Linking Narcolepsy to the Flu? Researchers Make Progress Identifying Molecular Mimicry0

Emmanuel Mignot, MD, PhD, and colleagues ID a particular piece of H1N1 hemagglutinin flu protein as a likely trigger.

One day, Claire Crisp told her daughter to meet her in the car, but when Crisp walked outside she found her three-year-old, Mathilda, asleep, facedown on the pavement in front of the family’s minivan.

In the months that followed, the child collapsed on the kitchen floor, just missing the knives sticking up in the dishwasher. She fell asleep in the bathtub, in the swimming pool, and at the beach.

“We were deeply concerned,” says Crisp.

After a whirlwind of doctor’s visits and hospital stays, Mathilda was diagnosed in 2010 with narcolepsy. She was one of a wave of new cases in Europe during the global swine flu outbreak. There are still questions about whether the H1N1 Pandemrix vaccine could have contributed. Mathilda’s mother thinks so.

Now research from Stanford University sheds light on the mechanism by which either contracting the flu or receiving the swine flu vaccine could trigger an immune reaction that may lead to narcolepsy. The study, published in Proceedings of the National Academy of Sciences, also provides a specific example that demonstrates the theory in immunology called molecular mimicry, that autoimmunity is the result of the immune system mistaking healthy cells in a person’s body for proteins within infectious pathogens. In this case, the research reveals the mechanism behind how the immune system can wreak havoc on the brains of people with narcolepsy, confusing a chemical in the nervous system that is responsible for wakefulness with a protein in some strains of influenza and in some versions of the swine flu vaccine.

Sleep specialist Emmanuel Mignot, MD, PhD, the study’s author and director of the Stanford Center for Sleep Sciences and Medicine, says the research started with a hunch nearly 20 years ago that infections could trigger an autoimmune response that leads to narcolepsy.

“We started to see a lot of kids who had narcolepsy very abruptly after an infection,” says Mignot. “Initially I saw a lot of kids who had strep infection and then they developed narcolepsy. I started to think that, maybe, to develop an autoimmune disease you first have to have some sort of immune reaction against something else that goes wrong.”

Data from Beijing University that tracked the occurrence of narcolepsy cases in China between 1998-2010 found that more children got diagnosed with the condition in the spring and summer, after the height of viral infections during the cold months. The researchers also noticed a sharp increase in narcolepsy cases following the 2009 H1N1 pandemic in China, so it appeared like infections were an important trigger for narcolepsy. The problem was that no one could find the antigens, the troublemaker proteins that trigger the immune system, says Mignot.

Mignot’s team went to work on the seemingly endless hunt for the antigens, screening microscopic pieces of the flu for any sign of T cell reactivity in blood samples from narcolepsy patients.

The researchers spent many hours in the lab looking for flu proteins, which they suspected would stir an immune response in the narcolepsy patients’ blood, but not in the blood from the control subjects.

“Indeed, we did find that piece of flu,” says Mignot.

A sequence of amino acids in one chunk of the flu looked similar to hypocretin, a chemical normally produced by neurons in the hypothalamus, which helps to regulate sleep. Prior research from The University of California, Los Angeles, has demonstrated that narcolepsy is caused by a loss of about 90% of the 80,000 brain cells containing hypocretin (also known as orexin).

Out of billions of human T cells in the human immune system, the team was able to zero in on the specific ones that were responsible for the false alarm.

“Finding the T cells that were involved in narcolepsy was like finding a needle in a haystack,” says Mignot. “What is really exciting now is that we have isolated the exact T cells that seem to recognize both the pieces of the virus and the pieces of hypocretin.”

Ultimately, researchers found that in subjects with narcolepsy the immune system confuses a piece of the flu with hypocretin, which causes the body to kill off cells in the brain. This demonstrates how a flu virus or even a flu vaccine, made with properties derived from the flu, could trigger narcolepsy.

Within three weeks of receiving the swine flu vaccine, Mathilda’s nights were consumed by tossing and turning in bed. She would scream out and when her parents came to comfort her. She would, in some cases, not recognize them.

“She went from a very typical three-year-old to a child that was literally unable to sleep,” says Crisp. The family later learned that she was also suffering from hypnogogic hallucinations, often associated with narcolepsy.

At preschool, things were not any better. Mathilda continued to fall asleep at bizarre times, regularly sleeping during class. Teachers would carry her to the car at the end of the day when she was unable to walk to the vehicle on her own.

Her family spent 9 months searching for answers, until they finally landed in California at Stanford University, where physicians asked outright, “Did Mathilda have the H1N1 vaccine?”

Six million people in Britain, and more across the continent, got the vaccine during the swine flu pandemic, but the vaccine was withdrawn after physicians observed an increase in narcolepsy cases.

The swine flu pandemic came on fast in 2009 and the British pharmaceutical company making a vaccine, GlaxoSmithKline (GSK), didn’t have much time to grow the virus to incorporate it into the vaccine, so they used an immune-booster called an adjuvant.

Adjuvants enhance the body’s immune response. In the case of the H1N1 vaccine, the formulation may have been too strong and could have resulted in more narcolepsy cases, says Mignot, but there are still questions about the connection between the development of narcolepsy and the H1N1 vaccine because some people who were vaccinated may have already been infected with the virus. A different version of the swine flu vaccine by a different manufacturer was utilized in the United States and it has not been linked to an increase in narcolepsy rates.

Mignot’s hope is that future developers will avoid certain flu proteins that may lead to an autoimmune response. Nevertheless, flu vaccines still protect many more people than they harm and adverse reactions are rare.

“I like to say, no effect without side effects. There is nothing that you can take in the human body, if it is effective, that also does not carry a risk,” says Mignot.

Lisa Spear is associate editor of Sleep Review.

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