BY TOM VALEO
For decades, circumstantial evidence has suggested that some people have a genetic susceptibility to narcolepsy, which produces excessive daytime sleepiness, cataplexy, and sleep abnormalities. However, unlike narcoleptic dogs, which lack a receptor for hypocretin (a hormone that promotes wakefulness), humans predisposed to narcolepsy seem to require an environmental trigger that somehow damages or destroys the 70,000 or so brain cells that produce hypocretin.
Now researchers at the Stanford University School of Medicine have found compelling evidence that human narcolepsy is an autoimmune disease that results when people with certain gene variants are exposed to a virus or a vaccine that induces the body to launch an attack on hypocretin-producing cells.
Also, signs of this autoimmune attack appear very early in the course of the disease, which may enable a prompt diagnosis with a simple blood test that would allow treatment to begin sooner, according to veteran sleep researcher Emmanuel Mignot, MD, PhD, director of the Stanford Center for Sleep Sciences and Medicine, the lead author of the study published in the Dec. 18 issue of Science Translational Medicine.
“With a blood test we might be able to diagnose milder cases of narcolepsy and do immune suppression before it’s too late,” said Dr. Mignot, who is also the Craig Reynolds professor of sleep medicine at the Stanford School of Medicine.
The research also provides the first evidence in vivo that autoimmune disease results from molecular mimicry, in which a virus or a bacterium displays molecules so similar to those found in the body’s own tissues that the immune system attacks both.
“This is a huge finding both for narcolepsy and for immunology in general,” Dr. Mignot said. “People have suspected for a long time that molecular mimicry was involved in autoimmune disease, but now we have demonstrated that the immune system sometimes gets confused and fails to distinguish self from virus. I think narcolepsy will become a model for other autoimmune disorders.”
In their Science Translational Medicine paper, Dr. Mignot and colleagues showed that people with narcolepsy possess a genetic variant of HLA — DQ0602 — which stimulates CD4+ T cells to attack two 13-amino acid peptides derived from hypocretin. These epitopes evoked an immune response to hypocretin in 23 patients with narcolepsy, but not in healthy DQ0602-positive control subjects. Also, in pairs of identical twins, the one with narcolepsy carried T cells activated by the hypocretin peptides, while the healthy twin did not.
This provides compelling evidence that narcolepsy requires genetic susceptibility plus an environmental trigger, such as exposure to the H1N1 flu virus, or Streptococcus pyogenes, said Dr. Mignot.
“We suspected narcolepsy was an autoimmune problem from all the genetic data that pointed to that conclusion, and from the fact that all these hypocretin cells were killed,” he said. “But we couldn’t find the epitope — the cross-reactive molecule, or autoantigen. In this study we have found the exact piece of hypocretin that triggers the autoimmune response, and that is very important.”
The appearance of the H1N1 virus preceded an outbreak of narcolepsy in several countries, including England, Sweden, and Ireland, suggesting that the immune system of those who developed the disease failed to distinguish hypocretin cells from the hemagglutinin molecule found in the virus.
GlaxoSmithKline, the manufacturer of the Pandemrix flu vaccine used in the 2009-2010 H1N1 outbreak, has identified at least 900 narcolepsy cases in people who received the vaccine, which contained portions of the virus. The Pandemrix vaccine, used with an adjuvant that induced a stronger immune response, was never used in the United States, and has been withdrawn from the market.
Dr. Mignot suspects that narcolepsy exists on a spectrum, with cases at the milder end now potentially identifiable with a blood test.
“This is speculation on my part, but I think onset in some cases is probably milder and harder to detect, and progressive,” he said. “People learn to live with it.”
A blood test could allow T cells from a subject to be exposed in vitro to cells containing the HLA variant associated with narcolepsy. “Then you add the piece of hypocretin that binds to [the haplotype] DQB1*06:02,” said Dr. Mignot. “T cells from normal people won’t proliferate, but if you put T cells from patients (with narcolepsy), they will get activated.”
See what sleep experts had to say about this research in our Feb. 6 issue of Neurology Today. For now, browse our archives on sleep disorders: http://bit.ly/1eFe2fZ.