Autoimmunity to hypocretin and molecular mimicry to flu in type 1 narcolepsy
Identifieur interne : 000168 ( Pmc/Checkpoint ); précédent : 000167; suivant : 000169Autoimmunity 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.
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
Affiliations:
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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 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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" 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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 sortKey="Ollila, Hm" uniqKey="Ollila H">HM Ollila</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Martinez Orozco, Fj" uniqKey="Martinez Orozco F">FJ Martinez-Orozco</name></author><author><name sortKey="Vicario, Jl" uniqKey="Vicario J">JL Vicario</name></author><author><name sortKey="De Andres, C" uniqKey="De Andres C">C De Andres</name></author><author><name sortKey="Fernandez Arquero, M" uniqKey="Fernandez Arquero M">M Fernandez-Arquero</name></author><author><name sortKey="Peraita Adrados, R" uniqKey="Peraita Adrados R">R Peraita-Adrados</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Singh, Ak" uniqKey="Singh A">AK Singh</name></author><author><name sortKey="Mahlios, J" uniqKey="Mahlios J">J Mahlios</name></author><author><name sortKey="Mignot, E" uniqKey="Mignot E">E Mignot</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Aran, A" uniqKey="Aran A">A Aran</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Han, F" uniqKey="Han F">F Han</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Dye, Tj" uniqKey="Dye T">TJ Dye</name></author><author><name sortKey="Gurbani, N" uniqKey="Gurbani N">N Gurbani</name></author><author><name sortKey="Simakajornboon, N" uniqKey="Simakajornboon N">N Simakajornboon</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Feltelius, N" uniqKey="Feltelius N">N Feltelius</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ambati, A" uniqKey="Ambati A">A Ambati</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Vaarala, O" uniqKey="Vaarala O">O Vaarala</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Nishino, S" uniqKey="Nishino S">S Nishino</name></author><author><name sortKey="Ripley, B" uniqKey="Ripley B">B Ripley</name></author><author><name sortKey="Overeem, S" uniqKey="Overeem S">S Overeem</name></author><author><name sortKey="Lammers, Gj" uniqKey="Lammers G">GJ Lammers</name></author><author><name sortKey="Mignot, E" uniqKey="Mignot E">E Mignot</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Peyron, C" uniqKey="Peyron C">C Peyron</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Thannickal, Tc" uniqKey="Thannickal T">TC Thannickal</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="De La Herran Arita, Ak" uniqKey="De La Herran Arita A">AK De la Herrán-Arita</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="Ramberger, M" uniqKey="Ramberger M">M Ramberger</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Tanaka, S" uniqKey="Tanaka S">S Tanaka</name></author><author><name sortKey="Honda, Y" uniqKey="Honda Y">Y Honda</name></author><author><name sortKey="Inoue, Y" uniqKey="Inoue Y">Y Inoue</name></author><author><name sortKey="Honda, M" uniqKey="Honda M">M Honda</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Cvetkovic Lopes, V" uniqKey="Cvetkovic Lopes V">V Cvetkovic-Lopes</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Lind, A" uniqKey="Lind A">A Lind</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ahmed, Ss" uniqKey="Ahmed S">SS Ahmed</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Giannoccaro, Mp" uniqKey="Giannoccaro M">MP Giannoccaro</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Luo, G" uniqKey="Luo G">G Luo</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Van Der Heide, A" uniqKey="Van Der Heide A">A van der Heide</name></author><author><name sortKey="Hegeman Kleinn, Im" uniqKey="Hegeman Kleinn I">IM Hegeman-Kleinn</name></author><author><name sortKey="Peeters, E" uniqKey="Peeters E">E Peeters</name></author><author><name sortKey="Lammers, Gj" uniqKey="Lammers G">GJ Lammers</name></author><author><name sortKey="Fronczek, R" uniqKey="Fronczek R">R Fronczek</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Ollila, H" uniqKey="Ollila H">H Ollila</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Bernard Valnet, R" uniqKey="Bernard Valnet R">R Bernard-Valnet</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Longstreth, Wt" uniqKey="Longstreth W">WT Longstreth</name></author><author><name sortKey="Ton, Tg" uniqKey="Ton T">TG Ton</name></author><author><name sortKey="Koepsell, Td" uniqKey="Koepsell T">TD Koepsell</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Han, F" uniqKey="Han F">F Han</name></author><author><name sortKey="Lin, L" uniqKey="Lin L">L Lin</name></author><author><name sortKey="Li, J" uniqKey="Li J">J Li</name></author><author><name sortKey="Dong, Xs" uniqKey="Dong X">XS Dong</name></author><author><name sortKey="Mignot, E" uniqKey="Mignot E">E Mignot</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Wu, H" uniqKey="Wu H">H Wu</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Weibel, D" uniqKey="Weibel D">D Weibel</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Sarkanen, T" uniqKey="Sarkanen T">T Sarkanen</name></author><author><name sortKey="Alakuijala, A" uniqKey="Alakuijala A">A Alakuijala</name></author><author><name sortKey="Julkunen, I" uniqKey="Julkunen I">I Julkunen</name></author><author><name sortKey="Partinen, M" uniqKey="Partinen M">M Partinen</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Jacob, L" uniqKey="Jacob L">L Jacob</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Han, F" uniqKey="Han F">F Han</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Miyagawa, T" uniqKey="Miyagawa T">T Miyagawa</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Mignot, E" uniqKey="Mignot E">E Mignot</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Tafti, M" uniqKey="Tafti M">M Tafti</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Bedford, T" uniqKey="Bedford T">T Bedford</name></author><author><name sortKey="Cobey, S" uniqKey="Cobey S">S Cobey</name></author><author><name sortKey="Beerli, P" uniqKey="Beerli P">P Beerli</name></author><author><name sortKey="Pascual, M" uniqKey="Pascual M">M Pascual</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="De La Herran Arita, Ak" uniqKey="De La Herran Arita A">AK De la Herran-Arita</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Latorre, D" uniqKey="Latorre D">D Latorre</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Nicolson, C" uniqKey="Nicolson C">C Nicolson</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Demachi Okamura, A" uniqKey="Demachi Okamura A">A Demachi-Okamura</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Dalal, J" uniqKey="Dalal J">J Dalal</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Kim, Y" uniqKey="Kim Y">Y Kim</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Glanville, J" uniqKey="Glanville J">J Glanville</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Sharon, E" uniqKey="Sharon E">E Sharon</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Sakurai, T" uniqKey="Sakurai T">T Sakurai</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Zougman, A" uniqKey="Zougman A">A Zougman</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Dendrou, Ca" uniqKey="Dendrou C">CA Dendrou</name></author><author><name sortKey="Petersen, J" uniqKey="Petersen J">J Petersen</name></author><author><name sortKey="Rossjohn, J" uniqKey="Rossjohn J">J Rossjohn</name></author><author><name sortKey="Fugger, L" uniqKey="Fugger L">L Fugger</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Raposo, B" uniqKey="Raposo B">B Raposo</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Risnes, Lf" uniqKey="Risnes L">LF Risnes</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Han, F" uniqKey="Han F">F Han</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Cushing, A" uniqKey="Cushing A">A Cushing</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Montplaisir, J" uniqKey="Montplaisir J">J Montplaisir</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="La Gruta, Nl" uniqKey="La Gruta N">NL La Gruta</name></author><author><name sortKey="Gras, S" uniqKey="Gras S">S Gras</name></author><author><name sortKey="Daley, Sr" uniqKey="Daley S">SR Daley</name></author><author><name sortKey="Thomas, Pg" uniqKey="Thomas P">PG Thomas</name></author><author><name sortKey="Rossjohn, J" uniqKey="Rossjohn J">J Rossjohn</name></author></analytic></biblStruct><biblStruct><analytic><author><name sortKey="Hahn, M" uniqKey="Hahn M">M Hahn</name></author><author><name sortKey="Nicholson, Mj" 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><pmc article-type="research-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Proc Natl Acad Sci U S A</journal-id><journal-id journal-id-type="iso-abbrev">Proc. Natl. Acad. Sci. U.S.A</journal-id><journal-id journal-id-type="hwp">pnas</journal-id><journal-id journal-id-type="pmc">pnas</journal-id><journal-id journal-id-type="publisher-id">PNAS</journal-id><journal-title-group><journal-title>Proceedings of the National Academy of Sciences of the United States of America</journal-title></journal-title-group><issn pub-type="ppub">0027-8424</issn><issn pub-type="epub">1091-6490</issn><publisher><publisher-name>National Academy of Sciences</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">30541895</article-id><article-id pub-id-type="pmc">6310865</article-id><article-id pub-id-type="publisher-id">201818150</article-id><article-id pub-id-type="doi">10.1073/pnas.1818150116</article-id><article-categories><subj-group subj-group-type="heading"><subject>PNAS Plus</subject></subj-group><subj-group subj-group-type="heading"><subject>Biological Sciences</subject><subj-group><subject>Immunology and Inflammation</subject></subj-group></subj-group><series-title>PNAS Plus</series-title></article-categories><title-group><article-title>Autoimmunity to hypocretin and molecular mimicry to flu in type 1 narcolepsy</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Luo</surname><given-names>Guo</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Ambati</surname><given-names>Aditya</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref><xref ref-type="author-notes" rid="fn1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Lin</surname><given-names>Ling</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref><xref ref-type="author-notes" rid="fn1"><sup>1</sup></xref></contrib><contrib contrib-type="author"><name><surname>Bonvalet</surname><given-names>Mélodie</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Partinen</surname><given-names>Markku</given-names></name><xref ref-type="aff" rid="aff2"><sup>b</sup></xref><xref ref-type="aff" rid="aff3"><sup>c</sup></xref></contrib><contrib contrib-type="author"><name><surname>Ji</surname><given-names>Xuhuai</given-names></name><xref ref-type="aff" rid="aff4"><sup>d</sup></xref></contrib><contrib contrib-type="author"><name><surname>Maecker</surname><given-names>Holden Terry</given-names></name><xref ref-type="aff" rid="aff4"><sup>d</sup></xref></contrib><contrib contrib-type="author"><name><surname>Mignot</surname><given-names>Emmanuel Jean-Marie</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref><xref ref-type="corresp" rid="cor1"><sup>2</sup></xref></contrib><aff id="aff1"><sup>a</sup>Center for Sleep Sciences and Medicine,<institution>Stanford University School of Medicine</institution>, Palo Alto,<addr-line>CA</addr-line> 94304;</aff><aff id="aff2"><sup>b</sup>Helsinki Sleep Clinic, Vitalmed Research Centre, 00380 Helsinki,<country>Finland</country>;</aff><aff id="aff3"><sup>c</sup>Department of Clinical Neurosciences,<institution>University of Helsinki</institution>, 00100 Helsinki,<country>Finland</country>;</aff><aff id="aff4"><sup>d</sup>Immune Monitoring Center, Institute for Immunity, Transplantation, and Infection,<institution>Stanford University School of Medicine</institution>, Palo Alto,<addr-line>CA</addr-line> 94305</aff></contrib-group><author-notes><corresp id="cor1"><sup>2</sup>To whom correspondence should be addressed. Email: <email>mignot@stanford.edu</email>.</corresp><fn fn-type="edited-by"><p>Contributed by Emmanuel Jean-Marie Mignot, November 17, 2018 (sent for review October 25, 2018; reviewed by Roland S. Liblau and Joseph S. Takahashi)</p></fn><fn fn-type="con"><p>Author contributions: G.L., A.A., and E.M. designed research; G.L., A.A., L.L., and X.J. performed research; M.B. and M.P. contributed new reagents/analytic tools; G.L., A.A., L.L., H.T.M., and E.M. analyzed data; and G.L., A.A., and E.M. wrote the paper.</p></fn><fn fn-type="con"><p>Reviewers: R.S.L., INSERM U1043; and J.S.T., Howard Hughes Medical Institute, University of Texas Southwestern Medical Center.</p></fn><fn fn-type="equal" id="fn1"><p><sup>1</sup>A.A. and L.L. contributed equally to this work.</p></fn></author-notes><pub-date pub-type="ppub"><day>26</day><month>12</month><year>2018</year></pub-date><pub-date pub-type="epub"><day>12</day><month>12</month><year>2018</year></pub-date><pub-date pub-type="pmc-release"><day>12</day><month>12</month><year>2018</year></pub-date><pmc-comment> PMC Release delay is 0 months and 0 days and was based on the
<volume>115</volume><issue>52</issue><fpage>E12323</fpage><lpage>E12332</lpage><permissions><copyright-statement>Copyright © 2018 the Author(s). Published by PNAS.</copyright-statement><copyright-year>2018</copyright-year><license license-type="open-access" xlink:href="https://creativecommons.org/licenses/by-nc-nd/4.0/"><license-p>This open access article is distributed under <ext-link ext-link-type="uri" xlink:href="https://creativecommons.org/licenses/by-nc-nd/4.0/">Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND)</ext-link>.</license-p></license></permissions><self-uri xlink:title="pdf" xlink:href="pnas.201818150.pdf"></self-uri><abstract abstract-type="executive-summary"><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></abstract><abstract><p>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.</p></abstract><kwd-group><kwd>narcolepsy</kwd><kwd>TCR</kwd><kwd>autoimmunity</kwd><kwd>DQ0602</kwd><kwd>tetramer</kwd></kwd-group><counts><page-count count="10"></page-count></counts></article-meta></front></pmc><affiliations><list><country><li>Finlande</li></country></list><tree><noCountry><name sortKey="Ambati, Aditya" sort="Ambati, Aditya" uniqKey="Ambati A" first="Aditya" last="Ambati">Aditya Ambati</name><name sortKey="Bonvalet, Melodie" sort="Bonvalet, Melodie" uniqKey="Bonvalet M" first="Mélodie" last="Bonvalet">Mélodie Bonvalet</name><name sortKey="Ji, Xuhuai" sort="Ji, Xuhuai" uniqKey="Ji X" first="Xuhuai" last="Ji">Xuhuai Ji</name><name sortKey="Lin, Ling" sort="Lin, Ling" uniqKey="Lin L" first="Ling" last="Lin">Ling Lin</name><name sortKey="Luo, Guo" sort="Luo, Guo" uniqKey="Luo G" first="Guo" last="Luo">Guo Luo</name><name sortKey="Maecker, Holden Terry" sort="Maecker, Holden Terry" uniqKey="Maecker H" first="Holden Terry" last="Maecker">Holden Terry Maecker</name><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></noCountry><country name="Finlande"><noRegion><name sortKey="Partinen, Markku" sort="Partinen, Markku" uniqKey="Partinen M" first="Markku" last="Partinen">Markku Partinen</name></noRegion><name sortKey="Partinen, Markku" sort="Partinen, Markku" uniqKey="Partinen M" first="Markku" last="Partinen">Markku Partinen</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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