A 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.
Prof. Mignot, who is co-senior author of the new paper, says:
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."
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:
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.
Prof. Mignot says this suggests other viruses or pathogens may sometimes cause a similar confusion in the immune system, adding that:
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.
No comments:
Post a Comment