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Understanding the Narcolepsy/Autoimmune Relationship

Research gives new perspective on the root of this sleep disorder.

We’re witnessing some significant breakthroughs in our understanding of the sleep disorder narcolepsy. Two new studies, conducted independently, provide strong evidence for what’s long been suspected: that narcolepsy is an autoimmune disorder, triggered by a mistaken response of the body’s defense system and strongly influenced by a particular variation of an immune-system gene. 

Narcolepsy is a neurological disorder, stemming from the brain’s inability to regulate periods of sleep and wakefulness. Studies have indicated that narcolepsy’s neurological dysfunction likely stems from a lack of hypocretin, a protein that works as a neuropeptide in the brain to stimulate wakefulness, and helps to govern the sleep-wake cycle. But the cause of this deficiency in hypocretin, and of narcolepsy itself, has remained unknown. Science has in recent years pointed to an immune system dysfunction as a trigger. And a growing body of research also has provided evidence of a strong genetic component to narcolepsy. The latest results into the origins of narcolepsy in the brain provide significant new information on both fronts. The findings of one study are compelling enough to essentially confirm narcolepsy as an autoimmune disorder. The other study pinpoints a specific, immune-related genetic variation as a near-certain prerequisite for the condition. 

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Researchers at Stanford University School of Medicine conducted a study of immune system T-cell activity in people with narcolepsy. Their subjects included volunteers who showed a genetic predisposition to the disease. Based on earlier research that established the role of hypocretin deficiency and gave strong indications of immune system dysfunction, they investigated the response of T-cells to hypocretin in patients with narcolepsy and in healthy control subjects. 

Researchers made a number of important discoveries. They found that in their patients with narcolepsy, hypocretin-producing neurons stimulated a T-cell immune response that did not occur in patients without narcolepsy. Autoimmune disorders occur when the body’s immune system misinterprets the body’s own healthy tissue as something potentially harmful. The immune system then goes into attack mode, destroying the healthy cells as though they were a threat to the body’s system, such as a virus, bacteria, or a toxin. In this study, the immune systems of narcolepsy patients reacted to hypocretin-producing neurons as though they were a threat, rather than the producers of an essential neurotransmitter. 

Researchers also discovered that a portion of the hypocretin protein bears a strong resemblance to the protein found in the H1N1 strain of influenza virus that was widespread in 2009 and was commonly known as “swine flu.” Vaccinations at the time of the 2009 H1N1 pandemic were later associated with a spike in cases of narcolepsy among populations that had been given the vaccine. The H1N1 vaccine was used widely in Europe during 2009-2010. It was never used in the United States and has not been used anywhere since the 2009-2010 flu season. This connection between H1N1 virus and narcolepsy spurred the Stanford researchers to examine whether the immune systems of people with narcolepsy might attack and destroy the neurons that produce hypocretin because of its similarity to the H1N1 virus. To test this thesis, researchers exposed T-cells from these patients to the H1N1 protein. They found that indeed, exposure to H1N1 caused a spike in T-cells targeting hypocretin-producing neurons. Researchers also found evidence that other similar viruses may also lead the immune system to attack the source of hypocretin in the body, in people who are genetically predisposed. 

That genetic predisposition is the subject of the other recent study, conducted by scientists at the Center for Integrative Genomics at Switzerland’s University of Lausanne. Researchers there investigated the link between narcolepsy and a variation of a gene that is involved in immune system function. The genetic variant is located within the human leukocyte antigen (HLA) system. This system plays a pivotal role in the immune system’s ability to accurately distinguish friend from foe, targeting potentially dangerous antigens and leaving healthy, normal tissue alone. Their study included 1,261 patients with narcolepsy and a control group of 1,422 people without the disorder. Researchers used highly precise genotyping to identify each participant’s individual genetic variations. The HLA system includes several already known genetic variants. Researchers found that people with a particular HLA variant were 251 times as likely to have narcolepsy as people without this particular variation. Among the participants with narcolepsy, nearly 100% had this gene variation. They also discovered four other HLA gene variations that appeared to have a protective effect against narcolepsy. The gene variant that is so strongly associated with narcolepsy is not especially rare—the scientists estimate that approximately 20% of the population of Europe has the variation. It is important to emphasize that not everyone who possesses this genetic variation will get narcolepsy. But because nearly everyone who develops narcolepsy appears to have this variant, this population is at higher risk. This information could be critical to identifying those at-risk individuals and to reducing the chance of misdiagnosis. 

While less common than many other sleep disorders, narcolepsy is less rare than most people believe it to be. The disorder is estimated by federal health officials to affect approximately 1 in 3,000 people in the United States. Its symptoms often begin in childhood or young adulthood but also can occur in older adults. Because of its highly disruptive and difficult symptoms, narcolepsy is a disorder that can often be highly debilitating, affecting normal daily functioning and relationships. People who suffer from narcolepsy experience extreme daytime tiredness, along with episodes of uncontrollable urges to sleep that often result in sudden and jarring “sleep attacks.” Many people with narcolepsy experience a symptom known as cataplexy, a sudden onset of muscle weakness that makes it difficult or even impossible for people to move. Other symptoms of narcolepsy include extremely poor nighttime sleep with frequent awakenings, intense dreams and hallucinations, and episodes of paralysis right before falling asleep and just after waking. 

Both of these studies offer compelling new information about the root causes and mechanisms of this very serious disorder. They also offer the promise of swifter and more accurate diagnoses, and of improvements to treatment. For people who suffer the often devastating effects of narcolepsy, those improvements can’t come quickly enough. 

Sweet Dreams, 

Michael J. Breus, Ph.D.

The Sleep Doctor™

www.thesleepdoctor.com

 

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Michael J. Breus, Ph.D., is a Clinical Psychologist and a Diplomate of the American Board of Sleep Medicine. He is the author of Beauty Sleep.

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