Genetically dominant spinal cord repair in a murine model of chronic progressive multiple sclerosis.
For reasons that are not well understood, central nervous system repair in multiple sclerosis is often minimal. We present evidence, in a murine model of chronic progressive multiple sclerosis, that genetic factors can substantially influence remyelination, axonal integrity, and neurologic function. Four inbred mouse strains, SJL, B10.D1-H2(q), FVB, and SWR, developed extensive inflammatory demyelination by 3 months after infection with Theiler's murine encephalomyelitis virus. Demyelination continued lifelong in SJL and B10.D1-H2(q) mice, accompanied by axonal injury, minimal remyelination, and progressive motor dysfunction. In contrast, FVB and SWR mice showed less axonal injury, progressive remyelination, and stabilization of motor function. Genetic dominance of the reparative traits was demonstrated by crossing remyelinating strains (FVB and SWR) with nonremyelinating strains (SJL and B10.D1-H2(q)). All F1 mice developed a phenotype identical to FVB and SWR, showing extensive remyelination, partial preservation of axons, and preserved motor function. Analyses of viral RNA and antigen, immune cell infiltration, and antiviral antibody titers did not predict the phenotypic differences between strains. These results highlight the significant extent to which hereditary factors can control disease course and demonstrate that the switch from a pathogenic to a reparative phenotype can occur even after prolonged inflammatory demyelination.
Bieber
Allan J
AJ
Department Neurology, Mayo Foundation and College of Medicine, Rochester, Minnesota, USA. bieber.allan@mayo.edo
Ure
Daren R
DR
Rodriguez
Moses
M
D000818:Animals; D004195:Disease Models, Animal; D005799:Genes, Dominant; D051379:Mice; D008810:Mice, Inbred C57BL; D020528:Multiple Sclerosis, Chronic Progressive / Q000235:genetics* / Q000503:physiopathology* / Q000821:virology; D009186:Myelin Sheath / Q000473:pathology / Q000821:virology; D009413:Nerve Fibers, Myelinated / Q000473:pathology / Q000821:virology; D013045:Species Specificity; D013116:Spinal Cord / Q000473:pathology*; D017945:Theilovirus / Q000235:genetics