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Multiple sclerosis: when and where do immune cells spark off an autoimmune disease?

Scientists of the University Medical Center Göttingen have developed a special biological fluorescent sensor technique that makes it possible for the first time in a model of MS to clarify how and exactly where self-destructive brain inflammation is sparked off. Publication in NATURE MEDICINE's May 2013 issue

Scientists from the Department of Neuroimmunology and the Institute for Multiple Sclerosis Research (IMSF), the latter founded by the Hertie Foundation, have developed a technology that has allowed them to track several previously unexplained phenomena in multiple sclerosis (MS). A research team headed by Prof. Alexander Flügel could employ fluorescent proteins to make visible the individual steps in the process that sparks off a destructive autoimmune disease in the brain.

A T lymphocyte is activated after contact with a phagocytic cell. Each picture shows a different time-point in a video recording of the interaction between the two cells.
Source: umg/imsf göttingen

An autoreactive T lymphocyte, here in contact with a microglia cell, is activated deep within inflamed nervous tissue.
Source: umg/imsf göttingen

Using this new technique, they could observe autoimmunological processes in living tissue and thereby elucidate previously unresolved questions relating to the immune cells that cause the disease. The results have been published in the May issue of the highly renowned journal NATURE MEDICINE.

Original publication: Dmitri Lodygin, Francesca Odoardi, Christian Schläger, Henrike Körner, Alexandra Kitz, Michail Nosov, Jens van den Brandt, Holger M Reichardt, Michael Haberl & Alexander Flügel. A combination of fluorescent NFAT and H2B sensors uncovers dynamics of T cell activation in real time during CNS autoimmunity, Nature Medicine (2013) doi:10.1038/nm.3182.

Autoimmune diseases are caused by a specific type of immune cell, namely T lymphocytes, which attack the body's own tissue. In multiple sclerosis (MS), an autoimmune disease of the central nervous system, brain-reactive T lymphocytes invade the nervous tissue and cause inflammatory reactions there which can lead to serious and sometimes permanent damage, for example motor deficits and sensibility dysfunctions.

Known facts: T lymphocytes cannot recognize brain tissue by themselves. To do their destructive work T lymphocytes need help. Apparently central nervous systems cells give away important information about the identity of brain tissue.

The rudimentary order of events behind this process was also known: unsuspecting helper cells offer the "blind” T lymphocytes fragments of the relevant brain tissue proteins on specialized carrier proteins, so-called MHC molecules. The T lymphocytes can sense these fragments with special feelers and then can recognize brain tissue. Ultimately it is this recognition of brain tissue that is the deciding factor for the development of an autoimmune disease, because it activates immune cells which then set an alarm program into motion that leads to the release of nerve-damaging neurotransmitters and antigens.

Unclear up until now was: Exactly which nervous system cells render this fatal aid? Where exactly in brain tissue does the activation takes place? In which phase of brain tissue inflammation is the recognition process significance to the disease manifestation?

Using the biological signaling system reported here, scientists at the Department of Neuroimmunology and Institute for Multiple Sclerosis Research (IMSF) headed by Professor Alexander Flügel look for the answers to these questions directly in the living nervous system. Thereby the scientists insert differently colored fluorescent proteins into the disease-causing T cells. These fluorescent signals form a specific dispersal pattern when a T lymphocyte is in its non-activated, internally resting state. But as soon as a T lymphocyte meets a helper and is activated by recognizing the brain substance offered to it, the fluorescent signals change their dispersal pattern in a clearly recognizable way”, explains Dr. Dimitri Lodygin, the first author of the paper (Figures 1 and 2). The scientists test this alarm system in a disease model for MS, using a special microscopy technique that allows them to film the dispersal of the fluorescent alarm signals in the T lymphocytes in real time.

In a healthy central nervous system tissue there are not many types of cells that could help the T lymphocytes to find their target brain tissue. But then what sparks off the autoimmune process? By employing their new technique the Göttingen scientists could now for the first time answer this question unequivocally. They found out that the disease-causing T lymphocytes meet their helpers as soon as the former leave the bloodstream. The helper cells are scavenger cells, so-called macrophages. The real role of macrophages is to guard the nervous tissue from potentially harmful intruders. However, these scavenger cells also appear to gather up brain proteins and to offer them to the the pathogenic T lymphocytes. The result is that these brain-specific T lymphocytes cause an inflammatory reaction to take place in the meninges (membranes of the brain and spinal cord) that quickly spreads to the neighboring tissue.

The Göttingen scientists observed something unusual when filming the first activation steps of T lymphocytes. Usually T lymphocytes are constantly underway, i.e. they restlessly move around looking for partners to give them the relevant activation signal. Once they meet one, they stop and usually form a long-lasting and close connection with the helper cell. "T lymphocytes in the nervous system showed a completely different behavior. When they met their partner they just made a quick stop, started up their activation program and then set off again. The T lymphocytes only made longer-lasting contacts once the inflammatory process was well under way” says Dr. Lodygin. The burning question for the researchers remains: Which kind of connection is is needed by the lymphocytes to become fully activated? Is it the short or the long contacts or a combination of both?”

Interestingly, the central nervous system can respond very quickly to an inflammation, illustrated by the fact that brain cells in inflamed tissue can rapidly have many MHC molecules on their surface. This is especially true for so-called microglia. Microglia cells are the central nervous system's "immune cells in disguise". They are distributed in large numbers throughout the nervous tissue and can build up MHC molecules very quickly in response to inflammation, and therefore are certainly capable of offering T lymphocytes the relevant protein fragments.
And it is exactly this that the Göttingen researchers observed. After invading the nervous tissue the T lymphocytes met microglia and other scavenger cells that the inflammation had attracted to leave the bloodstream. Then many of the T lymphocytes showed the specific "activation-pattern” of the fluorescent markers. "Apparently a lymphocytic activation sparked off by contacts with microglia and peripheral scavenger cells also takes place deep inside the nervous tissue during the advanced stages of inflammation”, says Prof. Flügel. (Figure 3).

These results caused the scientists to pose the deciding question: At which time point must the T lymphocytic activation take place so that it results in an autoimmune disease? Surprisingly, it was discovered that it is the early activation processes, occurring even before first disease symptoms, that are decisive for the course of the disease. "After the disease had started we could still successfully block the activation of T lymphocytes”, explained Dr. Lodygin "but this did not have any influence on the course of the disease.
The above observations made by the Göttingen research team could also be relevant for the human disease. Blocking T lymphocyte activation could be a target for therapeutic intervention. The results indicate, however, that such a therapy could only be effective when started before clinical symptoms appear.
University Medical Center Göttingen, Georg-August University
Department of Neuroimmunology / Institute for Multiple Sclerosis Research
Prof. Alexander Flügel
Phone: +49 (0)551 / 39-13332,

Stefan Weller | Uni Göttingen
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