Autoimmunity to hypocretin and molecular mimicry to flu in type 1 narcolepsy
Identifieur interne : 000F41 ( Ncbi/Merge ); précédent : 000F40; suivant : 000F42Autoimmunity to hypocretin and molecular mimicry to flu in type 1 narcolepsy
Auteurs : Guo Luo ; Aditya Ambati ; Ling Lin ; Mélodie Bonvalet ; Markku Partinen [Finlande] ; Xuhuai Ji ; Holden Terry Maecker ; Emmanuel Jean-Marie MignotSource :
- Proceedings of the National Academy of Sciences of the United States of America [ 0027-8424 ] ; 2018.
Descripteurs français
- KwdFr :
- Adolescent, Adulte, Adulte d'âge moyen, Auto-immunité (immunologie), Autoantigènes (métabolisme), Chaines bêta des antigènes HLA-DQ, Enfant, Femelle, Grippe humaine (immunologie), Humains, Hémagglutinines, Lymphocytes T CD4+ (immunologie), Mimétisme moléculaire (immunologie), Mâle, Narcolepsie (immunologie), Orexines (génétique), Orexines (immunologie), Orexines (métabolisme), Peptides (génétique), Protéines et peptides de signalisation intracellulaire (génétique), Récepteurs aux antigènes des cellules T (génétique), Sous-type H1N1 du virus de la grippe A (immunologie), Vaccination, Virus de la grippe A (immunologie), Virus de la grippe A (pathogénicité), Épitopes (immunologie).
- MESH :
- génétique : Orexines, Peptides, Protéines et peptides de signalisation intracellulaire, Récepteurs aux antigènes des cellules T.
- immunologie : Auto-immunité, Grippe humaine, Lymphocytes T CD4+, Mimétisme moléculaire, Narcolepsie, Orexines, Sous-type H1N1 du virus de la grippe A, Virus de la grippe A, Épitopes.
- métabolisme : Autoantigènes, Orexines.
- pathogénicité : Virus de la grippe A.
- Adolescent, Adulte, Adulte d'âge moyen, Chaines bêta des antigènes HLA-DQ, Enfant, Femelle, Humains, Hémagglutinines, Mâle, Vaccination.
English descriptors
- KwdEn :
- Adolescent, Adult, Autoantigens (metabolism), Autoimmunity (immunology), CD4-Positive T-Lymphocytes (immunology), Child, Epitopes (immunology), Female, HLA-DQ beta-Chains, Hemagglutinins, Humans, Influenza A Virus, H1N1 Subtype (immunology), Influenza A virus (immunology), Influenza A virus (pathogenicity), Influenza, Human (immunology), Intracellular Signaling Peptides and Proteins (genetics), Male, Middle Aged, Molecular Mimicry (immunology), Narcolepsy (immunology), Orexins (genetics), Orexins (immunology), Orexins (metabolism), Peptides (genetics), Receptors, Antigen, T-Cell (genetics), Vaccination.
- MESH :
- chemical , genetics : Intracellular Signaling Peptides and Proteins, Orexins, Peptides, Receptors, Antigen, T-Cell.
- chemical , immunology : Epitopes, Orexins.
- chemical , metabolism : Autoantigens, Orexins.
- immunology : Autoimmunity, CD4-Positive T-Lymphocytes, Influenza A Virus, H1N1 Subtype, Influenza A virus, Influenza, Human, Molecular Mimicry, Narcolepsy.
- pathogenicity : Influenza A virus.
- Adolescent, Adult, Child, Female, HLA-DQ beta-Chains, Hemagglutinins, Humans, Male, Middle Aged, Vaccination.
Abstract
This work shows that the amidated terminal ends of the secreted hypocretin (HCRT) peptides (HCRTNH2) are autoantigens in type 1 narcolepsy, an autoimmune disorder targeting HCRT neurons. The autoimmune process is usually initiated by influenza A flu infections, and a particular piece of the hemagglutinin (HA) flu protein of the pandemic 2009 H1N1 strain was identified as a likely trigger. This HA epitope has homology with HCRTNH2 and T cells cross-reactive to both epitopes are involved in the autoimmune process by molecular mimicry. Genes associated with narcolepsy mark the particular HLA heterodimer (DQ0602) involved in presentation of these antigens and modulate expression of the specific T cell receptor segments (TRAJ24 and TRBV4-2) involved in T cell receptor recognition of these antigens, suggesting causality.
Url:
DOI: 10.1073/pnas.1818150116
PubMed: 30541895
PubMed Central: 6310865
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PMC:6310865Le document en format XML
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last="Luo">Guo Luo</name><affiliation><nlm:aff id="aff1">Center for Sleep Sciences and Medicine,<institution>Stanford University School of Medicine</institution>, Palo Alto,<addr-line>CA</addr-line> 94304;</nlm:aff></affiliation></author><author><name sortKey="Ambati, Aditya" sort="Ambati, Aditya" uniqKey="Ambati A" first="Aditya" last="Ambati">Aditya Ambati</name><affiliation><nlm:aff id="aff1">Center for Sleep Sciences and Medicine,<institution>Stanford University School of Medicine</institution>, Palo Alto,<addr-line>CA</addr-line> 94304;</nlm:aff></affiliation></author><author><name sortKey="Lin, Ling" sort="Lin, Ling" uniqKey="Lin L" first="Ling" last="Lin">Ling Lin</name><affiliation><nlm:aff id="aff1">Center for Sleep Sciences and Medicine,<institution>Stanford University School of Medicine</institution>, Palo Alto,<addr-line>CA</addr-line> 94304;</nlm:aff></affiliation></author><author><name sortKey="Bonvalet, Melodie" sort="Bonvalet, Melodie" uniqKey="Bonvalet M" first="Mélodie" last="Bonvalet">Mélodie Bonvalet</name><affiliation><nlm:aff id="aff1">Center for Sleep Sciences and Medicine,<institution>Stanford University School of Medicine</institution>, Palo Alto,<addr-line>CA</addr-line> 94304;</nlm:aff></affiliation></author><author><name sortKey="Partinen, Markku" sort="Partinen, Markku" uniqKey="Partinen M" first="Markku" last="Partinen">Markku Partinen</name><affiliation wicri:level="1"><nlm:aff id="aff2">Helsinki Sleep Clinic, Vitalmed Research Centre, 00380 Helsinki,<country>Finland</country>;</nlm:aff><country xml:lang="fr">Finlande</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff3">Department of Clinical Neurosciences,<institution>University of Helsinki</institution>, 00100 Helsinki,<country>Finland</country>;</nlm:aff><country xml:lang="fr">Finlande</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Ji, Xuhuai" sort="Ji, Xuhuai" uniqKey="Ji X" first="Xuhuai" last="Ji">Xuhuai Ji</name><affiliation><nlm:aff id="aff4">Immune Monitoring Center, Institute for Immunity, Transplantation, and Infection,<institution>Stanford University School of Medicine</institution>, Palo Alto,<addr-line>CA</addr-line> 94305</nlm:aff></affiliation></author><author><name sortKey="Maecker, Holden Terry" sort="Maecker, Holden Terry" uniqKey="Maecker H" first="Holden Terry" last="Maecker">Holden Terry Maecker</name><affiliation><nlm:aff id="aff4">Immune Monitoring Center, Institute for Immunity, Transplantation, and Infection,<institution>Stanford University School of Medicine</institution>, Palo Alto,<addr-line>CA</addr-line> 94305</nlm:aff></affiliation></author><author><name sortKey="Mignot, Emmanuel Jean Marie" sort="Mignot, Emmanuel Jean Marie" uniqKey="Mignot E" first="Emmanuel Jean-Marie" last="Mignot">Emmanuel Jean-Marie Mignot</name><affiliation><nlm:aff id="aff1">Center for Sleep Sciences and Medicine,<institution>Stanford University School of Medicine</institution>, Palo Alto,<addr-line>CA</addr-line> 94304;</nlm:aff></affiliation></author></analytic><series><title level="j">Proceedings of the National Academy of Sciences of the United States of America</title><idno type="ISSN">0027-8424</idno><idno type="eISSN">1091-6490</idno><imprint><date when="2018">2018</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Adolescent</term><term>Adult</term><term>Autoantigens (metabolism)</term><term>Autoimmunity (immunology)</term><term>CD4-Positive T-Lymphocytes (immunology)</term><term>Child</term><term>Epitopes (immunology)</term><term>Female</term><term>HLA-DQ beta-Chains</term><term>Hemagglutinins</term><term>Humans</term><term>Influenza A Virus, H1N1 Subtype (immunology)</term><term>Influenza A virus (immunology)</term><term>Influenza A virus (pathogenicity)</term><term>Influenza, Human (immunology)</term><term>Intracellular Signaling Peptides and Proteins (genetics)</term><term>Male</term><term>Middle Aged</term><term>Molecular Mimicry (immunology)</term><term>Narcolepsy (immunology)</term><term>Orexins (genetics)</term><term>Orexins (immunology)</term><term>Orexins (metabolism)</term><term>Peptides (genetics)</term><term>Receptors, Antigen, T-Cell (genetics)</term><term>Vaccination</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Adolescent</term><term>Adulte</term><term>Adulte d'âge moyen</term><term>Auto-immunité (immunologie)</term><term>Autoantigènes (métabolisme)</term><term>Chaines bêta des antigènes HLA-DQ</term><term>Enfant</term><term>Femelle</term><term>Grippe humaine (immunologie)</term><term>Humains</term><term>Hémagglutinines</term><term>Lymphocytes T CD4+ (immunologie)</term><term>Mimétisme moléculaire (immunologie)</term><term>Mâle</term><term>Narcolepsie (immunologie)</term><term>Orexines (génétique)</term><term>Orexines (immunologie)</term><term>Orexines (métabolisme)</term><term>Peptides (génétique)</term><term>Protéines et peptides de signalisation intracellulaire (génétique)</term><term>Récepteurs aux antigènes des cellules T (génétique)</term><term>Sous-type H1N1 du virus de la grippe A (immunologie)</term><term>Vaccination</term><term>Virus de la grippe A (immunologie)</term><term>Virus de la grippe A (pathogénicité)</term><term>Épitopes (immunologie)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Intracellular Signaling Peptides and Proteins</term><term>Orexins</term><term>Peptides</term><term>Receptors, Antigen, T-Cell</term></keywords><keywords scheme="MESH" type="chemical" qualifier="immunology" xml:lang="en"><term>Epitopes</term><term>Orexins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Autoantigens</term><term>Orexins</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Orexines</term><term>Peptides</term><term>Protéines et peptides de signalisation intracellulaire</term><term>Récepteurs aux antigènes des cellules T</term></keywords><keywords scheme="MESH" qualifier="immunologie" xml:lang="fr"><term>Auto-immunité</term><term>Grippe humaine</term><term>Lymphocytes T CD4+</term><term>Mimétisme moléculaire</term><term>Narcolepsie</term><term>Orexines</term><term>Sous-type H1N1 du virus de la grippe A</term><term>Virus de la grippe A</term><term>Épitopes</term></keywords><keywords scheme="MESH" qualifier="immunology" xml:lang="en"><term>Autoimmunity</term><term>CD4-Positive T-Lymphocytes</term><term>Influenza A Virus, H1N1 Subtype</term><term>Influenza A virus</term><term>Influenza, Human</term><term>Molecular Mimicry</term><term>Narcolepsy</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Autoantigènes</term><term>Orexines</term></keywords><keywords scheme="MESH" qualifier="pathogenicity" xml:lang="en"><term>Influenza A virus</term></keywords><keywords scheme="MESH" qualifier="pathogénicité" xml:lang="fr"><term>Virus de la grippe A</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Adolescent</term><term>Adult</term><term>Child</term><term>Female</term><term>HLA-DQ beta-Chains</term><term>Hemagglutinins</term><term>Humans</term><term>Male</term><term>Middle Aged</term><term>Vaccination</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Adolescent</term><term>Adulte</term><term>Adulte d'âge moyen</term><term>Chaines bêta des antigènes HLA-DQ</term><term>Enfant</term><term>Femelle</term><term>Humains</term><term>Hémagglutinines</term><term>Mâle</term><term>Vaccination</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><title>Significance</title><p>This work shows that the amidated terminal ends of the secreted hypocretin (HCRT) peptides (HCRT<sub>NH2</sub>) are autoantigens in type 1 narcolepsy, an autoimmune disorder targeting HCRT neurons. The autoimmune process is usually initiated by influenza A flu infections, and a particular piece of the hemagglutinin (HA) flu protein of the pandemic 2009 H1N1 strain was identified as a likely trigger. This HA epitope has homology with HCRT<sub>NH2</sub> and T cells cross-reactive to both epitopes are involved in the autoimmune process by molecular mimicry. Genes associated with narcolepsy mark the particular HLA heterodimer (DQ0602) involved in presentation of these antigens and modulate expression of the specific T cell receptor segments (TRAJ24 and TRBV4-2) involved in T cell receptor recognition of these antigens, suggesting causality.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Han, F" uniqKey="Han F">F Han</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Faraco, J" uniqKey="Faraco J">J Faraco</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kornum, Br" uniqKey="Kornum B">BR Kornum</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hor, H" uniqKey="Hor H">H Hor</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hallmayer, J" uniqKey="Hallmayer J">J Hallmayer</name></author></analytic></biblStruct><biblStruct><analytic><author><name 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uniqKey="Nicholson M">MJ Nicholson</name></author><author><name sortKey="Pyrdol, J" uniqKey="Pyrdol J">J Pyrdol</name></author><author><name sortKey="Wucherpfennig, Kw" uniqKey="Wucherpfennig K">KW Wucherpfennig</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Riley, Tp" uniqKey="Riley T">TP Riley</name></author></analytic></biblStruct></listBibl></div1></back></TEI><double pmid="30541895"><pmc><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Autoimmunity to hypocretin and molecular mimicry to flu in type 1 narcolepsy</title><author><name sortKey="Luo, Guo" sort="Luo, Guo" uniqKey="Luo G" first="Guo" last="Luo">Guo Luo</name><affiliation><nlm:aff id="aff1">Center for Sleep Sciences and Medicine,<institution>Stanford University School of Medicine</institution>, Palo Alto,<addr-line>CA</addr-line> 94304;</nlm:aff></affiliation></author><author><name sortKey="Ambati, Aditya" sort="Ambati, Aditya" uniqKey="Ambati A" first="Aditya" last="Ambati">Aditya Ambati</name><affiliation><nlm:aff id="aff1">Center for Sleep Sciences and Medicine,<institution>Stanford University School of Medicine</institution>, Palo Alto,<addr-line>CA</addr-line> 94304;</nlm:aff></affiliation></author><author><name sortKey="Lin, Ling" sort="Lin, Ling" uniqKey="Lin L" first="Ling" last="Lin">Ling Lin</name><affiliation><nlm:aff id="aff1">Center for Sleep Sciences and Medicine,<institution>Stanford University School of Medicine</institution>, Palo Alto,<addr-line>CA</addr-line> 94304;</nlm:aff></affiliation></author><author><name sortKey="Bonvalet, Melodie" sort="Bonvalet, Melodie" uniqKey="Bonvalet M" first="Mélodie" last="Bonvalet">Mélodie Bonvalet</name><affiliation><nlm:aff id="aff1">Center for Sleep Sciences and Medicine,<institution>Stanford University School of Medicine</institution>, Palo Alto,<addr-line>CA</addr-line> 94304;</nlm:aff></affiliation></author><author><name sortKey="Partinen, Markku" sort="Partinen, Markku" uniqKey="Partinen M" first="Markku" last="Partinen">Markku Partinen</name><affiliation wicri:level="1"><nlm:aff id="aff2">Helsinki Sleep Clinic, Vitalmed Research Centre, 00380 Helsinki,<country>Finland</country>;</nlm:aff><country xml:lang="fr">Finlande</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff3">Department of Clinical Neurosciences,<institution>University of Helsinki</institution>, 00100 Helsinki,<country>Finland</country>;</nlm:aff><country xml:lang="fr">Finlande</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Ji, Xuhuai" sort="Ji, Xuhuai" uniqKey="Ji X" first="Xuhuai" last="Ji">Xuhuai Ji</name><affiliation><nlm:aff id="aff4">Immune Monitoring Center, Institute for Immunity, Transplantation, and Infection,<institution>Stanford University School of Medicine</institution>, Palo Alto,<addr-line>CA</addr-line> 94305</nlm:aff></affiliation></author><author><name sortKey="Maecker, Holden Terry" sort="Maecker, Holden Terry" uniqKey="Maecker H" first="Holden Terry" last="Maecker">Holden Terry Maecker</name><affiliation><nlm:aff id="aff4">Immune Monitoring Center, Institute for Immunity, Transplantation, and Infection,<institution>Stanford University School of Medicine</institution>, Palo Alto,<addr-line>CA</addr-line> 94305</nlm:aff></affiliation></author><author><name sortKey="Mignot, Emmanuel Jean Marie" sort="Mignot, Emmanuel Jean Marie" uniqKey="Mignot E" first="Emmanuel Jean-Marie" last="Mignot">Emmanuel Jean-Marie Mignot</name><affiliation><nlm:aff id="aff1">Center for Sleep Sciences and Medicine,<institution>Stanford University School of Medicine</institution>, Palo Alto,<addr-line>CA</addr-line> 94304;</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">30541895</idno><idno type="pmc">6310865</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6310865</idno><idno type="RBID">PMC:6310865</idno><idno type="doi">10.1073/pnas.1818150116</idno><date when="2018">2018</date><idno type="wicri:Area/Pmc/Corpus">000C22</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000C22</idno><idno type="wicri:Area/Pmc/Curation">000C22</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000C22</idno><idno type="wicri:Area/Pmc/Checkpoint">000168</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Checkpoint">000168</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Autoimmunity to hypocretin and molecular mimicry to flu in type 1 narcolepsy</title><author><name sortKey="Luo, Guo" sort="Luo, Guo" uniqKey="Luo G" first="Guo" last="Luo">Guo Luo</name><affiliation><nlm:aff id="aff1">Center for Sleep Sciences and Medicine,<institution>Stanford University School of Medicine</institution>, Palo Alto,<addr-line>CA</addr-line> 94304;</nlm:aff></affiliation></author><author><name sortKey="Ambati, Aditya" sort="Ambati, Aditya" uniqKey="Ambati A" first="Aditya" last="Ambati">Aditya Ambati</name><affiliation><nlm:aff id="aff1">Center for Sleep Sciences and Medicine,<institution>Stanford University School of Medicine</institution>, Palo Alto,<addr-line>CA</addr-line> 94304;</nlm:aff></affiliation></author><author><name sortKey="Lin, Ling" sort="Lin, Ling" uniqKey="Lin L" first="Ling" last="Lin">Ling Lin</name><affiliation><nlm:aff id="aff1">Center for Sleep Sciences and Medicine,<institution>Stanford University School of Medicine</institution>, Palo Alto,<addr-line>CA</addr-line> 94304;</nlm:aff></affiliation></author><author><name sortKey="Bonvalet, Melodie" sort="Bonvalet, Melodie" uniqKey="Bonvalet M" first="Mélodie" last="Bonvalet">Mélodie Bonvalet</name><affiliation><nlm:aff id="aff1">Center for Sleep Sciences and Medicine,<institution>Stanford University School of Medicine</institution>, Palo Alto,<addr-line>CA</addr-line> 94304;</nlm:aff></affiliation></author><author><name sortKey="Partinen, Markku" sort="Partinen, Markku" uniqKey="Partinen M" first="Markku" last="Partinen">Markku Partinen</name><affiliation wicri:level="1"><nlm:aff id="aff2">Helsinki Sleep Clinic, Vitalmed Research Centre, 00380 Helsinki,<country>Finland</country>;</nlm:aff><country xml:lang="fr">Finlande</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation><affiliation wicri:level="1"><nlm:aff id="aff3">Department of Clinical Neurosciences,<institution>University of Helsinki</institution>, 00100 Helsinki,<country>Finland</country>;</nlm:aff><country xml:lang="fr">Finlande</country><wicri:regionArea># see nlm:aff country strict</wicri:regionArea></affiliation></author><author><name sortKey="Ji, Xuhuai" sort="Ji, Xuhuai" uniqKey="Ji X" first="Xuhuai" last="Ji">Xuhuai Ji</name><affiliation><nlm:aff id="aff4">Immune Monitoring Center, Institute for Immunity, Transplantation, and Infection,<institution>Stanford University School of Medicine</institution>, Palo Alto,<addr-line>CA</addr-line> 94305</nlm:aff></affiliation></author><author><name sortKey="Maecker, Holden Terry" sort="Maecker, Holden Terry" uniqKey="Maecker H" first="Holden Terry" last="Maecker">Holden Terry Maecker</name><affiliation><nlm:aff id="aff4">Immune Monitoring Center, Institute for Immunity, Transplantation, and Infection,<institution>Stanford University School of Medicine</institution>, Palo Alto,<addr-line>CA</addr-line> 94305</nlm:aff></affiliation></author><author><name sortKey="Mignot, Emmanuel Jean Marie" sort="Mignot, Emmanuel Jean Marie" uniqKey="Mignot E" first="Emmanuel Jean-Marie" last="Mignot">Emmanuel Jean-Marie Mignot</name><affiliation><nlm:aff id="aff1">Center for Sleep Sciences and Medicine,<institution>Stanford University School of Medicine</institution>, Palo Alto,<addr-line>CA</addr-line> 94304;</nlm:aff></affiliation></author></analytic><series><title level="j">Proceedings of the National Academy of Sciences of the United States of America</title><idno type="ISSN">0027-8424</idno><idno type="eISSN">1091-6490</idno><imprint><date when="2018">2018</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><title>Significance</title><p>This work shows that the amidated terminal ends of the secreted hypocretin (HCRT) peptides (HCRT<sub>NH2</sub>) are autoantigens in type 1 narcolepsy, an autoimmune disorder targeting HCRT neurons. The autoimmune process is usually initiated by influenza A flu infections, and a particular piece of the hemagglutinin (HA) flu protein of the pandemic 2009 H1N1 strain was identified as a likely trigger. This HA epitope has homology with HCRT<sub>NH2</sub> and T cells cross-reactive to both epitopes are involved in the autoimmune process by molecular mimicry. Genes associated with narcolepsy mark the particular HLA heterodimer (DQ0602) involved in presentation of these antigens and modulate expression of the specific T cell receptor segments (TRAJ24 and TRBV4-2) involved in T cell receptor recognition of these antigens, suggesting causality.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Han, F" uniqKey="Han F">F Han</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Faraco, J" uniqKey="Faraco J">J Faraco</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kornum, Br" uniqKey="Kornum B">BR Kornum</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hor, H" uniqKey="Hor H">H Hor</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hallmayer, J" uniqKey="Hallmayer J">J Hallmayer</name></author></analytic></biblStruct><biblStruct><analytic><author><name 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University School of Medicine, Palo Alto</wicri:cityArea></affiliation></author><author><name sortKey="Ambati, Aditya" sort="Ambati, Aditya" uniqKey="Ambati A" first="Aditya" last="Ambati">Aditya Ambati</name><affiliation wicri:level="2"><nlm:affiliation>Center for Sleep Sciences and Medicine, Stanford University School of Medicine, Palo Alto, CA 94304.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>Center for Sleep Sciences and Medicine, Stanford University School of Medicine, Palo Alto</wicri:cityArea></affiliation></author><author><name sortKey="Lin, Ling" sort="Lin, Ling" uniqKey="Lin L" first="Ling" last="Lin">Ling Lin</name><affiliation wicri:level="2"><nlm:affiliation>Center for Sleep Sciences and Medicine, Stanford University School of Medicine, Palo Alto, CA 94304.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>Center for Sleep Sciences and Medicine, Stanford University School of Medicine, Palo Alto</wicri:cityArea></affiliation></author><author><name sortKey="Bonvalet, Melodie" sort="Bonvalet, Melodie" uniqKey="Bonvalet M" first="Mélodie" last="Bonvalet">Mélodie Bonvalet</name><affiliation wicri:level="2"><nlm:affiliation>Center for Sleep Sciences and Medicine, Stanford University School of Medicine, Palo Alto, CA 94304.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>Center for Sleep Sciences and Medicine, Stanford University School of Medicine, Palo Alto</wicri:cityArea></affiliation></author><author><name sortKey="Partinen, Markku" sort="Partinen, Markku" uniqKey="Partinen M" first="Markku" last="Partinen">Markku Partinen</name><affiliation wicri:level="1"><nlm:affiliation>Helsinki Sleep Clinic, Vitalmed Research Centre, 00380 Helsinki, Finland.</nlm:affiliation><country xml:lang="fr">Finlande</country><wicri:regionArea>Helsinki Sleep Clinic, Vitalmed Research Centre, 00380 Helsinki</wicri:regionArea><wicri:noRegion>00380 Helsinki</wicri:noRegion></affiliation></author><author><name sortKey="Ji, Xuhuai" sort="Ji, Xuhuai" uniqKey="Ji X" first="Xuhuai" last="Ji">Xuhuai Ji</name><affiliation wicri:level="2"><nlm:affiliation>Immune Monitoring Center, Institute for Immunity, Transplantation, and Infection, Stanford University School of Medicine, Palo Alto, CA 94305.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>Immune Monitoring Center, Institute for Immunity, Transplantation, and Infection, Stanford University School of Medicine, Palo Alto</wicri:cityArea></affiliation></author><author><name sortKey="Maecker, Holden Terry" sort="Maecker, Holden Terry" uniqKey="Maecker H" first="Holden Terry" last="Maecker">Holden Terry Maecker</name><affiliation wicri:level="2"><nlm:affiliation>Immune Monitoring Center, Institute for Immunity, Transplantation, and Infection, Stanford University School of Medicine, Palo Alto, CA 94305.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>Immune Monitoring Center, Institute for Immunity, Transplantation, and Infection, Stanford University School of Medicine, Palo Alto</wicri:cityArea></affiliation></author><author><name sortKey="Mignot, Emmanuel Jean Marie" sort="Mignot, Emmanuel Jean Marie" uniqKey="Mignot E" first="Emmanuel Jean-Marie" last="Mignot">Emmanuel Jean-Marie Mignot</name><affiliation wicri:level="1"><nlm:affiliation>Center for Sleep Sciences and Medicine, Stanford University School of Medicine, Palo Alto, CA 94304; mignot@stanford.edu.</nlm:affiliation><country wicri:rule="url">États-Unis</country><wicri:regionArea>Center for Sleep Sciences and Medicine, Stanford University School of Medicine, Palo Alto</wicri:regionArea><wicri:noRegion>Palo Alto</wicri:noRegion></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PubMed</idno><date when="2018">2018</date><idno type="RBID">pubmed:30541895</idno><idno type="pmid">30541895</idno><idno type="doi">10.1073/pnas.1818150116</idno><idno type="wicri:Area/PubMed/Corpus">000012</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Corpus" wicri:corpus="PubMed">000012</idno><idno type="wicri:Area/PubMed/Curation">000012</idno><idno type="wicri:explorRef" wicri:stream="PubMed" wicri:step="Curation">000012</idno><idno type="wicri:Area/PubMed/Checkpoint">000024</idno><idno type="wicri:explorRef" wicri:stream="Checkpoint" wicri:step="PubMed">000024</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en">Autoimmunity to hypocretin and molecular mimicry to flu in type 1 narcolepsy.</title><author><name sortKey="Luo, Guo" sort="Luo, Guo" uniqKey="Luo G" first="Guo" last="Luo">Guo Luo</name><affiliation wicri:level="2"><nlm:affiliation>Center for Sleep Sciences and Medicine, Stanford University School of Medicine, Palo Alto, CA 94304.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>Center for Sleep Sciences and Medicine, Stanford University School of Medicine, Palo Alto</wicri:cityArea></affiliation></author><author><name sortKey="Ambati, Aditya" sort="Ambati, Aditya" uniqKey="Ambati A" first="Aditya" last="Ambati">Aditya Ambati</name><affiliation wicri:level="2"><nlm:affiliation>Center for Sleep Sciences and Medicine, Stanford University School of Medicine, Palo Alto, CA 94304.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>Center for Sleep Sciences and Medicine, Stanford University School of Medicine, Palo Alto</wicri:cityArea></affiliation></author><author><name sortKey="Lin, Ling" sort="Lin, Ling" uniqKey="Lin L" first="Ling" last="Lin">Ling Lin</name><affiliation wicri:level="2"><nlm:affiliation>Center for Sleep Sciences and Medicine, Stanford University School of Medicine, Palo Alto, CA 94304.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>Center for Sleep Sciences and Medicine, Stanford University School of Medicine, Palo Alto</wicri:cityArea></affiliation></author><author><name sortKey="Bonvalet, Melodie" sort="Bonvalet, Melodie" uniqKey="Bonvalet M" first="Mélodie" last="Bonvalet">Mélodie Bonvalet</name><affiliation wicri:level="2"><nlm:affiliation>Center for Sleep Sciences and Medicine, Stanford University School of Medicine, Palo Alto, CA 94304.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>Center for Sleep Sciences and Medicine, Stanford University School of Medicine, Palo Alto</wicri:cityArea></affiliation></author><author><name sortKey="Partinen, Markku" sort="Partinen, Markku" uniqKey="Partinen M" first="Markku" last="Partinen">Markku Partinen</name><affiliation wicri:level="1"><nlm:affiliation>Helsinki Sleep Clinic, Vitalmed Research Centre, 00380 Helsinki, Finland.</nlm:affiliation><country xml:lang="fr">Finlande</country><wicri:regionArea>Helsinki Sleep Clinic, Vitalmed Research Centre, 00380 Helsinki</wicri:regionArea><wicri:noRegion>00380 Helsinki</wicri:noRegion></affiliation></author><author><name sortKey="Ji, Xuhuai" sort="Ji, Xuhuai" uniqKey="Ji X" first="Xuhuai" last="Ji">Xuhuai Ji</name><affiliation wicri:level="2"><nlm:affiliation>Immune Monitoring Center, Institute for Immunity, Transplantation, and Infection, Stanford University School of Medicine, Palo Alto, CA 94305.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>Immune Monitoring Center, Institute for Immunity, Transplantation, and Infection, Stanford University School of Medicine, Palo Alto</wicri:cityArea></affiliation></author><author><name sortKey="Maecker, Holden Terry" sort="Maecker, Holden Terry" uniqKey="Maecker H" first="Holden Terry" last="Maecker">Holden Terry Maecker</name><affiliation wicri:level="2"><nlm:affiliation>Immune Monitoring Center, Institute for Immunity, Transplantation, and Infection, Stanford University School of Medicine, Palo Alto, CA 94305.</nlm:affiliation><country xml:lang="fr">États-Unis</country><placeName><region type="state">Californie</region></placeName><wicri:cityArea>Immune Monitoring Center, Institute for Immunity, Transplantation, and Infection, Stanford University School of Medicine, Palo Alto</wicri:cityArea></affiliation></author><author><name sortKey="Mignot, Emmanuel Jean Marie" sort="Mignot, Emmanuel Jean Marie" uniqKey="Mignot E" first="Emmanuel Jean-Marie" last="Mignot">Emmanuel Jean-Marie Mignot</name><affiliation wicri:level="1"><nlm:affiliation>Center for Sleep Sciences and Medicine, Stanford University School of Medicine, Palo Alto, CA 94304; mignot@stanford.edu.</nlm:affiliation><country wicri:rule="url">États-Unis</country><wicri:regionArea>Center for Sleep Sciences and Medicine, Stanford University School of Medicine, Palo Alto</wicri:regionArea><wicri:noRegion>Palo Alto</wicri:noRegion></affiliation></author></analytic><series><title level="j">Proceedings of the National Academy of Sciences of the United States of America</title><idno type="eISSN">1091-6490</idno><imprint><date when="2018" type="published">2018</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Adolescent</term><term>Adult</term><term>Autoantigens (metabolism)</term><term>Autoimmunity (immunology)</term><term>CD4-Positive T-Lymphocytes (immunology)</term><term>Child</term><term>Epitopes (immunology)</term><term>Female</term><term>HLA-DQ beta-Chains</term><term>Hemagglutinins</term><term>Humans</term><term>Influenza A Virus, H1N1 Subtype (immunology)</term><term>Influenza A virus (immunology)</term><term>Influenza A virus (pathogenicity)</term><term>Influenza, Human (immunology)</term><term>Intracellular Signaling Peptides and Proteins (genetics)</term><term>Male</term><term>Middle Aged</term><term>Molecular Mimicry (immunology)</term><term>Narcolepsy (immunology)</term><term>Orexins (genetics)</term><term>Orexins (immunology)</term><term>Orexins (metabolism)</term><term>Peptides (genetics)</term><term>Receptors, Antigen, T-Cell (genetics)</term><term>Vaccination</term></keywords><keywords scheme="KwdFr" xml:lang="fr"><term>Adolescent</term><term>Adulte</term><term>Adulte d'âge moyen</term><term>Auto-immunité (immunologie)</term><term>Autoantigènes (métabolisme)</term><term>Chaines bêta des antigènes HLA-DQ</term><term>Enfant</term><term>Femelle</term><term>Grippe humaine (immunologie)</term><term>Humains</term><term>Hémagglutinines</term><term>Lymphocytes T CD4+ (immunologie)</term><term>Mimétisme moléculaire (immunologie)</term><term>Mâle</term><term>Narcolepsie (immunologie)</term><term>Orexines (génétique)</term><term>Orexines (immunologie)</term><term>Orexines (métabolisme)</term><term>Peptides (génétique)</term><term>Protéines et peptides de signalisation intracellulaire (génétique)</term><term>Récepteurs aux antigènes des cellules T (génétique)</term><term>Sous-type H1N1 du virus de la grippe A (immunologie)</term><term>Vaccination</term><term>Virus de la grippe A (immunologie)</term><term>Virus de la grippe A (pathogénicité)</term><term>Épitopes (immunologie)</term></keywords><keywords scheme="MESH" type="chemical" qualifier="genetics" xml:lang="en"><term>Intracellular Signaling Peptides and Proteins</term><term>Orexins</term><term>Peptides</term><term>Receptors, Antigen, T-Cell</term></keywords><keywords scheme="MESH" type="chemical" qualifier="immunology" xml:lang="en"><term>Epitopes</term><term>Orexins</term></keywords><keywords scheme="MESH" type="chemical" qualifier="metabolism" xml:lang="en"><term>Autoantigens</term><term>Orexins</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Orexines</term><term>Peptides</term><term>Protéines et peptides de signalisation intracellulaire</term><term>Récepteurs aux antigènes des cellules T</term></keywords><keywords scheme="MESH" qualifier="immunologie" xml:lang="fr"><term>Auto-immunité</term><term>Grippe humaine</term><term>Lymphocytes T CD4+</term><term>Mimétisme moléculaire</term><term>Narcolepsie</term><term>Orexines</term><term>Sous-type H1N1 du virus de la grippe A</term><term>Virus de la grippe A</term><term>Épitopes</term></keywords><keywords scheme="MESH" qualifier="immunology" xml:lang="en"><term>Autoimmunity</term><term>CD4-Positive T-Lymphocytes</term><term>Influenza A Virus, H1N1 Subtype</term><term>Influenza A virus</term><term>Influenza, Human</term><term>Molecular Mimicry</term><term>Narcolepsy</term></keywords><keywords scheme="MESH" qualifier="métabolisme" xml:lang="fr"><term>Autoantigènes</term><term>Orexines</term></keywords><keywords scheme="MESH" qualifier="pathogenicity" xml:lang="en"><term>Influenza A virus</term></keywords><keywords scheme="MESH" qualifier="pathogénicité" xml:lang="fr"><term>Virus de la grippe A</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Adolescent</term><term>Adult</term><term>Child</term><term>Female</term><term>HLA-DQ beta-Chains</term><term>Hemagglutinins</term><term>Humans</term><term>Male</term><term>Middle Aged</term><term>Vaccination</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Adolescent</term><term>Adulte</term><term>Adulte d'âge moyen</term><term>Chaines bêta des antigènes HLA-DQ</term><term>Enfant</term><term>Femelle</term><term>Humains</term><term>Hémagglutinines</term><term>Mâle</term><term>Vaccination</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Type 1 narcolepsy (T1N) is caused by hypocretin/orexin (HCRT) neuronal loss. Association with the HLA DQB1*06:02/DQA1*01:02 (98% vs. 25%) heterodimer (DQ0602), T cell receptors (TCR) and other immune loci suggest autoimmunity but autoantigens are unknown. Onset is seasonal and associated with influenza A, notably pandemic 2009 H1N1 (pH1N1) infection and vaccination (Pandemrix). Peptides derived from HCRT and influenza A, including pH1N1, were screened for DQ0602 binding and presence of cognate DQ0602 tetramer-peptide-specific CD4<sup>+</sup> T cells tested in 35 T1N cases and 22 DQ0602 controls. Higher reactivity to influenza pHA<sub>273-287</sub> (pH1N1 specific), PR8 (H1N1 pre-2009 and H2N2)-specific NP<sub>17-31</sub> and C-amidated but not native version of HCRT<sub>54-66</sub> and HCRT<sub>86-97</sub> (HCRT<sub>NH2</sub>) were observed in T1N. Single-cell TCR sequencing revealed sharing of CDR3β TRBV4-2-CASSQETQGRNYGYTF in HCRT<sub>NH2</sub> and pHA<sub>273-287</sub>-tetramers, suggesting molecular mimicry. This public CDR3β uses TRBV4-2, a segment modulated by T1N-associated SNP rs1008599, suggesting causality. TCR-α/β CDR3 motifs of HCRT<sub>54-66-NH2</sub> and HCRT<sub>86-97-NH2</sub> tetramers were extensively shared: notably public CDR3α, TRAV2-CAVETDSWGKLQF-TRAJ24, that uses TRAJ24, a chain modulated by T1N-associated SNPs rs1154155 and rs1483979. TCR-α/β CDR3 sequences found in pHA<sub>273-287</sub>, NP<sub>17-31</sub>, and HCRT<sub>NH2</sub> tetramer-positive CD4<sup>+</sup> cells were also retrieved in single INF-γ-secreting CD4<sup>+</sup> sorted cells stimulated with Pandemrix, independently confirming these results. Our results provide evidence for autoimmunity and molecular mimicry with flu antigens modulated by genetic components in the pathophysiology of T1N.</div></front></TEI></pubmed></double></record>Pour manipuler ce document sous Unix (Dilib)
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