CD4+ T cell autoimmunity to hypocretin/orexin and cross-reactivity to a 2009 H1N1 influenza A epitope in narcolepsy
Research output: Contribution to journal › Journal article › Research › peer-review
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.
|Journal||Science Translational Medicine|
|Publication status||Published - 18 Dec 2013|
- ADP-ribosyl Cyclase 1/immunology, Adolescent, Adult, Aged, Amino Acid Sequence, Autoimmunity/genetics, CD4-Positive T-Lymphocytes/immunology, Case-Control Studies, Child, Cross Reactions, Epitopes, T-Lymphocyte/genetics, Female, HLA-DQ alpha-Chains/genetics, HLA-DQ beta-Chains/genetics, Hemagglutinin Glycoproteins, Influenza Virus/genetics, Humans, Influenza A Virus, H1N1 Subtype/genetics, Influenza Vaccines/adverse effects, Influenza, Human/immunology, Interferon-gamma/biosynthesis, Intracellular Signaling Peptides and Proteins/genetics, Lymphocyte Activation, Male, Membrane Glycoproteins/immunology, Middle Aged, Molecular Mimicry/genetics, Molecular Sequence Data, Narcolepsy/etiology, Neuropeptides/genetics, Orexins, Sequence Homology, Amino Acid, Translational Medical Research, Twins, Monozygotic, Young Adult