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The Journal of Neuroscience, September 15, 1998, 18(18):7306-7314
Perforin-Dependent Neurologic Injury in a Viral Model of
Multiple Sclerosis
Paul D.
Murray1,
Dorian
B.
McGavern3,
Xiaoqi
Lin1,
M. Kariuki
Njenga1,
Julian
Leibowitz4,
Larry R.
Pease1, and
Moses
Rodriguez1, 2
Departments of 1 Immunology and 2 Neurology
and the 3 Program of Molecular Neuroscience, Mayo Clinic
and Foundation, Rochester, Minnesota 55905, and the
4 Department of Pathology and Laboratory Medicine, Texas A
& M College of Medicine, College Station, Texas 77843
In this study we demonstrate perforin-mediated cytotoxic effector
function is necessary for viral clearance and may directly contribute
to the development of neurologic deficits after demyelination in the
Theiler's murine encephalomyelitis virus (TMEV) model of multiple
sclerosis. We previously demonstrated major histocompatability complex
(MHC) class I-deficient ( 2m-deficient) mice with an otherwise resistant genotype develop severe demyelination with minimal neurologic disease when chronically infected with TMEV. These studies implicate CD8+ T cells as the pathogenic cell in the induction
of neurologic disease after demyelination. To determine which effector
mechanisms of CD8+ T cells, granule exocytosis or
Fas ligand expression, play a role in the development of demyelination
and clinical disease, we infected perforin-deficient,
lpr (Fas mutation), and gld (Fas ligand
mutation) mice with TMEV. Perforin-deficient mice showed viral
persistence in the CNS, chronic brain pathology, and demyelination in
the spinal cord white matter. Perforin-deficient mice demonstrated severely impaired MHC class I-restricted cytotoxicity against viral
epitopes, but normal MHC class II-restricted delayed-type hypersensitivity responses to virus antigen. Despite demyelination, virus-infected perforin-deficient mice showed only minimal neurologic deficits as indicated by clinical disease score, activity monitoring, and footprint analysis. Perforin- and MHC class II-deficient mice (with
functional CD8+ T cells and perforin molecules and
an H-2b haplotype) had comparable demyelination and
genotype, however, only the latter showed severe clinical disease.
Gld and lpr mice demonstrated normal
TMEV-specific cytotoxicity and maintained resistance to TMEV-induced
demyelinating disease. These studies implicate perforin release by
CD8+ T cells as a potential mechanism by which
neurologic deficits are induced after demyelination.
Key words:
Theiler's murine encephalomyelitis virus; picornavirus; MHC class I; perforin; granule exocytosis; cytotoxic T lymphocyte
Copyright © 1998 Society for Neuroscience 0270-6474/98/18187306-09$05.00/0
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