Preservation of neurologic function during inflammatory demyelination correlates with axon sparing in a mouse model of multiple sclerosis
Section snippets
Mice and viral infection
C57BL/6×129/J (H-2b, β2m−/−) mice were acquired from the Mayo Clinic Immunogenetic Mouse Colony, C. David Director. SJL/J mice were from Jackson Laboratories. Six- to eight-week-old mice were intracerebrally injected with 2.0×106 plaque forming units of Daniel’s strain of TMEV and maintained until experimental analysis at 8–9 months post-infection.
Motor function
Chronically infected mice (infected for 8–9 months) and uninfected littermates were tested on a Rotamex Rotarod (Columbus Instruments, Columbus, OH,
Relative preservation of motor function in β2m−/− mice
Chronically infected β2m−/− and SJL mice (8–9 months post-infection) both have inflammatory demyelination of the spinal cord but only SJL mice have obvious reductions in spontaneous activity (Rivera-Quinones et al., 1998). As a more sensitive and objective measure of motor function, we assayed mice by rotarod, a rotating cylinder upon which mice run under accelerating conditions (McGavern et al., 1999b). We found that most chronically infected mice from both strains performed more poorly than
Discussion
This study was undertaken principally to understand how neuronal integrity is affected by inflammatory demyelination and how changes in neuronal integrity relate to motor function. The Theiler’s virus model offers many advantages for addressing these issues. One advantage is that the duration of pathology is precisely known, in contrast to the unknown histories of post-mortem or biopsied MS plaques. Without knowing lesion age or its changing character, the rate at which neurons are injured or
Conclusion
Our results emphasize the need to consider neuronal injury as a major factor in neurological dysfunction in demyelinating disease. The data suggest that axonal destruction is an inevitable consequence of chronic disease, but could be ameliorated by therapies that target cytotoxic CD8 lymphocytes or activated immune or glial cells that specifically damage axons. Alternative therapies might involve neurotrophic factors or other molecules that bolster endogenous neuroprotective mechanisms or
Acknowledgements
This work was supported by NIH Grant NS32129 and the generous support of Ms. Kathryn Petersen and Mr. and Mrs. Eugene Applebaum. D.R.U. was supported by a fellowship from the Multiple Sclerosis Society of Canada and NIH Grants NS32129 and PO1-NS38468. The authors would like to thank Laurie Zoecklein for technical support.
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2013, Progress in NeurobiologyCitation Excerpt :However, the significant decrease observed in medium-to-large myelinated axons in normally myelinated areas during the chronic phase of TMEV infection (Sathornsumetee et al., 2000) suggests that axonal degeneration may be independent of demyelination in at least some CNS areas during the late chronic phase. There is no consensus about the timing and the precise mechanism of axonal damage in the TMEV-IDD model of MS. Nevertheless, the observed axonal and functional preservation in chronically demyelinated mice genetically deficient in perforin (Howe et al., 2006), and the preservation of motor function (Rivera-Quinones et al., 1998) and axon integrity (Ure and Rodriguez, 2002) seen following genetic disruption of MHC class I function during chronic demyelination, strongly support the immune-mediated injury model. In MS lesions, CD8+ T cells are the most abundant lymphocytes (Babbe et al., 2000) and their presence is correlated with axonal injury (Bitsch et al., 2000).
Rapid formation of extended processes and engagement of Theiler's virus-infected neurons by CNS-infiltrating CD8 T cells
2010, American Journal of Pathology