New Proof Narcolepsy is Autoimmune

Researchers at the University of Copenhagen have found autoreactive cells in people who suffer from narcolepsy. This is an important breakthrough that proves narcolepsy is indeed an autoimmune disease. For years doctors have suspected that narcolepsy had some connection between the area that controls wakefulness and the autoimmune system. They have found cytotoxic CD8 T-cells in the blood of narcoleptics. At this point, they know that the immune cells of the patient's body sees normal cells in the body as invaders and attacks them. This results in them having narcolepsy. Researchers have found a combination of genetics, autoimmune cells, and some type of trigger (like a virus) that then leads to this disease.

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Narcolepsy was first identified by Westphall in 1877 and the term was coined by Gélineáu in 1880 and is a chronic neurological sleep disorder that manifests as difficulty in maintaining wakefulness and sleep for long periods. Currently, narcolepsy is subdivided into two types according to the International Classification of Sleep Disorder; NT1 and NT2. Type 1 is characterized by excessive daytime sleepiness, cataplexy, hypnogogic hallucinations, and sleep paralysis. It is caused by a marked reduction in neurons in the hypothalamus and that produces orexin which is a wakefulness-associated neuropeptide. Except for the cataplexy, type 2 exhibits most of the same symptoms as NT1, NT2 is also a complex disorder but the underlying genetic architecture is poorly understood. Narcolepsy has no known cure but there are a few treatments available to help manage the symptoms. And although healthy individuals enter their first REM sleep after 90 minutes, narcoleptic individuals go directly to REM once they are asleep. Recent advances in next-generation sequencing technologies have had a strong impact on human genetics. The study, as a result, feels the future genomic research will provide important contributions to the understanding of the genetic basis and pathogenesis of narcolepsy (Miyagawa & Tokunaga, 2019).

Excessive daytime sleepiness (EDS) is a common complaint that brings people to be tested for narcolepsy. Narcolepsy is a sleep disorder characterized by EDS and involves a substantial burden of illness; often overlooked or misdiagnosed. In hospital polysomnograph (PSG) also known as a sleep study, is the major diagnostic tool of determining obstructive sleep apnea (OSA) as well as other sleep disorders. However, use of home sleep apnea (HSAT) testing to screen for OSA has started to increase in popularity partly because of its lower costs, lower technical complexity, and greater convenience as opposed to the overnight stay for PSG and the EEG that is included to screen for other sleep disorders like narcolepsy. Some of the other disorders that need PSG include Kleine-Levin syndrome, epilepsy, circadian rhythm sleep disorder, movement disorders (like restless leg syndrome) or CNS tumors. And while OSA and narcolepsy share many similarities, many with OSA don’t complain of ESD where narcoleptics, both type one and two, do. NT1 is defined as ESD that has been present ≥ three months with a PSG indicating an average of sleep onset latency ≤ eight minutes on multiple sleep latency testing (MSLT) following a nocturnal PSG negative for any comorbid sleep disorders. NT2 includes EDS≥ three months, positive PSG/MSLT results and normal or decreased CSF hypocretin/orexin levels. American Academy of Sleep Medicine (AASM) guidelines state that PSG should be used for evaluation of OSA in patients with the other symptoms. There is evidence that when narcolepsy and OSA occur at the same time use of CPAP is a useful tool to help both causes of daytime sleepiness (Rosenberg et al, 2019).

New possible causes of narcolepsy
The incidence of narcolepsy rose sharply after the swine influenza A H1N1 vaccination campaign. Narcolepsy is an immune-related disorder with excessive daytime sleepiness. There was found a novel connection between Pandemrix-induced narcolepsy and a change in regulating GDNF; associated with other neurodegenerative diseases. This study confirmed a strong association between HLA-DQB1*06:02 type and Pandemrix-associated narcolepsy. The study estimated that the risk of narcolepsy after vaccination with Pandemrix was 49-fold greater in people carrying HLA-DQB1*06:02 type. Approximately 93% of patients who were carriers of this HLA type had narcolepsy. In addition, there was a novel association between Pandemrix-associated narcolepsy and gene GDNF-AS1. Changes to this gene regulation have been associated with neurodegeneration disorders such as Alzheimer’s and Parkinson’s. The authors of the study have speculated that the genetic variants leading to a decrease in GDNF expression may increase the risk of narcolepsy through impaired neuronal survival in predisposed patients (Hallberg et al, 2019).

Excessive daytime sleepiness (ESD) and cataplexy (An emotionally-induced muscle atonia that manifests as limb, head, or facial weakness) are common in narcolepsy. Only a few drugs have met approval for narcolepsy treatment. Clinical trials have demonstrated the efficacy of classes of drugs from medicine to help with alertness, antidepressants, and H₃ receptor inverse agonist/antagonist pitolisant and many others. Narcolepsy has two types one with cataplexy and one without. In NT-2 a narcoleptic subtype is unclear but may be due to moderate Hcrt neuron loss or insufficient release of Hcrt neuropeptides without a detectable reduction in CSF Hcrt levels. Only 18% of patients with narcolepsy receive a correct diagnosis within one year of symptom onset. Multiple lines of evidence suggest that cataplexy and REM sleep paralysis share a common circuit involving medial prefrontal cortex ad amygdale pathways to the Pons, resulting in decreased suppression of REM sleep secondary to Hcrt deficiency. Narcolepsy is considered to affect individuals with a genetic susceptibility that predisposes to immune system activation when they are exposed to a yet unknown environmental stimulus. And while narcolepsy type 1 is caused by neurodegeneration of Hcrt cells, how this and the genetic component are factored together is unknown. CD4+ T-cells that recognized Hcrt did not react to influenza antigens. There has been an increased incidence of narcolepsy associated H1N1 virus. During the most recent pandemic (2008-2009), narcolepsy was noted to have a six to nine-fold increase in new patients after being given Pandemrix H1N1 vaccination. NT2 underlying neural circuits have remained elusive. Amphetamines are the drug of choice since the 1930s to combat the problem of EDS. Now, however, medicines like Adderall and Dexedrine are widely used to combat this issue (Szabo et al, 2019).

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Conclusion
Narcolepsy Type 1 is a neurological sleep disorder characterized by the loss of hypocretin/orexin signaling in the brain. Genetic and experimental data support the hypothesis that NT1 is a T-cell mediated autoimmune disease targeting the hypocretin-producing neurons. And while CD4+ T-cells have been detected in patients, CD8+ T-cells have only been looked at to a minor extent. Recent studies suggest there is a connection between HLA-DQB1*06.02 allele and auto-reactive CD8+ T-cells. Following the recent H1N1 influenza vaccination campaign with Pandemrix, as well as after the H1N1 epidemic itself, the cases of narcolepsy incidence increased dramatically in several countries. This result helps to substantiate the connection between the immune system and NT1 development. This study was able to map locations of possible NT1-related T-cell recognition observed in both patients and healthy controls (without narcolepsy). In studying NT1 peptide has revealed a difference only evident in two transcription factors indicating these may be important targets for disease development. Autoreactive CD4+ T-cells have so far almost exclusively been detected in NT1 patients and not healthy controls (Pederson et al, 2019).

Work Cited
Hallberg, P. et al. (2019). Pandemrix-induced narcolepsy is associated with genes related to immunity and neuronal survival. EBioMedicine, 40 (2019).

Miyagawa,T & Tokunaga, K. (2019). Genetics of Narcolepsy. Human Genome Variation, 6(4).

Pedersen, N.W. et al. (2019). CD8+ T-cells from patients with narcolepsy and healthy controls recognize hypocretin neuron-specific antigens. Nature Communications, 10(837).

Rosenberg, et al. (2019). The role of home sleep testing for evaluation of patients with excessive daytime sleepiness: Focus on OSA and narcolepsy. Sleep Medicine.

Szabo, ST. et al. (2019). Neurobiological and immunogenetic aspects of narcolepsy: Implications for pharmacotherapy. Sleep Medicine Review, 43 (2/2019).

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