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A scientific sequel to Stieg Larsson: relationship between Pandemrix – pandemic influenza vaccine – and the subsequent development of narcolepsy

2013; Wiley; Volume: 275; Issue: 2 Linguagem: Inglês

10.1111/joim.12158

1365-2796

Lars Fugger, Lawrence Steinman,

Neuroscience of respiration and sleep

How does a vaccine or a natural infection trigger narcolepsy? Vaccines, and of course natural infections, profoundly influence the immune system. We give vaccines in order to stimulate the adaptive immune system to provide protective immunity to a microbe. We survive natural infection by a successful battle against the infectious microbe, with long-lasting immune memory to protect us. We do not know as yet whether narcolepsy is a disease where the immune system goes awry and attacks self. We do know from Mignot's pioneering studies that in human narcolepsy as well as in spontaneous genetic models in the dog, narcolepsy results from a profound loss of neurons in the hypothalamus that produce hypocretin 10, 11. There are two major clues linking narcolepsy to the immune system. There is a dominant relationship between narcolepsy and the class II HLA molecule HLA-DQ0602. In vaccine-associated narcolepsy, there is also this strong nearly exclusive association 12. Mignot has also provided genetic evidence that there is an association between susceptibility to ‘spontaneous narcolepsy’ and genes encoding the alpha chain of the T-cell receptor 13. Given that both Pandemrix and the natural infection with H1N1a triggered narcolepsy, it is logical that there might be some sequence present in the natural organism and in the vaccine that provokes the immune system, leading to narcolepsy. The theory of molecular mimicry helps explain how this might happen 14. Immunologists have long grappled with how the immune system can distinguish ‘self’ from ‘nonself’, but actually many microbes – ‘nonself – share chemical structures with ‘self’. Immune recognition of a ‘mimic’ of ‘self’ found in a vaccine or a microbe could trigger autoimmunity (Fig. 1). Pandemrix is a split-virion vaccine, and Focetria is a subunit vaccine, and their antigenicity and composition are different. The differences in the composition of the influenza antigens in these two vaccines and their alignment with H1N1a may provide a major clue to where a mimic might be located. Was the adjuvant in Pandemrix responsible for the increased risk seen with this vaccine? Pandemrix used an adjuvant AS03 comprised of tocopherol and squalene 15, whilst Focetria contained MF59 consisting of squalene and polyoxyethylene sorbitan monooleate and sorbitan trioleate 16. Squalene, a natural metabolite in the cholesterol pathway, is known to trigger spontaneous autoimmune arthritis in rodents 17. Modulation of squalene synthase with an inhibitor, zaragozic acid, was shown to modulate experimental autoimmune encephalomyelitis 18. Yet, it is hard to invoke a role for squalene given that the natural infection with H1N1a triggered an increase in narcolepsy. This ‘logically’ rules out squalene in the relationship with Pandemrix. But Lisbeth Salander might pursue this lead a bit further to finally put to rest whether squalene plays a role. If squalene was not responsible and an antigenic mimic is present within H1N1a and Pandemrix, then Lisbeth Salander might ask the following: If there is a chemical structure in Pandemrix and H1N1a that mimics a structure that if targeted by the immune system might lead to narcolepsy, then one might be able to induce experimental autoimmune narcolepsy. This structure might not appear in Focetria and Celvapan. If such a structure were present in H1N1a and in Pandemrix, she could try an immunization with such a structure and ask whether it might trigger experimental narcolepsy? She might enquire whether this experiment could be performed in a mouse ‘humanized’ with a transgene for HLADQ*0602 19, 20? This is feasible and could potentially provide an explanation for this problem, akin to solving Koch's postulates for a putative autoimmune disease 21. The association of Pandemrix vaccine with increased susceptibility to narcolepsy is a mystery that will likely illuminate how vaccines and infections can trigger autoimmune disease. We await the screening of a story that would probably satisfy Stieg Larsson. No conflicts of interest to declare.