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Choice between two evils

Multiple sclerosis continues to puzzle scientists in all sorts of ways. Now researchers from the University of Würzburg have managed to make some progress in the search for the causes of this disease. They have revealed that in order to avoid greater damage the brain accepts a lesser evil.

The "disease with 1000 faces" is how multiple sclerosis (MS) is sometimes described. The reason for this name is that the clinical picture can differ dramatically from patient to patient - in terms of both the progression of the disease and the symptoms suffered. However, there is one finding that is the same in principle for everyone: multiple sclerosis is an autoimmune disease where one particular type of brain cell, known as an oligodendrocyte, is destroyed by the immune system. Oligodendrocytes form an insulating layer around the extensions of nerve cells that is required for efficient impulse conduction.

If this conduction is disturbed as a consequence of damage to the insulating layer, the nerves cannot transfer relevant "messages" as effectively as before. This is why multiple sclerosis sufferers often feel a tingling sensation in their extremities. Patients stumble more or have difficulties seeing. In extreme cases, they become incapable of moving around on their own and are confined to a wheelchair. According to the Multiple Sclerosis Society of Germany, around 2.5 million people worldwide have MS. The latest projections indicate that some 130,000 sufferers live in Germany; around 2,500 people are diagnosed with the disease each year.

Killer T cells are suspected of being a cause

The full details of what triggers the onset of the disease are not yet known. "Based on tests done on the brains of deceased MS patients, it has long been suspected that a certain type of lymphocyte, the killer T cell, is involved in destroying oligodendrocytes," says Professor Thomas Hünig from the Institute of Virology and Immunobiology at the University of Würzburg. Together with scientists from Cologne and Dresden, Hünig and his colleague, Dr. Shin-Young Na, have now taken a closer look at this process and have made a surprising discovery. This is reported in the latest issue of the journal Immunity. They found that the brain itself allows the T cells to attack the myelin sheath under specific conditions - because by doing so it may be able to prevent greater damage to the sufferer.

Even though the findings from the brains of deceased MS patients point to a strong involvement by killer T cells, scientists have always had a problem with this: "In animal experiments, which are unavoidable for the development of new treatment strategies, there has been no convincing demonstration of an attack on the nerve sheaths that is mediated by killer T cells," explains Hünig. For this reason, the research group made their search a little more complicated.

They infected mice in the laboratory with a specific species of bacteria - listeria -, which shares a protein with oligodendrocytes, and observed the consequences when peripheral parts of the body were infected and when the infection was confined to the brain.

The brain decides

The outcome: "With an infection in the periphery, the killer cells search for the pathogen all over the body, including the brain," says Hünig. However, in this case the immune system is able to identify those killer cells that mistake the myelin sheaths for something alien because they recognize the protein the sheaths share with listeria and so attack. It fights the killer cells and destroys them. It is a different story when the infection is in the brain itself: "Then the attack is allowed, which destroys the protective myelin sheath and leads to the formation of the plaques you see with multiple sclerosis," explains the scientist.

A kind of "trade-off" seems to be responsible for the difference in progression. The brain's "decision" to allow the attack helps combat the pathogen. It would appear that the brain is applying the motto: better that a few infected cells are destroyed and nerve cell extensions are demyelized than that the pathogen spreads and may therefore kill the sufferer. However, in the absence of an infection with menacing pathogens, the brain "recognizes" that this is a misguided attack by killer T cells and destroys them. It is possible, though, that the brain may sometimes "overestimate" the threat posed by a microbial pathogen and may sacrifice the protective myelin sheath unnecessarily.

Next steps

"These findings could form the basis for future therapies focused on combating microbial pathogens in the brain as well as reducing the local inflammation they cause," hopes Hünig. Since many researchers are convinced that viruses can trigger certain forms of multiple sclerosis, he believes it makes sense to continue to conduct research in this direction.

Oligodendrocytes Enforce Immune Tolerance of the Uninfected Brain by Purging the Peripheral Repertoire of Autoreactive CD8+ T Cells; Shin-Young Na, Andreas Hermann, Monica Sanchez-Ruiz, Alexander Storch, Martina Deckert and Thomas Hünig; Immunity, Published online: June 7, DOI: 10.1016/j.immuni.2012.04.009

Contact Prof. Dr. Thomas Hünig, Department of Immunology, T: +49 (0)931 201-49951, e-mail: huenig@vim.uni-wuerzburg.de

idw :: 13.06.2012