TY - JOUR
T1 - CD4+ T cell autoimmunity to hypocretin/orexin and cross-reactivity to a 2009 H1N1 influenza A epitope in narcolepsy
AU - De la Herrán-Arita, Alberto K
AU - Kornum, Birgitte Rahbek
AU - Mahlios, Josh
AU - Jiang, Wei
AU - Lin, Ling
AU - Hou, Tieying
AU - Macaubas, Claudia
AU - Einen, Mali
AU - Plazzi, Giuseppe
AU - Crowe, Catherine
AU - Newell, Evan W
AU - Davis, Mark M
AU - Mellins, Elizabeth D
AU - Mignot, Emmanuel
PY - 2013/12/18
Y1 - 2013/12/18
N2 - 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.
AB - 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.
KW - ADP-ribosyl Cyclase 1/immunology
KW - Adolescent
KW - Adult
KW - Aged
KW - Amino Acid Sequence
KW - Autoimmunity/genetics
KW - CD4-Positive T-Lymphocytes/immunology
KW - Case-Control Studies
KW - Child
KW - Cross Reactions
KW - Epitopes, T-Lymphocyte/genetics
KW - Female
KW - HLA-DQ alpha-Chains/genetics
KW - HLA-DQ beta-Chains/genetics
KW - Hemagglutinin Glycoproteins, Influenza Virus/genetics
KW - Humans
KW - Influenza A Virus, H1N1 Subtype/genetics
KW - Influenza Vaccines/adverse effects
KW - Influenza, Human/immunology
KW - Interferon-gamma/biosynthesis
KW - Intracellular Signaling Peptides and Proteins/genetics
KW - Lymphocyte Activation
KW - Male
KW - Membrane Glycoproteins/immunology
KW - Middle Aged
KW - Molecular Mimicry/genetics
KW - Molecular Sequence Data
KW - Narcolepsy/etiology
KW - Neuropeptides/genetics
KW - Orexins
KW - Sequence Homology, Amino Acid
KW - Translational Medical Research
KW - Twins, Monozygotic
KW - Young Adult
U2 - 10.1126/scitranslmed.3007762
DO - 10.1126/scitranslmed.3007762
M3 - Journal article
C2 - 24353159
SN - 1946-6234
VL - 5
SP - 216ra176
JO - Science Translational Medicine
JF - Science Translational Medicine
IS - 216
ER -
