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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 Rodriguez^{1, 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-2^b 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

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Copyright © 1998 Society for Neuroscience  0270-6474/98/18187306-09$05.00/0

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