Narcolepsy may be an autoimmune disease

Editor’s note: The research paper described in this story was retracted on July 30, 2014, after the authors were unable to replicate one of their main results.

Narcolepsy occurs when wayward immune forces launch an attack on brain cells responsible for wakefulness, a new study suggests. In a case of mistaken identity, immune cells that target a protein fragment from a microbial invader also on rare occasions ravage neurons that produce a similar protein fragment, or peptide, researchers report.

The victims of this cross fire are neurons that make a peptide called orexin, a neurotransmitter that is crucial for staying awake. The researchers say this could explain the lack of orexin neurons in people with narcolepsy, as shown previously in patient autopsies. A lack of orexin, also called hypocretin, leaves a person with disordered sleep, daytime drowsiness and the risk of nodding off abruptly — the hallmarks of narcolepsy.

The new findings along with previous work indicate that narcolepsy needs three conditions to occur. A person must harbor an immune system gene variation that shows up in about one-fourth of people but in 98 percent of narcolepsy patients. Second, the individual needs to encounter a pathogen in the environment that elicits an immune reaction against a foreign peptide that resembles orexin. Finally, the immune system must then destroy the brain’s orexin-making neurons.

It remains unclear precisely how the immune system kills the neurons. But immunologist Elizabeth Mellins of the Stanford University School of Medicine says the new findings point to narcolepsy as an autoimmune disease.

Evidence of an immune connection arose in 2009 when Stanford researchers reported that narcolepsy patients are more likely than other people to carry certain genetic variants related to immunity in addition to the well-known, common variant. Now the team has discovered an environmental trigger to go with these genetic hints. Writing in the Dec. 18 Science Translational Medicine, they show that a peptide on the H1N1 flu virus that caused a pandemic in 2009 can elicit an immune reaction that hits orexin neurons.

Mellins and others had noticed a spate of narcolepsy in China in 2010 in the wake of the H1N1 flu pandemic. There were also reports of narcolepsy in Northern Europe tied to a vaccine called Pandemrix that contained protein fragments from the H1N1 flu virus and special booster ingredients. About 31 million Europeans received the vaccine, and about 1 in 15,000 developed narcolepsy. That’s far higher than narcolepsy’s usual rate of less than 1 per 100,000 per year in Finland, where the link was first noted, says study coauthor Emmanuel Mignot, a Stanford sleep researcher. The vaccine, never given in the United States, is no longer in use, Mignot says.

Mignot, Mellins and colleagues screened H1N1 flu virus proteins and found a peptide in them that mimics the shape of orexin. They also tested in a lab dish immune cells called T cells from narcolepsy patients, most of whom hadn’t gotten the vaccine, and found the cells reacted potently to orexin, whereas T cells from healthy people didn’t. In another test, the researchers examined blood samples from four pairs of identical twins, each with one twin who had narcolepsy. These narcolepsy patients’ T cells also reacted to orexin; their healthy twins’ cells didn’t.

Something in the environment must have influenced the reactivity of T cells in the narcolepsy patients, says Mellins. “Most likely that explains why one twin was unlucky.”

A separate test of blood from 17 Irish children who had gotten the Pandemrix vaccine showed that those who developed narcolepsy later had T cells that reacted strongly to orexin, while T cells from their vaccinated siblings who didn’t’ develop narcolepsy were nonreactive.

“The T cell findings really provide one of the most robust clues we have that there is an autoimmune mechanism here,” says sleep researcher Thomas Scammell, a neurologist at Harvard Medical School. “Orexin neurons’ death is like a murder mystery. We didn’t know who did it or why it happened.” In the new report, he says, the immune reaction sheds light on why.

There could be a range of triggers in the environment tripping this reaction, Mellins says. She surmises that, in addition to the flu peptide, streptococcus or other pathogens might play a role.

Scammell offers a cautionary footnote. The H1N1 pandemic has passed. “This is sort of a postmortem on a failed vaccine,” he says. He recommends getting vaccinated.

The new findings also pose a parallel between narcolepsy and type 1 diabetes, an autoimmune disease in which a rogue immune attack kills off cells in the pancreas that make the hormone insulin. In type 1 diabetes, symptoms show up before all the cells are destroyed, a “honeymoon period” that may offer a chance for doctors to intervene, Mellins says. Scientists are guardedly optimistic regarding experimental treatments. A similar approach might someday be applied in narcolepsy, she says, if the condition can be caught early.  

Editor’s Note: This story was updated January 6, 2014, to correct the percentage of narcolepsy patients that carry the genetic mutation and to correct the attribution of the 2009 study.