Narcolepsy linked to immune system

Scientists have identified a second genetic tie that cements a connection between a disabling sleep disorder and the immune system.

Emmanuel Mignot, a sleep researcher and Howard Hughes Medical Institute investigator at Stanford University, led an international team searching for the genetic causes of narcolepsy. The team reports online May 3 in Nature Genetics that several genetic markers associated with narcolepsy map to a gene important for turning immature immune T cells into microbe killers.

For decades scientists have known that people with narcolepsy are more likely to have a particular version of an immune gene called HLA-DQB1*0602. The gene belongs to a class of genes called HLA, for human leukocyte antigens, that makes key immune proteins. These proteins present small bits of invading microbes to T cells, much like a handler waves a sweat-laden sock in front of a bloodhound. The proteins thus help T cells identify, track down and kill the foreign cells. In autoimmune disease, T cells may run amok, mistakenly attacking the body’s own, healthy cells.

Given the association between narcolepsy and the HLA gene, the lethality of T cells intrigued scientists studying the sleep disorder. Neurons that make a wake-promoting protein called hypocretin die in people who have narcolepsy. Death of the cells means that people can’t make enough hypocretin to stay awake, and they experience sudden bouts of sleep during the day and have disrupted sleep at night. About one in every 2,000 people in the United States has narcolepsy with cataplexy, a sudden loss of muscle tone that can cause people to collapse.

That T cells may cause the death of hypocretin-producing cells seemed like a no-brainer to Mignot.

“If you’re like me you think, ‘Duh, if you’ve got these associations; it’s got to be autoimmune,’” Mignot says. “The problem is no one has been able to prove that.” Because HLA proteins are also found in neurons and other nonimmune cells, it was possible that the death of the hypocretin cells had nothing to do with the immune system.

Now, Mignot and his colleagues have found a genetic link between narcolepsy and a gene that encodes the T cell receptor alpha, which interacts with HLA proteins to trigger an immune reaction.

“This solidly positive association provides additional evidence that narcolepsy is an autoimmune disorder,” says Masashi Yanagisawa, a neuroscientist and Howard Hughes Medical Institute investigator at the University of Texas Southwestern Medical Center at Dallas.

The researchers studied 1,830 people who have narcolepsy and cataplexy, and 2,164 healthy controls. The scientists found that people with narcolepsy were more likely than healthy people to carry one of three different genetic markers, called SNPs, in the area of the genome that contains the gene for T cell receptor alpha.

But the association is not the final piece of the puzzle, Mignot says. Even with all of the known genetic risk factors, including the newly discovered version of the T cell receptor gene, a person has only a 1.5 percent chance of developing narcolepsy, he says. That suggests that, while narcolepsy is probably an autoimmune disorder, further genetic and environmental triggers and risk factors remain to be found.

“It doesn’t answer the fundamental question of what goes wrong with the immune system that causes it to attack the brain,” Yanagisawa says.

Still the research “is a solid step” toward figuring out the interaction between the brain and immune system that leads to narcolepsy, says Merrill Mitler, a program director at the National Institute of Neurological Disorders and Stroke in Bethesda, Md. “The principles that we’re glimpsing because of this finding go well beyond narcolepsy.” The discovery may help focus the search for causes of other autoimmune disorders, he says.