For centuries, it was thought that individuals who displayed excessive sleepiness, were just not getting the appropriate amount of rest and lifestyle changes were needed to combat these scenarios. Early in the 20th century, physicians and scientists began to realize that some patients who were suffering from excessive tiredness had shared symptomology that was unique to their condition. As such, the diagnosis of narcolepsy began to become prevalent for this disorder and researchers began to look for the molecular mechanisms behind the symptoms.
While evidence of a neurotransmitter deficiency—hypocretin—was seen in certain populations diagnosed with narcolepsy, others lacked the deficiency and the associated cataplexy—sudden and uncontrollable muscle weakness or paralysis—that comes with it. While hunting for more molecular causes, scientists had suspected narcolepsy of being an autoimmune disease, though without being able to prove it conclusively.
Now, investigators at the University of Copenhagen, the Technical University of Denmark, and Rigshospitalet Hospital in Denmark, have discovered autoreactive cells in persons suffering from narcolepsy. This is new, important proof that the sleep disorder is an autoimmune disease. Findings from the new study—published recently in Nature Communications through an article entitled “CD8+ T cells from patients with narcolepsy and healthy controls recognize hypocretin neuron-specific antigens”—may lead to better treatment of the chronic condition.
“We have found autoreactive cytotoxic CD8 T cells in the blood of narcolepsy patients,” explained senior study investigator Birgitte Rahbek Kornum, PhD, associate professor in the department of neuroscience at the University of Denmark. “That is, the cells recognize the neurons that produce hypocretin which regulates a person’s waking state. It does not prove that they are the ones that killed the neurons, but it is an important step forward. Now we know what the cells are after.”
The immune system is designed to recognize viruses and bacteria. When its cells are autoreactive—which is the case in autoimmune diseases—the immune system recognizes the body’s own cells and attacks them. That they are cytotoxic means they can kill other cells. In most narcolepsy patients, the neurons that produce hypocretin and thus regulate our waking state have been destroyed.
“To kill other cells, e.g., neurons producing hypocretin, CD4 and CD8 T cells usually have to work together,” Rahbek Kornum stated. “In 2018, scientists discovered autoreactive CD4 T cells in narcolepsy patients. This was really the first proof that narcolepsy is, in fact, an autoimmune disease. Now we have provided more, important proof: that CD8 T cells are autoreactive too.”
In the current study, the researchers studied and analyzed blood samples from 20 individuals with narcolepsy. Moreover, the team analyzed blood samples from a control group of 52 healthy persons. In nearly all 20 narcolepsy patients the researchers found autoreactive CD8+ T cells. But autoreactivity was not only found in persons suffering from the sleep disorder. The researchers also discovered autoreactive cells in a lot of healthy individuals.
“We also found autoreactive cells in some of the healthy individuals, but here the cells probably have not been activated. It is something we see more and more often with autoimmunity—that it lies dormant in all of us but is not activated in everyone. The next big puzzle is learning what activates them,” noted Rahbek Kornum.
The discovery of autoreactive cells in healthy individuals also stresses the theory that something has to trigger narcolepsy and activate autoreactivity. Scientists still do not know what causes the disease. They expect a combination of genetics, autoreactive cells, and a form of trigger to bring about the disease, e.g., a virus infection. The disease can be treated medically today, but the new research results may pave the way for even better treatments.
“Now there will probably be more focus on trying to treat narcolepsy with drugs allaying the immune system,” Rahbek Kornum concluded. “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 even more effective and precise.”