What Causes Narcolepsy? Scientists Say It's an Autoimmune Disease

For the estimated 200,000 Americans with narcolepsy, sleep is an unpredictable part of life. While the condition affects people differently, it can involve uneven slumber, sleep paralysis, and unintentionally falling asleep in the middle of activities like talking or driving. Now, a new discovery means scientists are one step closer to creating treatments that can even out that unpredictability.

Last year, scientists began to suspect narcolepsy is an autoimmune disease, and on Friday a team of Danish scientists presented further proof that this is true. Writing in Nature Communications, they reveal that autoreactive cytotoxic CD8 T cells were found in the blood of narcolepsy patients. These are the cells that recognize neurons and produce hypocretin, which regulates a person’s waking state.

Autoreactive T cells are known to drive autoimmunity and contribute to the dysregulation of the immune system, leading to neurological disorders .The existence of these cells doesn’t show that they are killing neurons, but it certainly suggests that they are. Cytotoxic means that cells are capable of killing other cells — and in most narcolepsy patients, the neurons that produce hypocretin have been destroyed.

“To kill other cells, neurons producing hypocretin, CD4 and CD8 T cells usually have to work together,” co-author and University of Copenhagen neuroscience professor Birgitte Rahbek Kronum, Ph.D., explained Friday.

In 2018, scientists discovered autoreactive CD4 T cells in narcolepsy patients. Kronum says that “this was really the first proof that narcolepsy is, in fact, an autoimmune disease,” and “now we have provided more, important proof: that CD8 T cells are autoreactive too.”

Importantly, this study is specific to only one of the two types of narcolepsy. In type 1, the most common form, people lack hypocretin and suffer from cataplexy, which is a brief loss of muscle control. That’s what we’re talking about here. In type 2, patients experience the same narcoleptic symptoms but do not lack hypocretin.

For the study, 20 people with narcolepsy type 1 and 52 healthy people donated blood samples for Kronum’s team to analyze. Each of the 20 narcolepsy participants had autoreactive CD8 T cells in their blood.

But strangely enough, they found autoreactive cells in the healthy participants as well. The likely difference between the two groups, the scientists explain, is that the autoreactive cells in the healthy participants have not been activated. An integral component of autoimmune diseases is that autoimmunity lies dormant in most, if not all, people. What scientists don’t know is how these cells get activated and cause a disease to take root.

When it comes to narcolepsy, experts still aren’t sure what lies at the root of the disease: Scientists theorize that a combination of genetics and autoreactive cells trigger it, and that lower levels of the chemical hypocretin are found in the bodies of nearly all people with narcolepsy. While some treatments are available, including medications like modafinil and antidepressants, the team behind this latest study hopes its research can help pave the way for better treatments.

“Now there will probably be more focus on trying to treat narcolepsy with drugs allaying the immune system,” Kronum predicts. “This has already been attempted, though, because the hypothesis that it is an autoimmune disease has existed for many years. But now that we know that it is T cell-driven, we can begin to target and make immune treatments more effective and precise.”

Effective and precise treatments could change the lives of people who live with narcolepsy, which is a lifelong condition. Symptoms can partially improve over time but, without aid, never disappear entirely.

Abstract:

Narcolepsy Type 1 (NT1) is a neurological sleep disorder, characterized by the loss of hypocretin/orexin signaling in the brain. Genetic, epidemiological and experimental data support the hypothesis that NT1 is a T-cell-mediated autoimmune disease targeting the hypocretin producing neurons. While autoreactive CD4+ T cells have been detected in patients, CD8+ T cells have only been examined to a minor extent. Here we detect CD8+ T cells specific toward narcolepsy-relevant peptides presented primarily by NT1-associated HLA types in the blood of 20 patients with NT1 as well as in 52 healthy controls, using peptide-MHC-I multimers labeled with DNA barcodes. In healthy controls carrying the disease-predisposing HLA-DQB1*06:02 allele, the frequency of autoreactive CD8+ T cells was lower as compared with both NT1 patients and HLA-DQB1*06:02-negative healthy individuals. These findings suggest that a certain level of CD8+ T-cell reactivity combined with HLA-DQB1*06:02 expression is important for NT1 development.