Alpha-Tocopherol Contributes to Narcolepsy Risk in Susceptible Individuals
By Will Boggs MD
NEW YORK - Exposure to alpha-tocopherol, used as an adjuvant in at least one flu vaccine, can increase the risk of narcolepsy in individuals with HLA-subtype DQB1*602, researchers from Germany report.
"Our work is based on the observation that after the H1N1 swine flu vaccination campaign, an increased number of narcolepsy cases was observed in Scandinavian and later in further European countries that correlated with the vaccination using an AS03 adjuvanted vaccine (Pandemrix)," Dr. Eberhard Hildt from Paul-Ehrlich-Institute, Langen, Germany told Reuters Health by email.
"Since AS03 contains alpha-tocopherol we investigated in tissue culture whether alpha-tocopherol triggers mechanisms that could confer to the development of narcolepsy," he said.
In the murine neuronal cell line N29/1 and in human cell lines, alpha-tocopherol activated Nrf2/ARE-dependent gene expression that resulted in the expression of hypocretin (low levels of which have been implicated in narcolepsy), his team writes in a paper released online April 14th in Vaccine.
On the other hand, by activating the proteasome of the cell, alpha-tocopherol also increased the turnover of hypocretin, which could lead to an increased amount of hypocretin-specific fragments.
Other evidence suggests that alpha-tocopherol leads to a decreased activity of NF-kappaB that is associated with an increased sensitivity to apoptotic signals.
In patients with such predispositions as HLA-DQB1*602, they say, -tocopherol induces mechanisms that finally can result in narcolepsy.
"Under certain conditions (genetic predisposition, induction of T helper cell response, etc.) these mechanisms could be part of a multifactorial process that can lead to the development of narcolepsy in children and adolescents after vaccination with the AS03 adjuvanted flu vaccine Pandemrix," Dr. Hildt said.
He continued, "Based on these cell culture experiments, such mechanisms will have to be investigated to be triggered in neuronal brain cells in animals that have been vaccinated with AS03-adjuvanted flu-vaccine."
"The hypothesis underlying our experiments discussed above was that development of narcolepsy after vaccination with Pandemrix is a multifactorial process because it depends on a genetic predisposition, induction of Th cell response, induction of autoimmune response mechanisms, etc.," Dr. Hildt said. "In light of this our intention was to communicate to the scientific community a potential novel factor and its mechanism of action and thereby to contribute to the efforts to reveal the background of this severe disease."
"At the current stage of our knowledge, the message is that we and others are (working) to identify factors that could contribute to the development of narcolepsy following administration of AS03-containing vaccines," Dr. Hildt concluded. "Scientific honesty and humbleness require us to state that it could be a longer way before we will be able to draw any conclusions that will be of direct relevance to the clinic."
SOURCE: https://bit.ly/1naLRuT
Vaccine 2014.
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