Genetic association, seasonal infections and autoimmune basis of narcolepsy

Abinav Kumar Singh, Josh Mahlios, Emmanuel Mignot

Research output: Contribution to journalArticle

59 Citations (Scopus)

Abstract

In recent years, a growing number of potential autoimmune disorders affecting neurons in the central nervous system have been identified, including narcolepsy. Narcolepsy is a lifelong sleep disorder characterized by excessive daytime sleepiness with irresistible sleep attacks, cataplexy (sudden bilateral loss of muscle tone), hypnagogic hallucinations, and abnormalities of Rapid Eye Movement sleep. Narcolepsy is generally a sporadic disorder and is caused by the loss of hypocretin (orexin)-producing neurons in the hypothalamus region of the brain. Studies have established that more than 90% of patients have a genetic association with HLA DQB1*06:02. Genome-wide association analysis shows a strong association between narcolepsy and polymorphisms in the TCRα locus and weaker associations within TNFSF4 (also called OX40L), Cathepsin H and the P2RY11-DNMT1 (purinergic receptor subtype P2Y11 to DNMT1, a DNA methytransferase) loci, suggesting an autoimmune basis. Mutations in DNMT1 have also been reported to cause narcolepsy in association with a complex neurological syndrome, suggesting the importance of DNA methylation in the pathology. More recently, narcolepsy was identified in association with seasonal streptococcus, H1N1 infections and following AS03-adjuvanted pH1N1 influenza vaccination in Northern Europe. Potential immunological pathways responsible for the loss of hypocretin producing neurons in these cases may be molecular mimicry or bystander activation. Specific autoantibodies or T cells cross-reactive with hypocretin neurons have not yet been identified, however, thus narcolepsy does not meet Witebsky's criteria for an autoimmune disease. As the brain is not an easily accessible organ, mechanisms of disease initiation and progression remain a challenge to researchers.

Original languageEnglish (US)
Pages (from-to)26-31
Number of pages6
JournalJournal of Autoimmunity
Volume43
DOIs
StatePublished - Jun 2013
Externally publishedYes

Fingerprint

Narcolepsy
Infection
Neurons
Sleep
Cathepsin H
Cataplexy
Molecular Mimicry
Purinergic Receptors
Genome-Wide Association Study
Hallucinations
REM Sleep
Brain
DNA Methylation
Streptococcus
Autoantibodies
Human Influenza
Hypothalamus
Autoimmune Diseases
Disease Progression
Vaccination

Keywords

  • Autoimmune
  • H1N1 infection
  • HLA association
  • Hypocretin
  • Narcolepsy

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

Cite this

Genetic association, seasonal infections and autoimmune basis of narcolepsy. / Singh, Abinav Kumar; Mahlios, Josh; Mignot, Emmanuel.

In: Journal of Autoimmunity, Vol. 43, 06.2013, p. 26-31.

Research output: Contribution to journalArticle

Singh, Abinav Kumar ; Mahlios, Josh ; Mignot, Emmanuel. / Genetic association, seasonal infections and autoimmune basis of narcolepsy. In: Journal of Autoimmunity. 2013 ; Vol. 43. pp. 26-31.
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