In diseases such as multiple sclerosis, cells of the immune
system infiltrate the brain tissue, where they cause immense damage. For many
years, it was an enigma as to how these cells can escape from the bloodstream.
This is no trivial feat, given that specialized blood vessels act as a barrier
between the nervous system and the bloodstream. Until now, tissue sections
provided the sole evidence that the immune cells really do manage to reach the
nerve cells. Now, a team of scientists from the Max Planck Institute of
Neurobiology, the University Medical Center Göttingen, and other institutes,
has witnessed the movements of these cells "live" under the
microscope for the very first time. In the process, they discovered several new
behavioural traits of the immune cells. The consolidated findings mark a
significant step forward in our understanding of this complex disease. (Nature,
14 October 2009)
The brain and the spinal cord monitor and control the
functions of all body parts and co-ordinate the whole organism's movements,
senses and behaviour. Adequate protection of the brain and spinal cord are
therefore of the utmost importance. Physical influences and injuries are warded
off by the cranial bone and the vertebral column. Dangers lurking within the
body, such as viruses circulating in the bloodstream, are kept at bay by highly
specialized blood vessels. The vessels' walls form a barrier that cannot be
penetrated by the cells or various other small particles, thus serving to
protect the delicate nerve cells.
The picture shows the movement of creeping T-cells (green) inside blood vessels (red) over a period of about 20 minutes. It clearly shows that some T-cells leave the blood vessels -- the long exposure lets them leave a green trail as the cells make their way through the brain tissue. Credit: Image: Max Planck Institute of Neurobiology / Bartholomäus
There are, however, exceptions to the rule. In diseases such
as multiple sclerosis (MS), aggressive cells in the immune system manage to
break through the blood vessels' barrier. Having invaded the brain tissue,
these cells wreak havoc by triggering off inflammatory reactions and attacking
nerve cells. In Germany
alone, the resulting adverse effects afflict over 120,000 MS-patients.
Tracking down the
culprits
Since there is normally a clear division between the blood
circulatory system and the central nervous system (i.e. brain plus spinal
cord), scientists were baffled as to how immune cells manage to cross the
blood-brain-barrier. This knowledge may aid in understanding the origins of
multiple sclerosis. In the 1980s, scientists were able to prove conclusively
that, under certain conditions, so called T-cells can recognize and attack
components of the body's own brain cells. Thanks to tissue sections performed
over the last few decades, scientists now have much better knowledge of the
migration of these cells from their point of origin to their point of
penetration into the brain and the damage that they cause. However, actual
observations of such movements long remained impossible
Observing aggressive
cells in action
Scientists at the Max Planck Institute of Neurobiology, the
University Medical Center Göttingen and their colleagues have now overcome this
impossibility. Using a two-photon microscope, the researchers succeeded in
tracing the movements of aggressive T-cells labelled with the green fluorescent
protein (GFP) in the living tissue of rats. The systematic observation of these
cells during the course of the disease provided amazing new insights into the
cell's behaviour.
The scientists discovered that the aggressive T-cells
overcome the barrier between blood and nerve tissue in a number of steps.
Outside the nervous system, the labelled cells moved just as we would expect
them to; most cells were floating along with the flow of the bloodstream. Only
now and again did a cell attach itself briefly onto the vascular wall. Here they
rolled in the direction of the blood stream or were being carried off again by
the current. Yet, once the cells reached the blood vessels of the nervous
system, they began to act in a completely different manner. The scientists
observed here far more cells clinging to the vascular walls. "Things got
really exciting when we observed that the cells can actually creep, a behaviour
so far unheard of for T-cells", Ingo Bartholomäus relates his
observations. Here, "creeping" describes an active cell movement, usually
against the flow of the bloodstream. The scientists watched T-cells as they
took anything between a few minutes and several hours to creep along the
vessels' walls. At the end of such a search movement, the cells were either
swept away again by the bloodstream or they managed to squeeze through the
vascular wall.
Ominous encounters
Having successfully penetrated the blood-brain-barrier, the
cells continued their search in the vicinity of the blood vessels. It was thus
only a question of time before the T-cells encountered one of the phagocytic
cells abundant on the outer linings of blood vessels and on the surface of the
nerve tissue. When a mobile T-cell came across such a phagocyte, the two cells
formed a closely connected pair. Some of these pairs remained inseparable for
several minutes.
Although the scientists already knew that T-cells must make
contact with phagocytes in order to become immune-activated, they were now able
to observe these interactions right where they happened, i.e. at the blood-brain-barrier.
And indeed, the T-cells did not launch their attack on the nervous system by
releasing their inflammatory neurotransmitters until they had bonded with the
phagocytes. As a result of the T-cells' activation, more and more T-cells
passed through the vascular walls. "The activation of T-cells at the
border to the nerve tissue appears to be a decisive signal for the invasion of
the immune cells", concludes Alexander Flügel, supervisor of the study and
director of the Department of Experimental and Clinical Neuroimmunology at the
University Medical Center Göttingen and Head of the MS Hertie-Institute.
Light bulb moments
Thanks to their sophisticated observation methods, the
scientists also established that some of the antibodies already being used in
MS-therapy cause the creeping cells to disappear. As Ingo Bartholomäus explains
"Up to now, it was only known that these antibodies prevented the T-cells'
escaping from the blood vessels, but as our observations now show, they
actually prevent them from creeping".
Thanks to the scientists' observations, we now have a much
clearer picture of how the immune cells move and obtain access to the nervous
system. This knowledge is likely to also increase our knowledge of the immune
system's security system functions in healthy tissue. However, as is often the
case, new insights and information also give rise to many new questions. How do
the immune cells manage to cling to the lining of the blood vessels and how do
they recognize the weak spots, where they can slip through the barrier between
the bloodstream and the nervous system? What governs the cells once they have
surmounted the blood-brain-barrier? These are some of the questions the
scientists will be addressing next. The long-term goal will be to develop new
forms of therapy and medication for multiple sclerosis and other diseases.
Tracking down the causes of multiple sclerosis (MPS press
release, June 10, 2009)
http://goto.mpg.de/mpg/news/20090610/
Original work:
Ingo Bartholomäus*, Naoto Kawakami*, Francesca Odoardi,
Christian Schläger, Djordje Miljkovic, Joachim W. Ellwart, Wolfgang EF
Klinkert, Cassandra Flügel-Koch, Thomas B. Issekutz, Hartmut Wekerle, Alexander
Flügel [*equal contribution]
Effector T cell interactions with meningeal vascular structures in nascent
autoimmune CNS lesions, Nature, October 14, 2009
Original
article