Narcolepsy: Trouble With Tribbles?

Antibodies Kill Sleep-Regulating Brain Cells in People With Narcolepsy

Medically Reviewed by Louise Chang, MD on February 16, 2010

Feb. 16, 2010 -- A major cause of narcolepsy appears to be trouble with tribbles.

The tribbles in question are bits of RNA amusingly named after the cute and furry but dangerously fertile creatures made famous in a Star Trek TV episode. Not at all amusing is what happens when the body makes antibodies that attack tribbles in sleep-regulating brain cells.

New findings strongly suggest that anti-tribbles antibodies kill a population of brain cells that regulates sleep. This triggers narcolepsy, particularly the severe manifestation of narcolepsy called cataplexy, in which strong emotions trigger paralysis.

"We have identified reactive autoantibodies in human narcolepsy, providing evidence that narcolepsy is an autoimmune disorder," conclude Vesna Cvetkovic-Lopes and colleagues of the University of Geneva, Switzerland.

Scientists have long suspected that anti-self immune responses -- autoimmunity -- play a role in narcolepsy. People with narcolepsy have a dramatic loss of brain cells that produce hypocretin (also known as orexin), a chemical messenger crucial to normal sleep patterns.

But until now, nobody has been able to find abnormal immune responses in people with narcolepsy.

Using mice genetically engineered to overproduce tribbles, Cvetkovic-Lopes and colleagues screened for hypocretin structures that might be targets for immune attack. They found that hypocretin-producing brain cells make a large amount of a specific type of tribbles -- tribbles homolog 2 or Trib2.

Then they looked for the antibodies in people who had narcolepsy and people who didn't. Sure enough, the researchers found narcolepsy patients -- but not other people -- have a lot of antibodies against Trib2.

"These results indicate for the first time to our knowledge that Trib2 is an autoantigen in human narcolepsy and that Trib2-specific antibodies specifically target hypocretin neurons, ultimately leading to their disappearance and hypocretin deficiency," Cvetkovic-Lopes and colleagues conclude.

The finding does not prove that autoimmunity is behind all forms of narcolepsy. But some patients may benefit from the findings.

The researchers have already treated patients recently diagnosed with narcolepsy with immune globulins. These experiments, they report, had "unexpected positive results, suggesting that the autoimmune process may be counteracted if treated early."

The findings appear in the Feb. 15 online issue of the Journal of Clinical Investigation.

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Cvetkovic-Lopes, V. Journal of Clinical Investigation, published online Feb. 15, 2010.

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