tetano
Editor, Senior Moderator
Sci Transl Med 18 December 2013:
Vol. 5, Issue 216, p. 216ra176
Sci. Transl. Med. DOI: 10.1126/scitranslmed.3007762
Research Article
NARCOLEPSY
CD4+ T Cell Autoimmunity to Hypocretin/Orexin and Cross-Reactivity to a 2009 H1N1 Influenza A Epitope in Narcolepsy
Alberto K. De la Herr?n-Arita1,*,
Birgitte Rahbek Kornum1,2,*,
Josh Mahlios1,
Wei Jiang3,
Ling Lin1,
Tieying Hou3,
Claudia Macaubas3,
Mali Einen1,
Giuseppe Plazzi4,
Catherine Crowe5,
Evan W. Newell6,
Mark M. Davis6,
Elizabeth D. Mellins3,6,*,? and
Emmanuel Mignot1,6,*,?
+ Author Affiliations
1Center for Sleep Sciences and Medicine, Stanford School of Medicine, Palo Alto, CA 94304, USA.
2Molecular Sleep Lab, Department of Diagnostics, and Danish Center for Sleep Medicine, Department of Clinical Neurophysiology, Glostrup Hospital, 2600 Glostrup, Denmark.
3Department of Pediatrics, Stanford School of Medicine, Palo Alto, CA 94305, USA.
4IRCCS Institute of Neurological Sciences and Department of Biomedical and NeuroMotor Sciences, University of Bologna, Bologna 40123, Italy.
5Mater Private Sleep Laboratory, Dublin 7, Ireland.
6Program in Immunology, Stanford School of Medicine, Palo Alto, CA 94305, USA.
+ Author Notes
↵* These authors contributed equally to this work.
↵?Corresponding author. E-mail: mignot@stanford.edu (E.M.); mellins@stanford.edu (E.D.M.)
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.
Copyright ? 2013, American Association for the Advancement of Science
Citation: A. K. D. l. Herr?n-Arita, B. R. Kornum, J. Mahlios, W. Jiang, L. Lin, T. Hou, C. Macaubas, M. Einen, G. Plazzi, C. Crowe, E. W. Newell, M. M. Davis, E. D. Mellins, E. Mignot, CD4+ T Cell Autoimmunity to Hypocretin/Orexin and Cross-Reactivity to a 2009 H1N1 Influenza A Epitope in Narcolepsy. Sci. Transl. Med. 5, 216ra176 (2013).
http://stm.sciencemag.org/content/5/216/216ra176
Vol. 5, Issue 216, p. 216ra176
Sci. Transl. Med. DOI: 10.1126/scitranslmed.3007762
Research Article
NARCOLEPSY
CD4+ T Cell Autoimmunity to Hypocretin/Orexin and Cross-Reactivity to a 2009 H1N1 Influenza A Epitope in Narcolepsy
Alberto K. De la Herr?n-Arita1,*,
Birgitte Rahbek Kornum1,2,*,
Josh Mahlios1,
Wei Jiang3,
Ling Lin1,
Tieying Hou3,
Claudia Macaubas3,
Mali Einen1,
Giuseppe Plazzi4,
Catherine Crowe5,
Evan W. Newell6,
Mark M. Davis6,
Elizabeth D. Mellins3,6,*,? and
Emmanuel Mignot1,6,*,?
+ Author Affiliations
1Center for Sleep Sciences and Medicine, Stanford School of Medicine, Palo Alto, CA 94304, USA.
2Molecular Sleep Lab, Department of Diagnostics, and Danish Center for Sleep Medicine, Department of Clinical Neurophysiology, Glostrup Hospital, 2600 Glostrup, Denmark.
3Department of Pediatrics, Stanford School of Medicine, Palo Alto, CA 94305, USA.
4IRCCS Institute of Neurological Sciences and Department of Biomedical and NeuroMotor Sciences, University of Bologna, Bologna 40123, Italy.
5Mater Private Sleep Laboratory, Dublin 7, Ireland.
6Program in Immunology, Stanford School of Medicine, Palo Alto, CA 94305, USA.
+ Author Notes
↵* These authors contributed equally to this work.
↵?Corresponding author. E-mail: mignot@stanford.edu (E.M.); mellins@stanford.edu (E.D.M.)
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.
Copyright ? 2013, American Association for the Advancement of Science
Citation: A. K. D. l. Herr?n-Arita, B. R. Kornum, J. Mahlios, W. Jiang, L. Lin, T. Hou, C. Macaubas, M. Einen, G. Plazzi, C. Crowe, E. W. Newell, M. M. Davis, E. D. Mellins, E. Mignot, CD4+ T Cell Autoimmunity to Hypocretin/Orexin and Cross-Reactivity to a 2009 H1N1 Influenza A Epitope in Narcolepsy. Sci. Transl. Med. 5, 216ra176 (2013).
http://stm.sciencemag.org/content/5/216/216ra176