Ten years after researchers at Stanford University School of Medicine identified the culprit behind the sleep disorder narcolepsy, the researchers have shown for the first time that a specific immune cell is involved in the disorder—confirming long-held suspicion that narcolepsy is an autoimmune disease. The researchers say their 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,” says Emmanuel 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.”

 

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. Mignot 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.

 

The researchers 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.

 

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 says.

Mignot says 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 says future studies will focus on solving this mystery. 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 says.