Narcolepsy, scientists unmask the culprit of an enigmatic disease
Patients with narcolepsy suffer of excessive daytime sleepiness and brief episodes of loss of muscle tone triggered by emotions. A study published in Nature reports the existence in patients with narcolepsy of autoreactive T lymphocytes that recognize hypocretin and can mediate an immune response leading to loss of hypocretin-producing neurons.
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.
This 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 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.
external page Department of Neurology, at Inselspital, Bern University Hospital
(This text is based on a media release by Inselspital, Bern University Hospital)
The paper
«T cells in patients with narcolepsy target self-antigens of hypocretin neurons» (authors: 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)
Link to the paper in external page "Nature"