Absence of perforin expression confers axonal protection despite demyelination.
Current evidence suggests that demyelination may be a necessary but not a sufficient condition for neurologic deficits associated with multiple sclerosis. Axon injury that occurs within the permissive environment of the demyelinated lesion is better correlated with functional deficits, but the mechanisms and cellular effectors of this injury are largely unknown. In an effort to identify potential axon injury mediators, we examined demyelination, motor function, and the number of spinal axons in perforin-deficient mice. Perforin is a critical molecular mediator of cytotoxic immunological injury and we hypothesized that genetic deletion of perforin expression would protect demyelinated axons. Indeed, we found that while perforin-deficient mice had considerable spinal cord demyelination 180 days after infection with Theiler's murine encephalomyelitis virus, such mice exhibited functional and axonal preservation comparable to non-demyelinated perforin-competent controls. We conclude that perforin-dependent effector cells such as cytotoxic T cells, gammadelta T cells, and natural killer cells may play a role in axon damage that is dependent upon but separable from demyelination.
Howe
Charles L
CL
Department of Neuroscience, Mayo Clinic College of Medicine, 200 First St SW, Rochester, MN 55905, USA. howe.charles@mayo.edu
Adelson
Jaimie D
JD
Rodriguez
Moses
M
D000818:Animals; D001369:Axons / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D003711:Demyelinating Diseases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D004679:Encephalomyelitis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009103:Multiple Sclerosis / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins / Q000235:genetics*; D013116:Spinal Cord / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism; D017945:Theilovirus / Q000276:immunology; D014855:Wallerian Degeneration / Q000235:genetics / Q000276:immunology / Q000378:metabolism
D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D054353:Perforin