It was April 2009, and swine flu was terrifying the planet.

Borne in Mexico, the H1N1 influenza pandemic was particularly troubling because it preferentially targeted children and adolescents. So five months later, when the H1N1 vaccine Pandemrix was approved by the European Commission and backed by the World Health Organization, much of the world breathed a sigh of relief.

But reports began surfacing in Sweden that the vaccine was triggering a sudden sleep disorder — narcolepsy — in children. These claims were eventually confirmed in the summer of 2011.

Now a new study from Stanford University shows that the vaccine confuses a member of the human immune system, CD4 T-cells, into destroying a group of brain cells that regulate wakefulness.

"People have long thought that the brain is somewhat immune to autoimmune diseases," said senior author Dr. Emmanuel Mignot, a Stanford professor of psychiatry and behavioral sciences. "But we're learning this is wrong.”

It isn’t the vaccine per se that causes narcolepsy, but the underlying influenza virus on which the drug is based.

They found that part of the flu virus impersonates an arousal protein in the brain, called hypocretin — a type of cell lost during narcolepsy. The scientific term for this case of mistaken identity is “molecular mimicry.”

When T-cells from narcoleptics are exposed to the flu, they are tricked to attacking these hypocretin-producing brain cells.

"When we saw that the portion of the hypocretin that seemed to be recognized by the immune system in narcolepsy patients was similar to a part of the pandemic 2009 H1N1 influenza hemagglutinin molecule, we were very hopeful that we were on the right track," said Dr. Elizabeth Mellins, an immunologist and professor of pediatrics at Stanford, who was co-senior author on the Science Translational Medicine report.

Narcoleptics carry unique mutations in a set of immune-associated genes — called human leukocyte antigens — that govern how T-cells recognize friends from foes. These genetic aberrations predispose narcoleptics for this autoimmune disorder, according to the authors.

Unfortunately, once these brain cells are lost, there is no way to repair narcolepsy. But the scientists believe their findings may yield therapies that prevent the development of narcolepsy, even when it is not caused by the flu.

The scientists found which portions of hypocretin protein aggravate T-cells the most. They can now develop drugs that block this interaction and prevent T-cells from recognizing hypocretin as an enemy.

"This study will shape the next decade of research into narcolepsy. It will focus investigators on immune-mediated mechanisms of neuronal death, which ultimately may shed light on other autoimmune diseases, particularly of the brain," Mellins said.

The Pandemrix vaccine left a social mess in its wake that European health agencies are tyring to clean up. Though prevalence was low — only one in 15,000 vaccinated children developed narcolepsy — UK families may be entitled to nearly the equivalent of $200,000 if they can prove severe disability. The drug was discontinued, but there is no word yet if the Pandemrix developer GlaxoSmithKline will contribute to settlements. The U.S. never approved Pandemrix, dodging a sticky medical quagmire.

Yet many scientific lessons were learned from Pandemrix.

"This intersection of genetically susceptible people with a particular environmental trigger, in the form of the H1N1 virus or the Pandemrix vaccine, gave us a powerful scientific opportunity to begin to understand the molecular basis of narcolepsy," Mellins said.

She believes their findings will open new therapeutic inroads for the brain disorder, which affects one in 3,000.

"By giving us a new way to think about how neurons in these patients die, it also suggests new therapeutic approaches that we would not have considered if we hadn't learned that this is an autoimmune disease," Mellins said.

 

Source: De la Herrán-Arita AK, Kornum BR, Mahlios J, Jiang W, et al. CD4+ T Cell Autoimmunity to Hypocretin/Orexin and Cross-Reactivity to a 2009 H1N1 Influenza A Epitope in Narcolepsy. Science Translational Medicine. 2013.