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Narcolepsy Linked to H1N1 Influenza Virus
Narcolepsy is a disorder that is best known for causing rapid transitions from a wakeful state to REM sleep. Other symptoms include sudden tiredness and muscle weakness. A team of scientists at Stanford University have gathered evidence that links narcolepsy to the H1N1 influenza virus.
Narcolepsy has been thought to be an autoimmune disorder since it has a strong genetic association with HLA molecule DQ0602. HLA, or human leukocyte antigen, helps the immune system determine whether a protein belongs to the body or a foreign invader. The Stanford team discovered that 98% of narcoleptic patients have the DQ0602 molecule, while only 18-25% of the general population have it.
The first part of the study involved the identification of two similar orexin epitopes, HCRT56-68 and HCRT87-99, that bind to the DQ0602 molecule. An epitope is the component of an antigen that the immune system recognizes. This identification was achieved by screening various orexin epitopes for the ability to bind to the DQ0602 molecule. Then a cell line with only the DQ0602 HLA molecule was created to test the reactivity of CD4+ T cells.
CD4+ T cells specific for HCRT56-68 and HCRT87-99 have been found in narcoleptic patients, but not in healthy individuals that also have the DQ0602 molecule. CD4+ T cells are a type of T cell that alert killer T cells to the presence of pathogens, . Furthermore, comparisons of identical twins showed that the twin with narcolepsy had the specialized CD4+ T cells, while the unaffected twin did not.
The team administered a seasonal flu vaccine, containing H1N1 epitopes, to narcolepsy patients. There was an increase in specialized CD4+ T cells in the narcoleptic patient as compared with vaccinated controls. In these experiments, the controls are individuals that possess the DQ0602 HLA molecule but don’t have narcolepsy.
This evidence suggests that the H1N1 epitope may be cross-reactive with orexin epitopes. The H1N1 epitope is so similar to the orexin epitopes that the immune system attacks the orexin epitopes, mistaking them for the H1N1 epitope. As a result, certain neurons in the hypothalamus are attacked and orexin is not produced at a normal rate, leading to narcolepsy. This was verified by a bioinformatics analysis that revealed many similarities between the epitopes.
Based on their work, the Stanford team has stated that a cluster of narcolepsy diagnoses after the pandemic H1N1 outbreak could be due to the cross-reactivity between the H1N1 epitope and the orexin epitopes as a result of molecular similarity. Additionally, orexin-specific CD4+ T cells were identified in samples from before the H1N1 pandemic. This suggests a possibility that other flu strains could also play a role in the development of narcolepsy.