title: CD4+ T cell autoimmunity to hypocretin/orexin and cross-reactivity to a 2009 H1N1 influenza A epitope in narcolepsy.
abstract: 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.
authors.affiliation: Center for Sleep Sciences and Medicine, Stanford School of Medicine, Palo Alto, CA 94304, USA.
authors.forename: Alberto K
authors.initials: AK
authors.lastname: De la Herrán-Arita
authors.forename: Birgitte Rahbek
authors.initials: BR
authors.lastname: Kornum
authors.forename: Josh
authors.initials: J
authors.lastname: Mahlios
authors.forename: Wei
authors.initials: W
authors.lastname: Jiang
authors.forename: Ling
authors.initials: L
authors.lastname: Lin
authors.forename: Tieying
authors.initials: T
authors.lastname: Hou
authors.forename: Claudia
authors.initials: C
authors.lastname: Macaubas
authors.forename: Mali
authors.initials: M
authors.lastname: Einen
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Plazzi
authors.forename: Catherine
authors.initials: C
authors.lastname: Crowe
authors.forename: Evan W
authors.initials: EW
authors.lastname: Newell
authors.forename: Mark M
authors.initials: MM
authors.lastname: Davis
authors.forename: Elizabeth D
authors.initials: ED
authors.lastname: Mellins
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Mignot
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000276:immunology; D000293:Adolescent; D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D015551:Autoimmunity / Q000235:genetics; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D016022:Case-Control Studies; D002648:Child; D003429:Cross Reactions; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology; D005260:Female; D059848:HLA-DQ alpha-Chains / Q000235:genetics; D059866:HLA-DQ beta-Chains / Q000235:genetics; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000235:genetics / Q000276:immunology*; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000235:genetics / Q000276:immunology*; D007252:Influenza Vaccines / Q000009:adverse effects / Q000276:immunology; D007251:Influenza, Human / Q000276:immunology / Q000821:virology; D007371:Interferon-gamma / Q000096:biosynthesis; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000276:immunology*; D008213:Lymphocyte Activation; D008297:Male; D008562:Membrane Glycoproteins / Q000276:immunology; D008875:Middle Aged; D018716:Molecular Mimicry / Q000235:genetics / Q000276:immunology; D008969:Molecular Sequence Data; D009290:Narcolepsy / Q000209:etiology / Q000235:genetics / Q000276:immunology*; D009479:Neuropeptides / Q000235:genetics / Q000276:immunology*; D000068797:Orexins; D017386:Sequence Homology, Amino Acid; D057170:Translational Research, Biomedical; D014430:Twins, Monozygotic; D055815:Young Adult
chemical_list: D018984:Epitopes, T-Lymphocyte; C543345:H1N1 virus hemagglutinin; D059848:HLA-DQ alpha-Chains; D059866:HLA-DQ beta-Chains; C069050:HLA-DQA1 antigen; C069051:HLA-DQB1 antigen; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D007252:Influenza Vaccines; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D009479:Neuropeptides; D000068797:Orexins; C556153:pandemrix; D007371:Interferon-gamma; C498154:CD38 protein, human; D051997:ADP-ribosyl Cyclase 1