Study confirms narcolepsy as an autoimmune disease

Date: Dec-20-2013A new study that offers some of the most compelling evidence to date for the idea of

"mimicry," where the immune system attacks a body protein because of its similarity to a pathogen

protein, confirms that narcolepsy is an autoimmune disease.

Reporting in the latest online issue of Science Translational Medicine, researchers at

Stanford University School of Medicine in California show how in genetically susceptible

individuals, narcolepsy can be triggered because part of a wakefulness protein, called hypocretin, is

very similar to part of a protein from the pandemic 2009 H1N1 "swine flu" virus.

Narcolepsy is a chronic disorder where the brain cannot control sleep-wake cycles, leading to

sudden bouts of sleep, often accompanied by cataplexy, an abrupt loss of voluntary muscle tone that

can cause collapse.

The National Institutes of Health estimates that narcolepsy affects around 1 in

3,000 Americans. Currently, there is no cure.

Immune system attacks brain cells that make the 'wakefulness' protein

In 2009, Emmanuel Mignot, professor of psychiatry and behavioral sciences at Stanford, who has

been working on narcolepsy for over 20 years, led a study that gave the first genetic clue that narcolepsy is an autoimmune disorder

where the body's immune system attacks brain cells that make the "wakefulness" protein

hypocretin.

Prof. Mignot, who is co-senior author of the new paper, says:

"The relationship between H1N1 infection, vaccination and narcolepsy gave us some very

interesting insight into possible causes of the condition. In particular, it strongly suggested to

us that T cells of the immune system primed to attack H1N1 can occasionally also cross-react with

hypocretin and somehow cause the destruction of hypocretin-producing neurons."

The latest work suggests new ways to interrupt the process before all the hypocretin-producing

cells are lost and produce the dramatic symptoms of narcolepsy.

It also opens the prospect of a blood test to diagnose the disease, and it offers new insights into

a link between a pandemic H1N1 vaccine used in Europe in 2009 and a spike in narcolepsy cases in

Scandinavia the year after.

The team says their work will also give new ideas to researchers investigating other types of

autoimmune disorders, particularly those involving the brain.

Co-senior author Elizabeth Mellins, an immunology researcher and professor of pediatrics at

Stanford, adds:

"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."

Focus on T cells because of link to HLA signature

Previous studies have established that the vast majority of people with narcolepsy have a

variant of the human leukocyte antigen (HLA) gene that is found in only a quarter of the general

population.

For their work, Prof. Mignot and colleagues decided to focus on the T cells of the immune system

because of their association with the HLA signature found in nearly all narcolepsy patients.

HLA is a molecule that sits on the surface of cells that present antigens and bits of proteins

they gather from their environment. T cells come along and scan these proteins, and if any of these

is "foreign," they start to divide and go around the body looking for it so as to destroy it.

However, if there is a case of mistaken identity on the part of the T cells, then things can go

drastically awry. Prof. Mellins explains how they started to suspect this was the case in

narcolepsy:

"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."

They found that a short, 13-amino-acid section of the H1N1 hemagglutinin protein was very

similar to two equally short pieces of the hypocretin protein.

The resemblance was close enough so that the T cells of people who suffer from narcolepsy

reacted strongly to the hypocretin protein segments.

The researchers tested this by presenting the small piece of the H1N1 protein to cultured T

cells from narcolepsy patients, and saw how this increased the proportion of hypocretin-reactive

cells.

Other pathogens may cause similar confusion in immune system

The team was also surprised to find hypocretin cross-reactive T cells in blood taken from

narcolepsy patients before H1N1 began circulating in humans in 2009.

Prof. Mignot says this suggests other viruses or pathogens may sometimes cause a similar

confusion in the immune system, adding that:

"Indeed, there is a growing appreciation that cross-reactivity of immune T cell recognition may

not be as uncommon as once thought. Although this cross-reactivity may make the immune system more

adaptable to new infections, it may also increase the chance of mistakes that could result in

autoimmune diseases."

In another study published earlier this year, researchers at the UCLA Center for Sleep Research

offer another clue to the cause of

narcolepsy in humans. They suggest an excess of histamine brain cells may reduce hypocretin

cells.

Written by Catharine Paddock PhD

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