Scientists have once again found proof that narcolepsy, a lifelong neurological sleep disorder, is actually an autoimmune disease. It's something that experts have suspected for many years, but only recently has there been any real evidence.
The first missing link came last year, when scientists noticed the presence of autoimmune cells in blood samples from narcolepsy patients. These autoreactive cells, called CD4 T cells, were targeting the body's own healthy neurons in the hypothalamus - the same ones that produce hypocretin (aka orexin), a protein that regulates wakefulness.
At the time, this was considered the first real proof that narcolepsy was, at its roots, an autoimmune disease. Before that, it was widely acknowledged that narcolepsy patients lacked hypocretin and that they also shared genes with other autoimmune patients.
But for all that, there was no clear biological cause. Now, half a year later, scientists have caught two culprits - and, like Bonnie and Clyde, they're more destructive together.
"To kill other cells... CD4 and CD8 T cells usually have to work together," says Birgitte Rahbek Kornum, a neuroscientist at the University of Copenhagen.
"In 2018, scientists discovered autoreactive CD4 T cells in narcolepsy patients... Now we have provided more, important proof: that CD8 T cells are autoreactive too."
Analysing the blood samples from 20 patients with narcolepsy, the new research found CD8 T cells in much higher number than in the 52 healthy controls. In fact, nearly all patients with narcolepsy showed the presence of CD8 T cells.
Plus, while it's true that some healthy individuals also had autoreactive cells, the authors say the were just lying dormant, waiting for a trigger to set them off.
"We have found autoreactive cytotoxic CD8 T cells in the blood of narcolepsy patients," explains Rahbek Kornum.
"That is, the cells recognise 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."
Scientists aren't really sure what causes narcolepsy - a disorder marked by excessive daytime sleepiness - but many suspect it is a combination of genetics and an environmental trigger for autoreactive cells. When triggered, the latter can throw the immune system out of whack, causing it to attack healthy tissue.
The trigger can be something as simple as the influenza virus or even the vaccination. Recently, in fact, CD4 T cells were found to react with the H1N1 influenza strain from 2009 and 2010. This was the year of the swine flu, and afterwards, researchers noticed a three-fold increase in the incidence of narcolepsy in China.
But while CD4 T cells can infiltrate the brain and cause inflammation, the authors think this is only what starts the process of narcolepsy. In the end, only CD8 T cells are cytotoxic, meaning they can actually kill the hypocretin-producing neurons.
"Thus, even though autoreactive CD4 T cells might initiate the disease process," the authors explain, "we hypothesise that the presence of autoreactive CD8 T cells could be necessary for the development of genuine [narcolepsy]."
This isn't to say that CD8 T cells are more important. In fact, the authors think they might even depend upon CD4 T cells to function properly.
Obviously, there is still a ton of research that needs to be done before we can truly understand this debilitating condition. But with brand new targets for treatment, the new research could have an immense impact.
"Now there will probably be more focus on trying to treat narcolepsy with drugs allaying the immune system," says Rahbek Kornum.
"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."
This study has been published in Nature Communications.