Abstract
After the pandemic influenza A (H1N1) vaccination in 2009, an increase in narcolepsy incidence was detected, suggesting a possible link between vaccination and narcolepsy. Narcolepsy is a chronic sleep disease that is characterized by sudden sleep attacks and brief losses of muscle tone (cataplexy). People with narcolepsy have very low concentrations of the neurotransmitter hypocretin in their cerebrospinal fluid, caused by selective destruction of hypocretin-producing cells in the hypothalamus. In addition, narcolepsy is highly associated with the HLA subtype DQB1*0602, as more than 99 % of all narcolepsy patients have this genetic predisposition suggesting a link to an autoimmune-mediated process. The strongest association between the pandemic vaccination and narcolepsy was observed with the AS03-adjuvanted vaccine Pandemrix first reported from Scandinavia, later also from other European countries. Recently, in Canada an increase in narcolepsy cases was detected and correlated to the vaccination with Arepanrix that was also adjuvanted with AS03. In contrast, other adjuvanted or non-adjuvanted influenza vaccines had no link to narcolepsy so far. Compared to other adjuvants used during the pandemic vaccination, AS03 is unique as it additionally contains α-tocopherol. Based on this, it was suspected that α-tocopherol could be causative for the increased incidence of narcolepsy after vaccination. α-Tocopherol is the most bioactive form of vitamin E and acts as an antioxidant. It was recently observed to activate the transcription factor Nrf2. Under basal conditions, Nrf2 is associated with its inhibitor Keap1 and constantly degraded by the proteasomal pathway. After the activation of Nrf2, it dissociates from Keap1 and translocates into the nucleus where it binds to the antioxidant response element (ARE) in the promoter region of its target genes, inducing the expression of these genes. Sequence analyses predicted a functional ARE site in the promoter region of hypocretin, suggesting that hypocretin could be expressed in an Nrf2-dependent manner. Furthermore, the catalytic active subunits of the constitutive proteasome have ARE sequences in their promoters. It has been demonstrated that the activation of Nrf2 leads to increased proteasomal activity. In addition, a crosstalk between Nrf2 and the transcription factor NF-κB is known, implying that the activation of Nrf2 leads to decreased NF-κB activity and vice versa. In this study, it was observed that α-tocopherol activates Nrf2 in neuronal cells and induces thereby on the one hand the expression of hypocretin and on the other hand the expression of the proteasomal subunit PSMB5 leading to an enhanced proteasomal activity. High amounts of hypocretin and increased activity of the proteasome result in a strong turnover of hypocretin. Moreover, also in neuronal cells activation of Nrf2 leads to decreased activity of NF-κB that sensitizes the cells for TNF-α-dependent apoptosis. In case of a genetic predisposition (DQB1*0602), that is found in almost all narcolepsy cases, longer hypocretin-derived peptides generated by proteasomal degradation could be presented on the cell surface to the T-cells that might trigger an autoimmune process leading to the destruction of hypocretin-producing neurons. Furthermore, cytokines such as TNF-α that are released in elevated amounts after vaccination could additionally trigger apoptosis in sensitized cells. Taken together, α-tocopherol could confer to the development of narcolepsy by activation of Nrf2 that could finally lead to the loss of hypocretin-producing neurons which is the reason for narcolepsy.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".