Researchers at the Netherlands Institute for Neuroscience have found evidence that type-1 narcolepsy, a condition known for its 'sleep attacks', is caused by the body's own immune system.
Narcolepsy is a chronic condition in which someone feels excessively sleepy, occasionally falling asleep without warning. This can have a major impact on their daily lives, affecting not only their education and employment, but also their ability to drive, their relationships, and their emotional health. "It's quite striking when you're talking to a narcoleptic patient. If you make a joke, they collapse immediately", Ling Shan, first author and researcher in the Swaab group, explains.
For over two decades, experts have known that narcolepsy is caused by the reduction of a brain chemical known as hypocretin. Hypocretin helps regulate wakefulness and sleep and is released throughout the brain by a small cluster of cells in the brain's hormone centres. But how or why it is reduced was, up until now, never officially confirmed.
Shan explains the mystery: "There are so many hints that narcolepsy is caused by the body's own immune system; it has been associated with other autoimmune diseases, there is a strong genetic link, and it can be triggered by influenza".
Because the disease onset was tied to environmental factors decades ago, and the cells expressing hypocretin reside deep in the human brain, it has been difficult for researchers to find conclusive evidence that narcolepsy is, in fact, an autoimmune disorder.
But with samples from deceased brain donors from the Netherlands Brain Bank, Shan was finally able to take a look inside the narcoleptic brain. This allowed him to confirm that body's own immune system is responsible for the loss of cells that release hypocretin.
Immune cells in the brain
Shan's research focused on T-cells. These are immune cells that fight infections and can remain in the tissue throughout someone's lifetime. If the infection ever returns, the T-cells can immediately recognise the threat and kill the infection. This feature means that Shan could look for the same T-cells that had once destroyed the important hypocretin cells in the narcoleptic brain, even if it had happened decades earlier.
Since there are different kinds of T-cells, Shan searched for a specific type known as CD4 T-cells. These are responsible for coordinating immune reactions and point towards a chronic autoimmune response. These specific CD4 T-cells were eleven-times higher in the region when compared to other types of T-cells.
Upon having a closer look, Shan found that the heightened number of CD4 T-cells also expressed specific features. These features gave them the ability to infiltrate the area and specifically target the cells that expressed hypocretin. "After such a long time we finally have conclusive evidence that narcolepsy type 1 is a result of the body's own immune system", Shan exclaims.
More than semantics
Whether narcolepsy is an autoimmune disease is incredibly important because it can steer research in the right direction. Current medication for narcolepsy only combats its symptoms. But there is still no cure.
"Researchers in this field are rushing into this as well", Shan explains. "If we find a way to block this immune activity before it starts, we could potentially prevent narcolepsy from the beginning".
This work was in collaboration with Dr. Rolf Fronczek from LUMC and Dr. Joost Smolders from NIN neuroimmunology group and Erasmus UMC.
Source: Annals of Neurology
https://onlinelibrary.wiley.com/doi/10.1002/ana.78199
The search for more participants and donors
People with narcolepsy are valuable research participants, not only as brain donors, but also for sleep research. Normally, sleep research relies on participants who can spend an entire night at the lab. Whether the participants will be able to fall asleep long enough to enter REM sleep is also not always a given.
