T-cell mediated neurodegeneration and repair

Speaker: Frauke Zipp

Location: Erasmus MC

Date: 6 February 2017

Author: Carolien Bastiaanssen

 Frauke Zipp conducts research to learn more about the crosstalk of the immune system and the nervous system in neurology. In this field Multiple Sclerosis (MS) is studied as a model disease. In her talk she first explained about the pathology of MS and the current view on the mechanisms behind this disease. Next she showed some of the results of her own experimental work. Finally she highlighted several novel concepts that followed from recent experimental work.

mri-scan-ms

Figure 1: The white marks indicated by the red arrows are referred to as plaques. They are the result of damaged myelin. Adapted from http://www.radiologyassistant.nl/en/p4556dea65db62/multiple-sclerosis.html

MS is an immune-mediated disease. It is a chronic inflammation of the central nervous system (CNS), where the patient’s immune system attacks cells in the CNS by mistake. Especially the coating that protects nerve fibers, called myelin, is attacked by T-cells that entered the CNS. The damaged myelin causes scar tissue and as a consequence nerve impulses are distorted or interrupted. The demyelination can be visualized using an MRI scan. The scar tissue will show as white plaques (Figure 1). The current view is that due to the damaged myelin, there is less nutrition and support for the axons. Thus leading to axonal damage (Figure 2).  However there is also evidence that suggests demyelination does not have to occur before axon degeneration (Tomassy et al. 2014, Science). Both CD4 and CD8 cells can interact directly with axons, making it possible to attack the axon without demyelination. MS patients show a wide variety of symptoms including walking difficulties, numbness or spasticity. It is a very heterogenic disease with periodic relapses. It is unknown what triggers the disease, although it is thought that a combination of genetic susceptibility and environmental factors are involved.

demyelination

Figure 2: At the top of the image healthy neurons and axons are shown. The axons are protected by a myelin sheath. When the protective layer of myelin is broken down, a process called demyelination, the axons are exposed, leading to axonal damage. Adapted from: Susuki, K. (2010), Myelin: A specialized membrane for cell communication, Nature Education, 3(9):59

Zipp and her colleagues monitored in vivo what happens during MS in the brain stem. For this purpose they used an experimental autoimmune encephalomyelitis (EAE) mouse model. This enabled the live imaging of T-cells in the CNS. The experiments showed that T helper 17 (Th17) cells are attracted by CD11c+ cells. Depletion of the CD11c+ cells caused a significant reduction in the number of Th17 cells that entered the CNS. Another result that followed from their experiments was that Th17 cells are able to interact directly with demyelinating axons on their own without the recruitment of other cells.

In her talk, Frauke Zipp presented three novel concepts. First of all she described counterbalancing inflammatory processes. During their experiments they observed macrophage cells in the CNS called microglia. These cells can transport Th17 cells within the CNS. The microglia engulfs a living Th17 cell and then two different outcomes are possible. Either the Th17 cell escapes and lives on or the it goes into apoptosis. This work shows one of the mechanisms the CNS employs in an attempt to defend itself.

The second novel concept that was presented concerns the characteristic relapses in MS. Using the animal model, Zipp and her colleagues mimicked the relapses. They found that during a relapse there was no demyelination.

The final novel concept concerned neuroprotection, regeneration, plasticity and homeostasis. There are patients that have little lesions growing into large damage sites. Some damaged sites even disappear and are thus in some way repaired. In the animal model the same phenomenon is observed. It was for example shown that T helper 2 cells promote axonal outgrowth and that they can promote axonal regeneration after spinal cord injury in vivo.

The research of Frauke Zipp, has led to a different view in the field of neuroimmunology. Her interdisciplinary approach has provided new insights into the mechanisms of MS. By gaining a better understanding of these mechanisms, she hopes to contribute to the development of therapeutic strategies and the improvement of diagnostics.

 

 

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