Narcolepsy affects about one in 2,000 people and is characterized by daytime drowsiness, irregular sleep at night and cataplexy — a sudden loss of muscle tone and strength. Stanford University School of Medicine scientist Emmanuel Mignot, MD, PhD, and others showed in the late 1990s that the disease stems from a lack of hypocretin, a hormone that promotes wakefulness; they later showed that narcoleptics are missing brain cells that produce this hormone.

 Now Mignot and collaborators say that a specific immune cell is involved in the disorder — adding evidence that narcolepsy may be an autoimmune disease.

The work, published in Nature Genetics, could lead to better treatments for the sleep disorder and help immunologists understand other, more common autoimmune diseases, such as multiple sclerosis and juvenile diabetes.

"We're now getting the main pieces of what's happening in narcolepsy," said Mignot, a Howard Hughes Medical Institute investigator who has been studying the disease for more than two decades. "What's most satisfying to me is that we're bringing this story to a close and that we can use narcolepsy as a model for other diseases."

Mignot and others believe that the body's immune system plays a role in killing hypocretin-making cells, primarily because of scientific literature showing a link between narcolepsy and a variant for the human leukocyte antigen, or HLA, gene. The immune system uses HLAs to differentiate between "self" cells and foreign cells (and attacks those presented as foreign), and most autoimmune diseases are associated with variants of HLA. In recent studies, more than 90 percent of narcolepsy patients were shown to carry one such variant.

"For a long time, people have suspected narcolepsy had something to do with the immune system — that it was killing cells that produce hypocretin," said Mignot, a professor of psychiatry and behavioral sciences and director of Stanford's Center for Narcolepsy. "But there hasn't been direct proof."

During this study, the researchers ran whole-genome scans — which allow for the analysis of hundreds of thousands of genetic variations — of 1,800 people carrying the same HLA gene variant. Of the group, 800 had narcolepsy, and the goal was to find what differentiated these people from control subjects. The team found that a specific variation of a gene belonging to T cells — specialized immune cells that play a role in all immune responses — was present in narcolepsy.

Because T cells are involved, Mignot believes the mechanism behind narcolepsy stems from the immune system. "Our discovery clearly shows narcolepsy is an autoimmune disease," he said.

"This is a very important finding," said Merrill Mitler, PhD, a sleep disorders expert and program director at the National Institute of Neurological Disorders and Stroke, who was not involved in the study. "It puts in place another piece of the puzzle and shows a way to link [this gene variant] to hypocretin-containing neurons via an autoimmune attack."

Mignot said it's likely that HLA and this T cell variant interact in a way that kills hypocretin cells. How exactly this interaction is triggered is not yet known, and he said future studies will focus on solving this mystery. Once more details emerge, he said, scientists may be able to identify people who are predisposed to narcolepsy and block specific gene variants in that person to stop the development of the disease.

In the meantime, Mignot expects the findings to aid researchers studying other autoimmune diseases. No other autoimmune disease has shown an association with this specific T cell gene, he noted.

"I'm sure immunologists are going to be very excited," said Mignot of the findings. "If we can work out what happens specifically in patients with narcolepsy, we'll be able to better understand the role of T cells in other autoimmune diseases that are more complicated and difficult to detect."

The work was primarily funded by NINDS. The co-first authors are Juliette Faraco, PhD, and Joachim Hallmayer, MD; other Stanford co-authors are Ling Lin, MD, PhD; Minae Kawashima, PhD, and Mali Einen.