TY - JOUR
T1 - Preservation of neurologic function during inflammatory demyelination correlates with axon sparing in a mouse model of multiple sclerosis
AU - Ure, D. R.
AU - Rodriguez, M.
N1 - Funding Information:
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.
PY - 2002/5/10
Y1 - 2002/5/10
N2 - 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/6×129 mice deficient in β2-microglobulin and therefore CD8 lymphocytes. After 8 months of disease, SJL mice had considerably worse motor function than β2-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 β2-microglobulin-deficient mice. The labeling was superior in β2-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 β2-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.
AB - 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/6×129 mice deficient in β2-microglobulin and therefore CD8 lymphocytes. After 8 months of disease, SJL mice had considerably worse motor function than β2-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 β2-microglobulin-deficient mice. The labeling was superior in β2-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 β2-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.
KW - Axon injury
KW - CD8 lymphocytes
KW - Lesions
KW - Motor deficits
KW - Retrograde labeling
UR - http://www.scopus.com/inward/record.url?scp=0037052704&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0037052704&partnerID=8YFLogxK
U2 - 10.1016/S0306-4522(02)00012-X
DO - 10.1016/S0306-4522(02)00012-X
M3 - Article
C2 - 11983325
AN - SCOPUS:0037052704
SN - 0306-4522
VL - 111
SP - 399
EP - 411
JO - Neuroscience
JF - Neuroscience
IS - 2
ER -