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BRISBANE: Narcolepsy is caused by a confused immune system destroying hormone-producing cells in the brain, says a new study.
Sufferers of the disabling sleep disorder – who suffer from sudden and frequent bouts of daytime sleepiness – often have a unique version of the immune-related gene TCR-alpha, report researchers this week in the journal Nature Genetics.
TCR-alpha codes for a receptor that identifies foreign proteins in the body and triggers the immune system to attack.
Mistaken identity
An unusual form of that receptor may lead the immune system to mistakenly recognise parts of the brain as foreign, leading it to attack them, said lead author Emmanuel Mignot a sleep researcher at Stanford University in Palo Alto, California.
"An autoimmune etiology has been suggested for narcolepsy but never proven [before now] despite decades of intensive research," he said.
Narcolepsy is caused by a lack of cells in the brain that produce hypocretin, a hormone that helps regulate the sleep-wake cycle. In the 1980s it was discovered that narcolepsy was also strongly associated with unique variants of the gene HLA-DQB1*0602.
This gene codes for a protein that presents foreign proteins to the immune system, which becomes activated to destroy pathogens carrying those proteins. Researchers have long suspected that having a variant version of the gene predisposes people to an autoimmune reaction against hypocretin-producing cells.
However, not everyone with HLA-DQB1*0602 variants has narcolepsy, so Mignot's team scanned the entire genome of more than 4,000 people who have the variant gene, to find other genes associated with narcolepsy. The people who did have narcolepsy were 20 times more likely to also have a variant TCR-alpha gene, Mignot's team found.
"Both sides of the story"
TCR-alpha receptors found on the T-cells of the immune system, work closely with HLA proteins to recognise and destroy cells that have been identified as foreign. This strongly suggests that the two variant proteins working together can turn the immune system against hypocretin-producing cells, causing narcolepsy.
The discovery means that it might be possible to prevent narcolepsy by blocking the variant proteins, so they can't trigger the destruction of hypocretin-producing cells.
Gethin Thomas, an immunologist at the University of Queensland in Brisbane, Australia, said the research was important because, while HLA proteins were known to be involved in dozens of autoimmune diseases, it was the first time anyone had found both a HLA protein and a T-cell receptor linked to an autoimmune disease. "They've found both sides of the story," he said.
