Genetic Study Confirms the Immune System’s
Role in Narcolepsy
Scientists funded by the National Institutes of Health have identified
a gene associated with narcolepsy, a disorder that causes disabling
daytime sleepiness, sleep attacks, irresistible bouts of sleep
that can strike at any time, and disturbed sleep at night. The
gene has a known role in the immune system, which strongly suggests
that autoimmunity, in which the immune system turns against the
body’s own tissues, plays an important role in the disorder.
"The link between narcolepsy and autoimmunity was proposed
decades ago, but efforts to verify it have failed repeatedly. Current
findings leave little doubt that autoimmunity plays a role," says
Merrill Mitler, Ph.D., a program director with the National Institute
of Neurological Disorders and Stroke (NINDS). The study was funded
principally by NINDS, with additional support from the National
Institute of Mental Health (NIMH), the National Heart, Lung and
Blood Institute (NHLBI), and the National Institute of Allergy
and Infectious Diseases (NIAID), all components of NIH.
The new study, which appears today in Nature Genetics, focused
on narcolepsy with cataplexy – a sudden loss of muscle tone that
can cause a person to collapse, with or without falling asleep.
About 1 in 2,000 Americans have narcolepsy-cataplexy. The symptoms
of narcolepsy-cataplexy have been shown to result from the death
of a small group of brain cells that normally regulate the sleep-wake
cycle by releasing chemicals called hypocretins.
Genetic and environmental factors both clearly play a role in
narcolepsy-cataplexy. Until now, the best evidence for autoimmunity
as a cause of the disorder was the discovery that nearly everyone
with the disorder has unique variants of a gene called HLA-DQB1*0602.
This is one of the genes that encodes HLA proteins, which dot the
surface of the body's cells and help the immune system identify
foreign proteins. Some researchers theorize that the HLA variants
found in people with narcolepsy-cataplexy predispose them to an
autoimmune reaction that destroys their hypocretin-producing cells.
There are gaps in that theory, however, says Emmanuel Mignot,
M.D., Ph.D., director of the Center for Narcolepsy at Stanford
University School of Medicine in Palo Alto, Calif., and a Howard
Hughes Medical Institute investigator. Dr. Mignot discovered the
link between narcolepsy and the hypocretins, and helped establish
the link to the HLA system. HLA proteins are found in many tissues
including the brain, where they may affect brain development, he
says.
HLA variations, however, do not fully account for narcolepsy-cataplexy.
Dr. Mignot led a genome-wide association study to search for other
genes associated with narcolepsy-cataplexy. These studies involve
scanning the genome — the entire set of DNA — for
small differences between people who have a disorder and people
who do not. Dr. Mignot’s study included more than 4,000 individuals,
all of whom had the HLA variants that predispose to narcolepsy-cataplexy
but only about half of whom had the disorder. Participants were
recruited so that many genetic groups were represented. Subjects
were from the United States and eight countries in Europe and Asia;
hundreds were African-American, Korean, and Japanese, groups known
to have a high incidence of the disorder.
The researchers discovered that in addition to unique HLA variants,
people with narcolepsy-cataplexy are also more likely to have unique
variants of the TCRA gene, which encodes a receptor protein on
the surface of T cells. T cells are the mobile infantry of the
immune system. In concert with the HLA proteins, the T cell receptor
enables T cells to recognize and attack foreign invaders, such
as bacteria and viruses. Changes to the T cell receptor could increase
the likelihood that the cells will direct their attack against
the body.
The findings of Dr. Mignot’s group indicate that narcolepsy-cataplexy
is linked to autoimmunity and involves T-cells. The research could
lead to new approaches to prevention and treatment. One possibility
may be preventing the disorder by stopping the effects of the autoimmune
process. " If we can define the changes in the T cell receptor
associated with narcolepsy-cataplexy, we might be able to develop
drugs that block the protein’s abnormal activity and prevent the
onset of the disorder," says Dr. Mignot. Current treatments
such as stimulant drugs for combating daytime sleepiness and antidepressants
for cataplexy are only able to control symptoms, and do not address
the underlying loss of hypocretin cells.
It is important to note that this study, like most genome-wide
association studies, did not identify genetic variants that directly
cause narcolepsy-cataplexy. Instead it identifies groups that are
more likely to show narcolepsy-cataplexy and groups that are less
likely to show the disorder. In people with the HLA variants that
predispose to narcolepsy-cataplexy, there is about a 20-fold higher
frequency of the disorder if variants in the TCRA gene are present.
It is yet to be known which people with the genetic variants will
go on to develop narcolepsy-cataplexy.
Other risk factors for narcolepsy-cataplexy remain to be discovered,
and Dr. Mignot’s findings could provide clues to their identity.
For example, further studies to characterize the T cells in people
with narcolepsy-cataplexy could help reveal whether specific environmental
factors — such as infections — contribute to the
disorder. Dr. Mignot’s findings also could lead to a better understanding
of other autoimmune diseases where HLA genes are known to play
a role, such as multiple sclerosis and type 1 diabetes.
NINDS (www.ninds.nih.gov)
is the nation’s primary supporter of biomedical research on the
brain and nervous system. The mission of NIMH (www.nimh.nih.gov)
is to reduce the burden of mental and behavioral disorders through
research on mind, brain and behavior. NIAID (www.niaid.nih.gov)
conducts and supports research to study the causes of infectious
and immune-mediated diseases, and to develop better means of preventing,
diagnosing and treating these illnesses. NHLBI (www.nhlbi.nih.gov)
plans, conducts, and supports research related to the causes, prevention,
diagnosis, and treatment of heart, blood vessel, lung, and blood
diseases; and sleep disorders.
For more information about narcolepsy, visit http://www.ninds.nih.gov/disorders/narcolepsy/narcolepsy.htm or http://www.nhlbi.nih.gov/health/dci/Diseases/nar/nar_what.html.
The National Institutes of Health (NIH) — The Nation's
Medical Research Agency — includes 27 Institutes and Centers
and is a component of the U.S. Department of Health and Human Services.
It is the primary federal agency for conducting and supporting basic,
clinical and translational medical research, and it investigates
the causes, treatments, and cures for both common and rare diseases.
For more information about NIH and its programs, visit www.nih.gov.
Reference: Hallmayer J et al. “Narcolepsy is Strongly Associated
with the TCR alpha locus.” Nature Genetics, published online May
3, 2009. |