Speaker

Emmanuel Mignot, Stanford University, USA

Emmanuel Mignot

Emmanuel Mignot, MD, PhD is the Craig Reynolds Professor of Psychiatry and Behavioral Sciences at Stanford University and the Director of the Stanford Center for Sleep Sciences and Medicine.  He discovered that narcolepsy, affecting 1/2000 people, is caused by an immune-mediated destruction of 70,000 hypocretin/orexin neurons in the hypothalamus, also revealing hypocretins as a novel critical sleep-regulatory pathway. Most of his current research focuses on the neurobiology, genetics and immunology of narcolepsy, with indirect interest in the neuroimmunology of other brain disorders.  His laboratory uses state of the art human genetics techniques, such as genome wide association, exome or whole genome sequencing in the study of human sleep and sleep disorders, with parallel studies in animal models.  His laboratory is also interested in web-based assessments of sleep disorders, computer-based processing of polysomnography (PSG), and outcome research.


Presentation abstract

The genetics of narcolepsy: immune and viral mechanisms

Professor Emmanuel Mignot, MD, PhD
Stanford University Center For Sleep Sciences and Medicine, School of Medicine, 3165 Porter Drive, Palo Alto CA 94304; Phone: +1(650) 7256517; email: mignot@stanford.edu

Narcolepsy is a neurological disorder characterised by excessive daytime sleepiness, cataplexy, hypnagogic hallucinations, sleep paralysis, and disturbed nocturnal sleep patterns. Narcolepsy is caused by the loss of hypocretin (orexin)-producing neurons in the lateral hypothalamus. Genetic evidence, such as a strong (97%) association with the HLA-DQB1*06:02 allele suggests an autoimmune origin of this disease, involving mechanisms that target hypocretin neurons. A spike in cases of narcolepsy occurred in 2010 following the H1N1 influenza pandemic (pH1N1) in China and vaccination with an adjuvanted H1N1 vaccine, that had been previously used in Europe. Findings from genome-wide association studies, have confirmed the association between narcolepsy and polymorphisms in genes involved in immunity modulation, and are starting to reveal disease mechanisms. Specifically, we found significant associations of narcolepsy with HLA (two GWA-significant subloci) and 11 other immune loci (TRA, TRB, CTSH, IFNAR1, ZNF365, P2RY11,PRF1, CD207, SIRPG, IL27 and ZFAND2A). Effects in CTSH, PRF1, CD207, SIRPG, and IL27 are likely mediated through aminoacid changes, with functional effects on antigen presentation or processing and subsequent T-cell responses. The genetic association of narcolepsy with T cell receptor TRA and TRB loci co-localises with cis-regulatory elements of TRAJ*24 and TRAJ*28 usage for the TCRA locus, and of TRBV*4-2 usage for the TRB locus. The functional effects of IFNAR1-associated polymorphisms can increase the response to influenza-A infection in dendritic cells, but are not genetically associated with post-vaccination narcolepsy cases, suggesting effects via viral infection. Studies of partitioned heritability in narcolepsy indicate enrichment of functional elements that are active specifically in T cells. Finally, DQ0602 tetramer studies with influenza and auto-antigen epitopes are now revealing cross reactivity that might explain genetic effects that lead to the specific elimination of hypocretin-producing neurons. Together, these findings suggest that narcolepsy is a T-cell mediated autoimmune disease, and that influenza-A can be a trigger of this disease.

Funding: This study is being funded by donations from patients, the patient organization Wake Up Narcolepsy, and a gift from Jazz Pharmaceuticals. Jazz Pharmeceutical is the maker of XYREM, a narcolepsy treatment. Some of the data and samples generated by the study have been gathered thanks to prior NIH funding that ended 2 years ago.

Conflict of interest: None

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