T cells attack neurons in MS

In a rare glimpse inside a diseased brain, researchers watch for the first time as immune cells directly attack neurons in a mouse model of multiple sclerosis (MS). Published this week in linkurl:Immunity,;http://www.cell.com/immunity/home the surprising role of T helper cells in neurodegeneration may provide a novel therapeutic target for blocking neuron dysfunction in patients with MS.

Brain with MS lesions
U.S. Brookhaven National Laboratory,
linkurl:Wikimedia Commons;http://commons.wikimedia.org/wiki/File:Monthly_multiple_sclerosis_MRI.gif

"It's a beautiful paper," said linkurl:Howard Gendelman,;http://www.unmc.edu/pharmacology/gendelman/ chair of the department of pharmacology and experimental neuroscience at the University of Nebraska Medical Center, who was not involved in the research. "Axonal degeneration is a big part of MS, but nobody knew until this paper what the mechanism was." MS was first described as a demyelinating disease in which immune cells in the brain attack the protective myelin sheath around axons, tearing it apart and slowing or stopping nerve signals, leading to muscle spasms, weakness, and other symptoms of MS. Over the last decade, however, scientists have come to realize that axons are also part of the pathology of MS: Direct damage to neurons and their processes, and not just the myelin sheath, causes disability. linkurl:Frauke Zipp;http://www.unimedizin-mainz.de/neurologie/patienten/mitarbeiter/aerzte/univprof-dr-frauke-zipp.html?L=1 and colleagues at the Johannes Gutenberg University Mainz in Germany used live imaging to demonstrate how T cells cause severe, yet partially reversible, damage to axons and neuronal bodies in a mouse model of MS, mice induced with experimental autoimmune encephalomyelitis (EAE). In these mice, the team labeled neurons with green fluorescent protein and T cells with red. Then, using two-photon laser scanning microscopy, a relatively new tool that allows live imaging over several hours, the researchers observed, in real time, how T cells enter and move about the central nervous system. The results showed that some T cells directly kiss neuronal cell bodies, forming immune-neuronal synapses, indicating communication between the two cells. The cells forming these synapses were T helper cells called Th17 cells, which have linkurl:previously been implicated;http://www.the-scientist.com/blog/display/55517/ in MS inflammation. Indeed, time-lapse imaging showed axons falling apart at locations where synapses formed between the Th17 cells and neurons. Further experiments revealed that the Th17 cells caused an increase in calcium inside the neurons, followed by cell injury and death. A linkurl:2001 in vitro study;http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1850471/?tool=pubmed found that CD8 T cells, which predominate in human MS lesions, can also directly attack neurons, suggesting this may also be an important mechanism of neurodegeneration in human MS. That's not to say that T cell-induced neuronal damage is the only cause of MS, said Zipp, as demyelinaton is obviously a significant part of the disease. "It's really not clear when and to which extent the different types of pathology take place," she said. "But what is clear is an inflammatory attack against neurons and axons is a major part [of MS] and can be reversed." After the team determined the cause of damage, they successfully prevented it by blocking NMDA receptors, which allow calcium into a cell. When the receptors were blocked during T cell-neuron contact, calcium levels decreased. MS symptoms do not always get worse over time, but can often get better, even without treatment, implying that there are compensatory mechanisms in the brain to regenerate areas of damage. "This was always interpreted as remyelination," said Zipp, because the myelin sheath was believed to be the main source of damage. "Now we see that these calcium changes in the neuron, induced by the T cells, can be reversed." The next step, she added, is to find neuroprotective drugs that interfere with this newly discovered mechanism of neurodegeneration. The research also suggests a link between MS, classified as an autoimmune disease, and neurodegenerative disorders like Parkinson's disease, which are not typically linked to the immune system, said Gendelman. In a linkurl:Journal of Immunology paper;http://www.ncbi.nlm.nih.gov/pubmed/20118279 published earlier this year, Gendelman and colleagues found that Th17 cells are also involved in Parkinson's disease, perhaps as an immune system reaction to the buildup of toxic proteins in the brain. "We're finding that we may want to reexamine this whole deal," said Gendelman. "It's not just multiple sclerosis that is engaging these parts of the adaptive immune system; we're seeing it in animal models reflective of Parkinson's and Alzheimer's and possibly for ALS and Huntington's disease...[The immune system] may play a part in a broader spectrum of neurological diseases." V. Siffrin, et al., "In vivo imaging of partially reversible Th17 cell-induced neuronal dysfunction in the course of encephalomyelitis," Immunity, 32(4):424-36, 2010.
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[23rd March 2009]