Genetic association, seasonal infections and autoimmune basis of narcolepsy

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.

Vaccination and Autoimmune Phenomena

“…This disorder is associated with a strong genetic predisposition, most commonly HLA DQB1*06:02, although other gene polymorphisms may also play a role (39). Antibodies to hypokretin, a protein known to participate in maintaining wakefulness, have been proposed as a potential causative mechanism.…”

Nasal vaccination using novel mucosal adjuvants : with main focus on influenza A virus

“…Streptococcal infection have also been associated with the onset of narcolepsy [228] and observed in China, the virus itself can cause narcolepsy [226]. It is hypothesized that a cross-reaction is occurring between H1N1-specific CD4+ T cells and an epitope presented on hypocretin-producing cells [229]. The T cells recognize the epitopes that lead to cytokine and chemokine release that will attract other immune cells that will damage the cells.…”

Animal Models of Narcolepsy

“…However, in most cases of human narcolepsy, onset of symptoms occurs during adolescence. Based on the late onset, as well as a strong association of human narcolepsy with certain HLA alleles (Kadotani et al 1998;Singh et al 2013), it has been thought that narcolepsy result from acquired, selective autoimmune degeneration of orexin neurons.…”