Narcolepsy, scientists unmask the culprit of an enigmatic disease

Patients with a rare disease, called narcolepsy, suffer of excessive daytime sleepiness and cataplexy. A study published in the renowned scientific journal Nature reports the cause of the disease, which has previously been a mystery. The study is the result of a close collaboration between researchers from the University Sleep-Wake-Epilepsy-Centre Bern at the University Hospital (Inselspital), the Institute for Research in Biomedicine in Bellinzona and ETH Zurich.

The study is the result of a close collaboration between basic and clinical scientists and was jointly coordinated by Prof. Federica Sallusto at the Institute for Research in Biomedicine in Bellinzona (IRB, affiliated to USI Università della Svizzera italiana) and at ETH Zurich, and Prof. Claudio Bassetti at the University Sleep-Wake-Epilepsy-Center Bern of the Department of Neurology at the University Hospital (Inselspital) in Bern. The study also involved the Neurocenter of Southern Switzerland of the Ente Ospedaliero Cantonale, the Center for Sleep Research and Sleep Medicine of the Clinic Barmelweid, the Department of Physiology at the University of Lausanne, the Institute of Experimental Immunology at the University of Zurich, and the Institute of Immunology at the University Witten/Herdecke in Germany. The work was supported by the Swiss National Science Foundation, the European Research Council (ERC) and the Helmut Horten Foundation.

According to Prof. Federica Sallusto: «Using new sensitive methods we have been able to identify T lymphocytes reactive against hypocretin as the culprit of this disease. These autoreactive T lymphocytes can cause inflammation leading to neuronal damage or even kill hypocretin-producing neurons. By blocking them at early stages, it may be possible to limit neuronal loss and prevent progression of the disease.»

According to Prof. Claudio Bassetti: «This publication will increase the awareness about narcolepsy, which remains poorly known in the general population and often is not, or belatedly, diagnosed by physicians. This study will also open new opportunities for an early diagnosis and novel treatment approaches of this disabling disease.»


Narcolepsy is a rare chronic brain disorder, which affects about 0.05% of the general population and manifests with excessive daytime drowsiness (with “sleep attacks”), cataplexy (loss of muscle control, typically triggered by a sudden, positive emotion), sleep paralysis, hallucinations, and disturbed sleep. The cause of narcolepsy is the loss of neurons in the hypothalamus (a region of the brain), which produces hypocretin (HCRT), a protein which regulates sleep-wake, emotional and feeding behaviors. The presence in over 95% of patients of a specific genetic marker (the HLA allele DQB1*0602) suggests that narcolepsy could be an autoimmune disease. The observations of identical twins that are discordant for the disease (one has narcolepsy, the other one not) and of an increased frequency of narcolepsy after certain infections or types of influenza vaccinations suggest the potential role of environmental factors as triggers of the autoimmune process. However, the mechanisms involved in the loss of hypocretin neurons remained until today unknown.

The discovery

In this study, the IRB researchers used a sensitive method that they have developed in Bellinzona to interrogate the T lymphocyte repertoire of narcolepsy patients to identify, for the first time, T lymphocytes of the CD4 and, in some cases, of the CD8 type that react against hypocretin and against other proteins expressed in hypocretin neurons. These autoreactive lymphocytes can cause inflammation leading to neuronal damage or even kill hypocretin-producing neurons. They also identified the molecular interactions leading to hypocretin recognition and a possible mechanism by which the autoreactive T cells may have escaped tolerance.  Finally, in the patients studied, it was possible to exclude a role for the influenza virus in the induction of T lymphocytes reactive against hypocretin.


Publication details:

Daniela Latorre, Ulf Kallweit, Eric Armentani, Mathilde Foglierini, Federico Mele, Antonino Cassotta, Sandra Jovic, David Jarrossay, Johannes Mathis, Francesco Zellini, Burkhard Becher, Antonio Lanzavecchia, Ramin Khatami, Mauro Manconi, Mehdi Tafti, Claudio L. Bassetti, Federica Sallusto): T cells in patients with narcolepsy target self-antigens of hypocretin neurons. Nature, 19. September 2018,

Advance Online Publication (AOP) available at:


Source: IRB / Insel Gruppe AG