{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T01:25:08Z","timestamp":1790645108412,"version":"4.1.0"},"reference-count":191,"publisher":"EDP Sciences","issue":"3-4","license":[{"start":{"date-parts":[[2019,12,12]],"date-time":"2019-12-12T00:00:00Z","timestamp":1576108800000},"content-version":"vor","delay-in-days":345,"URL":"https:\/\/www.edpsciences.org\/en\/authors\/copyright-and-licensing"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biologie Aujourd\u2019hui"],"published-print":{"date-parts":[[2019]]},"abstract":"<jats:p>La narcolepsie et la cataplexie sont d\u00e9crites pour la premi\u00e8re fois \u00e0 la fin du XIX<jats:sup>e<\/jats:sup>\u2009si\u00e8cle en Allemagne et en France. La pr\u00e9valence de la maladie est \u00e9tablie \u00e0 0,05\u2009% et un mod\u00e8le canin est d\u00e9couvert dans les ann\u00e9es\u20091970. En 1983, une \u00e9tude japonaise r\u00e9v\u00e8le que les patients narcoleptiques sont porteurs d\u2019un marqueur g\u00e9n\u00e9tique unique, l\u2019antig\u00e8ne leucocytaire\u2009HLA-DR2, sugg\u00e9rant l\u2019auto-immunit\u00e9 comme cause de la maladie. Il faudra attendre 1992 pour qu\u2019il soit montr\u00e9, gr\u00e2ce \u00e0 une \u00e9tude chez des patients afro-am\u00e9ricains, que <jats:italic>DQ0602<\/jats:italic>, un autre g\u00e8ne HLA, est la v\u00e9ritable cause de cette association. Des \u00e9tudes pharmacologiques conduites sur le mod\u00e8le canin \u00e9tablissent que la stimulation dopaminergique est le mode d\u2019action des stimulants sur l\u2019\u00e9veil, tandis que les antid\u00e9presseurs suppriment la cataplexie en inhibant la recapture adr\u00e9nergique. Aucune association HLA n\u2019est cependant mise en \u00e9vidence chez les chiens, sugg\u00e9rant une cause distincte de la maladie humaine. Une \u00e9tude de liaison g\u00e9n\u00e9tique chez les chiens, initi\u00e9e en 1988, r\u00e9v\u00e8le en 1999 que la narcolepsie canine est caus\u00e9e par des mutations du r\u00e9cepteur\u20092 de l\u2019hypocr\u00e9tine (orexine). En 2000, l\u2019hypocr\u00e9tine-1\/orexine\u2009A est mesur\u00e9e dans le liquide c\u00e9phalo-rachidien (LCR) et on d\u00e9couvre qu\u2019elle est ind\u00e9tectable chez la plupart des patients narcoleptiques, \u00e9tablissant qu\u2019un d\u00e9ficit hypocr\u00e9tinergique est la cause de la narcolepsie humaine. La diminution de l\u2019hypocr\u00e9tine-1 dans le LCR, secondaire \u00e0 la perte des 70\u2009000\u2009neurones hypothalamiques produisant l\u2019hypocr\u00e9tine, est d\u00e9montr\u00e9e, ce qui, avec l\u2019association au <jats:italic>locus<\/jats:italic> HLA, sugg\u00e8re qu\u2019une destruction immunitaire de ces cellules est la cause de la maladie. D\u2019autres \u00e9tudes g\u00e9n\u00e9tiques, notamment d\u2019association \u00e0 l\u2019\u00e9chelle du g\u00e9nome (<jats:italic>GWAS<\/jats:italic>), r\u00e9v\u00e8lent l\u2019existence de nombreux facteurs g\u00e9n\u00e9tiques pr\u00e9disposant \u00e0 la narcolepsie, la plupart \u00e9tant \u00e9galement impliqu\u00e9s dans d\u2019autres maladies auto-immunes. Une association forte et unique avec les <jats:italic>loci<\/jats:italic> des r\u00e9cepteurs lymphocytaires\u2009T (<jats:italic>TCR<\/jats:italic>) alpha et b\u00eata est aussi observ\u00e9e, sugg\u00e9rant un r\u00f4le pr\u00e9pond\u00e9rant des lymphocytes\u2009T. En d\u00e9pit de nombreux efforts, toutes les tentatives visant \u00e0 d\u00e9montrer la pr\u00e9sence d\u2019auto-anticorps contre les cellules \u00e0 hypocr\u00e9tine dans la narcolepsie \u00e9chouent, et la cause auto-immune pr\u00e9sum\u00e9e de cette maladie reste \u00e0 l\u2019\u00e9tat d\u2019hypoth\u00e8se. \u00c0 la suite de la grippe pand\u00e9mique influenza\u2009A\u2009pH1N1 en 2009, de nombreux cas de narcolepsie apparaissent, sugg\u00e9rant un mim\u00e9tisme mol\u00e9culaire avec le virus de la grippe qui pourrait d\u00e9clencher la maladie auto-immune. Cette hypoth\u00e8se est confirm\u00e9e par un criblage peptidique montrant une plus grande r\u00e9activit\u00e9 des lymphocytes\u2009T\u2009CD4<jats:sup>+<\/jats:sup> \u00e0 un segment sp\u00e9cifique de l\u2019hypocr\u00e9tine (HCRT<jats:sub>NH2<\/jats:sub>) et une r\u00e9activit\u00e9 crois\u00e9e des <jats:italic>TCR<\/jats:italic> correspondants \u00e0 un segment d\u2019h\u00e9magglutinine de pH1N1 qui partage une homologie avec HCRT<jats:sub>NH2<\/jats:sub>. De fa\u00e7on remarquable, le <jats:italic>TCR<\/jats:italic> le plus fr\u00e9quent dans la population et qui reconna\u00eet ces antig\u00e8nes contient des s\u00e9quences TRAJ24 ou TRVB4-2, segments modul\u00e9s par des polymorphismes g\u00e9n\u00e9tiques associ\u00e9s \u00e0 la narcolepsie dans les \u00e9tudes <jats:italic>GWAS<\/jats:italic>. Il est probable que les lymphocytes\u2009T\u2009CD4<jats:sup>+<\/jats:sup> autor\u00e9actifs avec HCRT<jats:sub>NH2<\/jats:sub> recrutent par la suite des lymphocytes\u2009T\u2009CD8<jats:sup>+<\/jats:sup> qui d\u00e9truisent les cellules \u00e0 hypocr\u00e9tine. On peut s\u2019attendre \u00e0 ce que d\u2019autres s\u00e9quences mimiques grippales inconnues soient d\u00e9couvertes prochainement puisque la narcolepsie existait avant 2009. Ces d\u00e9couvertes d\u00e9montrent enfin la cause auto-immune de la narcolepsie. Les travaux men\u00e9s au cours des ann\u00e9es sur la narcolepsie offrent une perspective unique sur la conduite de la recherche sur l\u2019\u00e9tiopathog\u00e9nie d\u2019une maladie bien identifi\u00e9e.<\/jats:p>","DOI":"10.1051\/jbio\/2019026","type":"journal-article","created":{"date-parts":[[2019,12,12]],"date-time":"2019-12-12T09:00:17Z","timestamp":1576141217000},"page":"87-108","source":"Crossref","is-referenced-by-count":2,"title":["Narcolepsie\u2009: une maladie auto-immune affectant un peptide de l\u2019\u00e9veil li\u00e9e \u00e0 un mim\u00e9tisme mol\u00e9culaire avec des \u00e9pitopes du virus de la grippe"],"prefix":"10.1051","volume":"213","author":[{"given":"Jean-Marie","family":"Ravel","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emmanuel 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