Preservation of neurologic function during inflammatory demyelination correlates with axon sparing in a mouse model of multiple sclerosis.
Axonal injury has been proposed as the basis of permanent deficits in the inflammatory, demyelinating disease, multiple sclerosis. However, reports on the degree of injury are highly variable, and the responsible mechanisms are poorly understood. We examined the relationships among long-term demyelination, inflammation, axonal injury, and motor function in a model of multiple sclerosis, in which mice develop chronic, immune-mediated demyelination of the spinal cord resulting from persistent infection with Theiler's virus. We studied two strains of mice, inbred SJL/J and C57BL/6x129 mice deficient in beta(2)-microglobulin and therefore CD8 lymphocytes. After 8 months of disease, SJL mice had considerably worse motor function than beta(2)-microglobulin-deficient mice. Motor dysfunction correlated linearly with the extent of demyelinated lesions in the spinal cord (lesion load) within each strain, but no difference in lesion load was present between strains. Also, the extent of remyelination did not differ between strains. Instead, the disparity in motor deficits reflected differences in the integrity of descending neurons. That is, retrograde labeling of reticulospinal, vestibulospinal, and rubrospinal neurons, although reduced in all chronically diseased mice, was two to seven times higher in beta(2)-microglobulin-deficient mice. The labeling was superior in beta(2)-microglobulin-deficient mice despite the fact that lesion expanse and therefore the number of axons traversing lesions were similar in both strains. Thus, by all criteria axons were equivalently demyelinated in SJL and beta(2)-microglobulin-deficient mice, but the extent of axonal injury differed significantly. These results indicate that mechanisms of demyelination and axonal injury are at least partly separable, and are consistent with the hypothesis that cytotoxic CD8 lymphocytes may selectively injure demyelinated axons. Additionally, the data suggest that axonal injury obligatorily results from chronic inflammatory demyelination and significantly contributes to neurological deficits.
Ure
D R
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Department of Immunology, Mayo Medical and Graduate School, 428 Guggenheim Building, 200 1st Street SW, Rochester, MN 55905, USA. ure.daren@mayo.edu
Rodriguez
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D000818:Animals; D001369:Axons / Q000502:physiology*; D002908:Chronic Disease; D003711:Demyelinating Diseases / Q000473:pathology / Q000503:physiopathology*; D004195:Disease Models, Animal; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout / Q000235:genetics; D009043:Motor Activity; D009103:Multiple Sclerosis / Q000503:physiopathology*; D009186:Myelin Sheath / Q000502:physiology; D009187:Myelitis / Q000473:pathology / Q000503:physiopathology*; D009420:Nervous System / Q000503:physiopathology*; D001613:beta 2-Microglobulin / Q000172:deficiency / Q000235:genetics
D001613:beta 2-Microglobulin