Immune cells (red) attack nerve cells of mice. This leads to lethally elevated calcium levels within the neurons. (Photo: Dr. Volker Siffrin/Copyright: MDC)
Using imaging tools which enable investigation of processes in living organisms, they were able to show a direct interaction between immune cells and neurons which plays a significant role in neuronal injury. However, this direct interaction may respond to therapeutic intervention. The study by Dr. Volker Siffrin and Professor Dr. Frauke Zipp (formerly Max Delbrück Center for Molecular Medicine, MDC, Berlin-Buch, now University Medical Center Johannes Gutenberg University, Mainz) has now been published in the journal Immunity (DOI 10.1016/j.immuni.2010.08.018)*.
Multiple sclerosis is an autoimmune disease in which a person’s own immune system attacks the central nervous system. Symptoms of the disease are variable depending on which nerves are affected, but often include muscle weakness, walking difficulties, numbness and visual disturbances. Research has shown that MS is caused by damage to the protective myelin sheath, an insulating substance that surrounds nerve processes and is critical for transmission of nerve impulses.
Research has also indicated that direct damage to neurons is prominent in early disease stages. “The contribution of direct neuronal damage to MS pathology has been debated since the first description of the disease,” explained Professor Frauke Zipp, senior author of the study. “Although many different theories about possible underlying mechanisms have been proposed – such as neuron damage being a secondary effect of the disrupted myelin sheath – actual events leading to neural damage are not well understood.”
To investigate processes in the living organisms, Dr. Zipp and her colleagues used two-photon laser scanning microscopy (TPLSM), with which they studied the role immune cells play in neuronal damage in mice with experimental autoimmune encephalomyelitis (EAE), an animal model of MS. They observed direct synapse-like interactions between immune cells and neurons.
Immune cells called Th17 cells, which have been linked to autoimmune inflammation, induced elevated calcium levels in the neurons, which in the long run are toxic to the cells. Normally, calcium within the neuron plays a crucial role in exciting nerve cells as well as muscle cells.
This is significant because fluctuations in neuronal intracellular calcium levels that are linked to cell injury are partially reversible when the researchers expose the lesions of the animals to compounds used to treat excitotoxicity.
These results highlight a specific interaction between the immune system and the nervous system, implicating direct neuronal damage in autoimmune-mediated inflammation. “Our use of in vivo imaging during disease has led to the characterization of neuronal dysfunction as early and potentially reversible, and suggests that immune-mediated disturbances of the neurons themselves contribute to multiple sclerosis, in addition to interruptions in nerve cell transmission as a result of changes to the myelin sheath,” Professor Zipp concluded.
“Furthermore, immune-mediated reversible calcium increases in neurons are a potential target for future therapeutics.” However, it will take many years to find out if this is a strategy which will work for treating MS.
*In vivo imaging of partially reversible Th17 cell-induced neuronal dysfunction in the course of encephalomyelitis
Volker Siffrin,1,2* Helena Radbruch,2,3* Robert Glumm,2,3 Raluca Niesner,2,3 Magdalena Paterka,2 Josephine Herz,2,3 Tina Leuenberger,2 Sabrina M. Lehmann, 4 Sarah Luenstedt,2,3 Jan Leo Rinnenthal,2 Gregor Laube,4 Hervé Luche,5 Seija Lehnardt,4 Hans-Joerg Fehling,5 Oliver Griesbeck,6 Frauke Zipp1,2
* equal contribution
1Neurology Department, University Medical Center Mainz, Johannes Gutenberg University Mainz, 55131 Mainz, Germany
2Max Delbrück Center for Molecular Medicine Berlin-Buch, 13125 Berlin, Germany
3Charité – University Medical Center Berlin, 10117 Berlin, Germany
4Institute of Cell Biology and Neurobiology, Charité – University Medicine Berlin, 10117 Berlin, Germany
5Institute of Immunology, University Clinics Ulm, Ulm, Germany
6Max Planck Institute of Neurobiology, 82152 Martinsried, Germany
*Correspondence: firstname.lastname@example.org (F.Z.), email@example.com (V.S.)
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