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The disease is considered to be the result of the selective disruption of neuronal cells in the lateral hypothalamus expressing the neuropeptide hypocretin, which controls the sleep-wake cycle. Diagnosis and management of narcolepsy represent still a substantial medical challenge due to the large heterogeneity in the clinical manifestation of the disease as well as to the lack of understanding of the underlying pathophysiological mechanisms. However, significant advances have been made in the last years, thus opening new perspective in the field. This review describes the current knowledge of clinical presentation and pathology of narcolepsy as well as the existing diagnostic criteria and therapeutic intervention for the disease management. Recent evidence on the potential immune-mediated mechanisms that may underpin the disease establishment and progression are also highlighted.<\/jats:p>","DOI":"10.1007\/s00281-022-00933-9","type":"journal-article","created":{"date-parts":[[2022,4,21]],"date-time":"2022-04-21T15:05:11Z","timestamp":1650553511000},"page":"611-623","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Narcolepsy: a model interaction between immune system, nervous system, and sleep-wake regulation"],"prefix":"10.1007","volume":"44","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1031-1534","authenticated-orcid":false,"given":"Daniela","family":"Latorre","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3750-2752","authenticated-orcid":false,"given":"Federica","family":"Sallusto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4535-0245","authenticated-orcid":false,"given":"Claudio L. 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