Sleep Disorder May Have Autoimmune Link

by Elizabeth Norton Lasley

July 8, 2009

Narcolepsy is considered a sleep disorder, since its chief symptom is a sudden plunge from waking into the rapid-eye-movement stage of sleep. But a new study suggests that autoimmunity—a mistaken attack by the immune system—may be involved.

The finding could lead to new treatments for a disorder that afflicts 1 in about 2,000 people, not only with sleep problems but a condition called cataplexy—a sudden, sometimes disabling, loss of muscle tone that often follows a burst of emotion. Teasing out a possible involvement of the immune system might also reveal previously unsuspected pathways of autoimmunity in the brain.

Psychiatrist Emmanuel Mignot, who heads the Center for Sleep Science at Stanford University, has long suspected that narcolepsy involves an autoimmune component. Virtually all of his narcolepsy patients have a specific form of a gene that encodes human leukocyte antigen (HLA), a molecule that starts the immune response by “presenting” fragments of an invading germ to white blood cells called T cells, which then destroy the invader. Mignot’s research also shows another trademark of narcolepsy: The disease destroys almost all neurons that produce the chemical messenger hypocretin in a brain region called the hypothalamus. Narcolepsy is likely to develop as the result of a sudden loss of hypocretin cells, as rodents born without the hypocretin gene have narcolepsy at birth, while in humans it typically start around adolescence.

With two such striking anomalies coexisting in one disease, it seemed obvious that one might cause the other—that the unusual HLA gene could be directing an immune attack on the hypocretin-producing neurons. But despite almost two decades of research, no one has proved a causal link.

One problem is that HLA is found on many types of cells and is involved in processes unrelated to immunity. For example, neurobiologist Carla Shatz, also at Stanford, has shown that HLA plays a key role in synaptic plasticity, through which the brain rewires connections between neurons. So the presence of an HLA variant in cases of narcolepsy does not conclusively prove that the immune system is at fault.

The new study, posted online May 3 in Nature Genetics, offers stronger evidence. Joining forces with an international team—including geneticists from Munich, Tokyo, Prague, Bologna and Suwon, Korea—Mignot analyzed the genes of more than 4,000 people with the HLA variant, about half of whom had narcolepsy. Those with the disease showed yet another distinctive mutation, this time in a gene that encodes a type of T-cell receptor known as TCR alpha.

“This is the second immune-related genetic factor to be identified in narcolepsy,” says Mignot. If T cells are wrongly forming receptors for hypocretin-producing neurons, then specialized molecules, such as monoclonal antibodies, could be developed to block this process. Such a treatment, Mignot says, could also prevent the disease. Because only about one-quarter of people who have the HLA variant show signs of narcolepsy, it’s likely that the gene merely confers susceptibility, with a “second hit” required for the disease to begin.

“Normally you only see T cells in the brain after an infection or injury, which may trigger an autoimmune attack in vulnerable individuals,” he says. Thus a treatment to neutralize rogue T cells might stop the disease before it even begins.

Shatz is intrigued by the study but not entirely convinced that an autoimmune process is at work in narcolepsy. In the October 28, 2003, issue of Proceedings of the National Academy of Sciences, she and colleague Josh Syken of Harvard University found evidence of another type of T cell receptor (TCR beta) in neurons. “If TCR alpha is also expressed in neurons, the mutation found in narcolepsy might be interfering with synaptic plasticity in a way that leads to the death of the hypocretin-producing cells,” she says.

Mignot says that if further research shows how T cells might destroy key neurons, narcolepsy could prove a useful model for studying the interactions between HLA and T-cell receptors in the hundred or more diseases involving HLA mutations. “I wouldn’t be surprised if autoimmunity turns out to play a role in other brain diseases, such as schizophrenia,” he says.