Narcolepsy is a disorder that causes extreme daytime sleepiness and muscle weakness in patients. Source: http://en.wikipedia.org/wiki/File:Sleeping-girl.jpg
Mellin, Mignot, and colleagues recently found evidence supporting a view of narcolepsy as an autoimmune disease when they discovered CD4+ T cells that specifically target orexin’s precursor HCRT. Narcolepsy, a chronic disorder caused by a lack of orexin, has a strong genetic association with the antigen DQ0602; 98% of patients with narcolepsy have the antigen DQ0602 compared to only 25% of the general population.
Believing that the lack of orexin in narcolepsy patients is due to an autoimmune response to antigen DQ0602, Mellin and his fellow researchers first screened for orexin epitopes that bound to DQ0602. These orexin epitopes are chemical groups that bind to an antigen and are used by the immune system to identify targets for T cells. They identified two orexin epitopes, HCRT56-68 and HCRT87-99, that strongly bound to DQ0602.
The group then tested CD4+ T cell reactivity toward the two orexin epitopes and found that they were reactive. Patients with narcolepsy had CD4+ T cells specific to the two orexin epitopes, but healthy patients did not.
The team also found that this was the case for monozygotic twins. The twin with narcolepsy was the only one with CD4+ T cells specific for the orexin epitopes. These results suggest that auto-reactivity to orexin through the DQ0602 antigen and CD4+ T cells is important to developing narcolepsy.
Considering that narcolepsy has also been associated with the H1N1 influenza virus infections and Pandemrix (an influenza vaccine), Mellin and his co-authors gave vaccines with H1N1 epitopes to patients with narcolepsy. They found an increased frequency of CD4+ T cells specific for the two orexin epitopes in narcolepsy patients compared to healthy patients.
Because of these results, they searched for H1N1 epitopes that would stimulate orexin-specific CD4+ T cells. Mellin found HA1275-287, which was very similar to the two orexin epitopes. The results suggest that the mimicry between the two orexin epitopes and the H1N1 epitope may have triggered narcolepsy in some H1N1 patients.
Mellin and his colleagues contributed to identifying the development of narcolepsy in patients. They plan to continue their research as they now speculate that other influenza virus strains could also increase orexin specific CD4+ T cell counts.
References:
1. E.D. Mellins et al., Sci. Transl. Med. 216, 216-229 (2013).