An international team of researchers has found some
of the first solid evidence that narcolepsy may be a
so-called "hit-and-run" autoimmune disease.
The researchers sought to determine why, of two
different flu vaccines widely deployed during the
2009 swine flu pandemic, only one was associated
with a spike in the incidence of narcolepsy, a rare
sleep disorder.
A paper describing their findings has been published
July 1 2015 in Science Translational Medicine.
Lawrence Steinman, MD, a professor of pediatrics and
of neurology and neurological sciences, is the
senior author. The first author is Sohail Ahmed, MD,
who was global head of clinical sciences at Novartis
Vaccines at the time of the study.
Autoimmune diseases, such as multiple sclerosis and
rheumatoid arthritis, are well-known for taking
decades to ravage the nervous system, joints or
other organ systems. But since the late 1990s,
researchers have hypothesized a different kind of
autoimmune disease, one that may incur rapid,
pinpoint damage and leave virtually no trace of its
work. Narcolepsy is suspected of being one of these
hit-and-run diseases.
Narcolepsy is a chronic, incurable and lifelong
brain disorder that interferes with normal
sleep-wake cycles and causes an array of symptoms,
including overwhelming daytime sleepiness and sleep
attacks that can strike at any time, even in the
middle of a conversation. What causes narcolepsy has
been a source of fascination among scientists for
decades.
Narcolepsy cases mostly occur at random, as opposed
to being strictly inherited, although certain gene
variants can make people more susceptible to it.
For example, nearly everyone who has narcolepsy
accompanied by cataplexy, a condition that causes
sudden episodes of muscle weakness, carries a gene
variant called HLA-DQB1*0602, which codes for a
receptor found on the surface of immune cells.
"HLA variants are associated with a lot of
autoimmune diseases," said Steinman, who also holds
the George A. Zimmermann Professorship. But by
themselves, they don't cause narcolepsy. Rather, the
disease seems to be triggered by a combination of
genetic predisposition and infection.
People with narcolepsy carry more antibodies to
pathogens such as strep bacteria or the H1N1 virus,
which caused the 2009 swine flu pandemic.
Importantly, narcoleptic patients have very low
levels of the neurotransmitter hypocretin, which
normally helps to keep us awake when it binds to the
hypocretin receptors in the brain. They also have
fewer of the brain neurons that produce hypocretin.
What could explain this constellation of signs?
The answer began to emerge in 2010, soon after the
2009 pandemic, when researchers reported a sharp
uptick in the diagnoses of new cases of narcolepsy,
but only in some places. Populations that had been
immunized with GlaxoSmithKline's Pandemrix vaccine
showed an increase in narcolepsy, but those
immunized with Novartis' Focetria did not.
The researchers wondered whether this difference
could be explained by the fact that Pandemrix and
Focetria were made from two different strains of the
H1N1 virus. The team found that H1N1 contains a
protein whose structure partially mimics a portion
of a human hypocretin receptor. This H1N1 protein
was contained, as expected, in the Pandemrix
vaccine, but at much higher amounts than that found
in the Focetria vaccine.
Could antibodies normally generated to this flu
protein by Pandemrix vaccination also be latching
onto hypocretin receptors and causing an autoimmune
reaction?
To find out if narcoleptic patients even had such
antibodies, the team examined a sample of 20
individuals who developed narcolepsy after Pandemrix
vaccination. Seventeen of them had elevated
antibodies to the hypocretin receptor. However,
among six individuals immunized with Focetria, none
had these antibodies.
How H1N1 and Pandremix might cause narcolepsy? The
authors propose a hit-and-run autoimmune mechanism
for how both swine flu and Pandemrix might cause
narcolepsy. They suggest that in genetically
predisposed people, high levels of the H1N1 protein
stimulate the production of large amounts of
antibodies to both the virus and the hypocretin
receptor. These antibodies may persist in the blood
for months.
Either the large numbers of antibodies or
inflammation from an unrelated infection could alter
the blood-brain barrier, allowing the antibodies to
enter the brain. There, the antibodies may latch
onto hypocretin receptors, possibly directing the
immune system to destroy or suppress brain cells
critical to regulating sleep-wake cycles.
Indeed, compared to Pandemrix, Focetria contains 72
percent less of the H1N1 protein and, for this
reason, it doesn't appear to have stimulated
specific flu antibodies capable of binding to the
receptor, according to the researchers.
Because Pandemrix was associated with an increased
risk of narcolepsy, it was withdrawn from the
market. But Steinman is quick to point out that,
even with that risk, the vaccine was far safer than
being infected with swine flu. In the United States
alone, the 2009 swine flu pandemic resulted in
274,304 hospitalizations and 12,469 deaths.
The work advances the understanding of narcolepsy,
but Steinman said he isn't claiming they have nailed
down the cause. For now, he's calling the proposed
mechanism "an inviting possibility." Future work
could include comparisons of different vaccines and
in vitro studies of banked human blood samples.
Other Stanford co-authors of the paper are senior
research scientist Jonathan Rothbard, PhD, and
Christopher Adams, PhD, director of proteomics at
the Stanford University Mass Spectrometry
Laboratory.
For more information
Science Translational Medicine
Antibodies to influenza nucleoprotein cross-react
with human hypocretin receptor 2.
MDN |