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Immune System Tied to Narcolepsy

A new finding provides evidence that autoimmunity, in which the immune system turns against the body's own tissues, may play an important role in narcolepsy.

Narcolepsy is a disorder that causes periods of extreme daytime sleepiness. About 1 in 2,000 Americans has narcolepsy with cataplexy—a sudden loss of muscle tone that can cause a person to collapse, with or without falling asleep. The symptoms of narcolepsy-cataplexy have been shown to result from the death of a small group of brain cells that normally regulate the sleep-wake cycle by releasing chemicals called hypocretins.

Scientists have thought that autoimmunity was a cause of narcolepsy-cataplexy because many people with the disorder have unique variants of a gene that encodes HLA proteins. These proteins dot the surface of the body's cells and help the immune system identify foreign proteins. HLA proteins are found in many tissues, including the brain. Researchers theorized that the variants found in people with narcolepsy-cataplexy predispose them to an autoimmune reaction that destroys their hypocretin-producing cells. HLA variations, however, don't fully account for narcolepsy-cataplexy.

Dr. Emmanuel Mignot of the Stanford University School of Medicine led a genome-wide association study to search for other genes associated with narcolepsy-cataplexy. The researchers scanned the genomes—the entire sets of DNA—of more than 4,000 people. All the participants had the HLA variants that have been linked to narcolepsy-cataplexy, but only about half actually had the disorder. The researchers looked for small DNA differences between the 2 groups. The work was funded by NIH's ×îÐÂÂ鶹ÊÓƵ Institute of Neurological Disorders and Stroke (NINDS) along with several other NIH components.

The researchers reported on May 3, 2009, in Nature Genetics that people with narcolepsy-cataplexy are more likely to have unique variants of the TCRA gene, which encodes a receptor protein on the surface of T cells. T cells are the mobile infantry of the immune system. TCRA encodes the major receptor that, in concert with HLA, enables T cells to recognize and attack foreign invaders, such as bacteria and viruses. Changes to this receptor may mistakenly lead the cells to direct their attack against the body.

The researchers calculated that variants in HLA and TCRA together can cause up to a 20-fold increase in risk for narcolepsy-cataplexy.

"The link between narcolepsy and autoimmunity was proposed decades ago," says Dr. Merrill Mitler of NINDS, "but efforts to verify it have failed repeatedly. The current findings leave little doubt that autoimmunity plays a role."

Current treatments for narcolepsy-cataplexy control symptoms rather than addressing the underlying loss of hypocretin cells. This research could lead to new prevention and treatment strategies. "If we can define the changes in the T cell receptor associated with narcolepsy-cataplexy, we might be able to develop drugs that block the protein's abnormal activity and prevent the onset of the disorder," Dr. Mignot says.