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The immunopathogenesis of narcolepsy type 1

Nature Reviews Immunology volume 24, pages 33–48 (2024)Cite this article

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Abstract

Narcolepsy type 1 (NT1) is a chronic sleep disorder resulting from the loss of a small population of hypothalamic neurons that produce wake-promoting hypocretin (HCRT; also known as orexin) peptides. An immune-mediated pathology for NT1 has long been suspected given its exceptionally tight association with the MHC class II allele HLA-DQB1*06:02, as well as recent genetic evidence showing associations with polymorphisms of T cell receptor genes and other immune-relevant loci and the increased incidence of NT1 that has been observed after vaccination with the influenza vaccine Pandemrix. The search for both self-antigens and foreign antigens recognized by the pathogenic T cell response in NT1 is ongoing. Increased T cell reactivity against HCRT has been consistently reported in patients with NT1, but data demonstrating a primary role for T cells in neuronal destruction are currently lacking. Animal models are providing clues regarding the roles of autoreactive CD4+ and CD8+ T cells in the disease. Elucidation of the pathogenesis of NT1 will allow for the development of targeted immunotherapies at disease onset and could serve as a model for other immune-mediated neurological diseases.

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Fig. 1: HLA effects and HLA-DQ allele competition in narcolepsy type 1.
Fig. 2: Hypothetical scheme for the immunopathogenesis of narcolepsy type 1.

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Acknowledgements

The authors thank L. Chatenoud, R. Mallone and D. Dunia for their feedback on the manuscript, and T. Sarkanen and D. Frieser for their help with Supplementary Fig. 1 and Supplementary Fig. 2, respectively. R.S.L. is supported by Institut Universitaire de France and grants from Fondation pour la Recherche Médicale, the Agence Nationale de la Recherche (BETPSY RHU consortium, NARCOMICS consortium and ANR-18-CE17-0014-03). Y.D. is supported by grants from Agence Nationale de la Recherche (NARCOMICS consortium and ANR-18-CE17-0014-03). D.L. is supported by a PRIMA grant from the Swiss National Science Foundation (PR00P3_185742). B.R.K. is supported by the Lundbeck Foundation (grant R344-2020-749), and a Carlsberg Foundation Young Researcher Fellowship. E.J.M.’s research on narcolepsy is supported by National Institutes of Health grant R01 AI144798.

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Authors and Affiliations

  1. Toulouse Institute for Infectious and Inflammatory Diseases (Infinity), University of Toulouse, CNRS, INSERM, Toulouse, France

    Roland S. Liblau

  2. Department of Immunology, Toulouse University Hospitals, Toulouse, France

    Roland S. Liblau

  3. Institute of Microbiology, ETH Zurich, Zurich, Switzerland

    Daniela Latorre

  4. Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

    Birgitte R. Kornum

  5. National Reference Center for Orphan Diseases, Narcolepsy, Idiopathic Hypersomnia and Kleine-Levin Syndrome, Department of Neurology, Gui-de-Chauliac Hospital, CHU de Montpellier, Montpellier, France

    Yves Dauvilliers

  6. INSERM Institute for Neurosciences of Montpellier, Montpellier, France

    Yves Dauvilliers

  7. Stanford University, Center for Narcolepsy, Department of Psychiatry and Behavioral Sciences, Palo Alto, CA, USA

    Emmanuel J. Mignot

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Contributions

R.S.L. and E.J.M. conceived the idea and the structure of the manuscript. All authors contributed to the content. R.S.L., B.R.K., Y.D and E.J.M. designed the tables and figures. All authors reviewed and edited the manuscript before submission.

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Correspondence to Roland S. Liblau or Emmanuel J. Mignot.

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Competing interests

R.S.L. has received grant support from GlaxoSmithKline and Roche and has consulted for Merck, Novartis, Biogen and Sanofi-Genzyme. B.R.K. has consulted for UCB Pharma, Lundbeck, Gubra and Orexia Therapeutics, has submitted patent applications within the field of narcolepsy and is a founder of the University of Copenhagen spin-out company Ceremedy ApS. Y.D. is a consultant for and has participated in advisory boards for Jazz Pharmaceuticals, UCB Pharma, Avadel, Idorsia, Orexia, Takeda and Bioprojet. In the last 3 years, E.J.M. received grant support from, is a consultant for or has participated in advisory boards for Apple, Avadel, Axsome, Huami, Harmony, Idorsia, Jazz Pharmaceuticals, Orexia/Centessa, Sunovion and Takeda. D.L. declares no competing interests.

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Supplementary information

Glossary

Anti-Ma2 antibody-associated paraneoplastic neurological syndrome

One of the paraneoplastic neurological syndromes, a rare set of autoimmune neurological disorders that occur in association with specific cancers (such as seminomas in this case) when a productive adaptive immune response against tumour (neo)antigens (such as autoantibodies against the Ma2 protein in this case) cross-reacts with normal neurons or glial cells, leading to neural tissue damage.

AS03

A proprietary adjuvant comprising the polyunsaturated fatty acid squalene, α-tocopherol (vitamin E) and the surfactant and emulsifier polysorbate 80.

Bystander activation

Activation of T cells or B cells occurring without specific antigen recognition. During an inflammatory response, such bystander activation of self-reactive lymphocytes by inflammatory mediators or metabolic stimuli may trigger autoimmunity as a side effect of a broader activation of the immune system.

Cataplexy

The most specific symptom of narcolepsy type 1, characterized by a transient loss of muscle tone triggered by laughing, joking or other emotions.

Expression quantitative trait locus

(eQTL). Genetic polymorphism that explains variation in expression of an mRNA or protein.

Idiopathic hypersomnia

A frequent sleep disorder associated with daytime sleepiness but no cataplexy or REM (rapid eye movement) sleep abnormalities, which is differentiated from type 1 narcolepsy.

Immune checkpoint inhibitors

Antineoplastic drugs, mostly monoclonal antibodies, that interfere with inhibitory immune pathways, such as CTLA4–CD80/CD86 or PD1–PDL1, thereby enhancing the antitumour immune response.

Molecular mimicry

A mechanism by which infectious or other foreign antigens inappropriately activate autoreactive T cells or B cells owing to structural similarities between foreign antigens and self-antigens, thereby initiating autoimmunity.

Neuromyelitis optica spectrum disorder

A relapsing autoimmune neurological disorder characterized by inflammation of the optic nerve and the spinal cord, which is usually associated with autoantibodies to aquaporin 4.

Pleocytosis

An abnormally increased number of leukocytes in the cerebrospinal fluid.

REM (rapid eye movement) sleep

A stage of sleep associated with dreaming, muscle paralysis and rapid eye movements, occurring normally 1–2 h after sleep onset and reoccurring every 90 min with increasing duration throughout the night.

Witebsky’s postulates

A set of criteria proposed by Ernst Witebsky in 1957, and later revised by Noel Rose and Constantin Bona in 1993, to help establish whether a disease entity can be regarded as autoimmune.

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Liblau, R.S., Latorre, D., Kornum, B.R. et al. The immunopathogenesis of narcolepsy type 1. Nat Rev Immunol 24, 33–48 (2024). https://doi.org/10.1038/s41577-023-00902-9

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