CD4+ T Cell Autoimmunity to Hypocretin/Orexin and Cross-Reactivity to a 2009 H1N1 Influenza A Epitope in Narcolepsy

Patients with narcolepsy carry CD4+ T cells that react to peptides from both the sleep-regulating neuropeptide hypocretin and a 2009 H1N1 influenza A protein. New Clues About Narcolepsy Most adults long for more sleep, but patients with narcolepsy would rather be free of their excessive sleepiness. Some things about narcolepsy are clear: It is caused by the loss of the peptide hypocretin from neurons that control wakefulness, and it has a remarkably strong association with a particular human leukocyte antigen (HLA) molecule (DQ0602), suggesting that there is an immune contribution to the disease. Other things are not so clear: We do not know what triggers the disease, and there is no way to prevent it. The neurons that are destroyed in narcolepsy contain the body’s only store of hypocretin, so an immune response against hypocretin could conceivably be responsible for the disease. Although no antibodies to hypocretin have been found in patients, now De la Herrán-Arita et al. have identified CD4+ T cells that react against several peptides derived from hypocretin when they are presented by HLA DQ0602. The two 13–amino acid peptides, corresponding to the N-terminal ends of the mature, secreted forms of hypocretin, triggered responses in T cells from 23 patients with narcolepsy but not in matched DQ0602-positive healthy control subjects. Similarly, in pairs of twins discordant for narcolepsy, the twin with disease carried cells that were activated by hypocretin peptides, whereas the healthy twin did not. Clues about environmental factors that might contribute to narcolepsy have come from epidemiology studies that associate Streptococcus, influenza, and other infections with the disease. In Scandinavia, a particular flu vaccine was associated with increased narcolepsy risk. To investigate these associations further, the authors searched for epitopes in proteins from the flu virus that might activate the same T cells that responded to the hypocretin peptides. Within the flu protein hemagglutinin, they found a small segment that had this effect, amino acids 275 to 287. When cells from patients were incubated with this peptide presented by DQ0602, there was an increase in the number of cells reactive to both the hemagglutinin peptide and the hypocretin peptides, suggesting cross-reactivity between these epitopes. Although more research is necessary to understand the effects of the hypocretin-reactive cells in patients, these results point to a possible molecular mimicry between epitopes on hypocretin and the influenza hemagglutinin protein. Narcolepsy, a disorder strongly associated with human leukocyte antigen (HLA)–DQA1*01:02/DQB1*06:02 (DQ0602), is characterized by excessive daytime sleepiness, cataplexy, and rapid eye movement sleep abnormalities. It is caused by the loss of ~70,000 posterior hypothalamic neurons that produce the wake-promoting neuropeptide hypocretin (HCRT) (orexin). We identified two DQ0602-binding HCRT epitopes, HCRT56–68 and HCRT87–99, that activated a subpopulation of CD4+ T cells in narcolepsy patients but not in DQ0602-positive healthy control subjects. Because of the established association of narcolepsy with the 2009 H1N1 influenza A strain (pH1N1), we administered a seasonal influenza vaccine (containing pH1N1) to patients with narcolepsy and found an increased frequency of circulating HCRT56–68– and HCRT87–99–reactive T cells. We also identified a hemagglutinin (HA) pHA1 epitope specific to the 2009 H1N1 strain, pHA1275–287, with homology to HCRT56–68 and HCRT87–99. In vitro stimulation of narcolepsy CD4+ T cells with pH1N1 proteins or pHA1275–287 increased the frequency of HCRT56–68– and HCRT87–99–reactive T cells. Our data indicate the presence of CD4+ T cells that are reactive to HCRT in narcolepsy patients and possible molecular mimicry between HCRT and a similar epitope in influenza pH1N1, pHA1275–287.