CD4+ T cell autoimmunity to hypocretin/orexin and cross-reactivity to a 2009 H1N1 influenza A epitope in narcolepsy

Alberto K De la Herrán-Arita; Birgitte Rahbek Kornum; Josh Mahlios; Wei Jiang; Ling Lin; Tieying Hou; Claudia Macaubas; Mali Einen; Giuseppe Plazzi; Catherine Crowe; Evan W Newell; Mark M Davis; Elizabeth D Mellins; Emmanuel Mignot

doi:10.1126/scitranslmed.3007762

CD4+ T cell autoimmunity to hypocretin/orexin and cross-reactivity to a 2009 H1N1 influenza A epitope in narcolepsy

Alberto K De la Herrán-Arita, Birgitte Rahbek Kornum, Josh Mahlios, Wei Jiang, Ling Lin, Tieying Hou, Claudia Macaubas, Mali Einen, Giuseppe Plazzi, Catherine Crowe, Evan W Newell, Mark M Davis, Elizabeth D Mellins, Emmanuel Mignot

Section of General Practice

74 Citations (Scopus)

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.

Original language	English
Journal	Science Translational Medicine
Volume	5
Issue number	216
Pages (from-to)	216ra176
ISSN	1946-6234
DOIs	https://doi.org/10.1126/scitranslmed.3007762
Publication status	Published - 18 Dec 2013

Keywords

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1126/scitranslmed.3007762

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De la Herrán-Arita, A. K., Kornum, B. R., Mahlios, J., Jiang, W., Lin, L., Hou, T., Macaubas, C., Einen, M., Plazzi, G., Crowe, C., Newell, E. W., Davis, M. M., Mellins, E. D., & Mignot, E. (2013). CD4+ T cell autoimmunity to hypocretin/orexin and cross-reactivity to a 2009 H1N1 influenza A epitope in narcolepsy. Science Translational Medicine, 5(216), 216ra176. https://doi.org/10.1126/scitranslmed.3007762

De la Herrán-Arita, AK, Kornum, BR, Mahlios, J, Jiang, W, Lin, L, Hou, T, Macaubas, C, Einen, M, Plazzi, G, Crowe, C, Newell, EW, Davis, MM, Mellins, ED & Mignot, E 2013, 'CD4+ T cell autoimmunity to hypocretin/orexin and cross-reactivity to a 2009 H1N1 influenza A epitope in narcolepsy', Science Translational Medicine, vol. 5, no. 216, pp. 216ra176. https://doi.org/10.1126/scitranslmed.3007762

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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. ",

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author = "{De la Herr{\'a}n-Arita}, {Alberto K} and Kornum, {Birgitte Rahbek} and Josh Mahlios and Wei Jiang and Ling Lin and Tieying Hou and Claudia Macaubas and Mali Einen and Giuseppe Plazzi and Catherine Crowe and Newell, {Evan W} and Davis, {Mark M} and Mellins, {Elizabeth D} and Emmanuel Mignot",

year = "2013",

month = dec,

day = "18",

doi = "10.1126/scitranslmed.3007762",

language = "English",

volume = "5",

pages = "216ra176",

journal = "Science Translational Medicine",

issn = "1946-6234",

publisher = "american association for the advancement of science",

number = "216",

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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 -

CD4+ T cell autoimmunity to hypocretin/orexin and cross-reactivity to a 2009 H1N1 influenza A epitope in narcolepsy

Abstract

Keywords

UN SDGs

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