Perforin-dependent neurologic injury in a viral model of multiple sclerosis

Paul D. Murray, Dorian B. McGavern, Xiaoqi Lin, M. Kariuki Njenga, Julian Leibowitz, Larry R. Pease, Moses Rodriguez

Research output: Contribution to journalArticle

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Abstract

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 (β2m-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, Ipr (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 Ipr 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.

Original languageEnglish (US)
Pages (from-to)7306-7314
Number of pages9
JournalJournal of Neuroscience
Volume18
Issue number18
StatePublished - Sep 15 1998

Fingerprint

Nervous System Trauma
Perforin
Demyelinating Diseases
Multiple Sclerosis
Theilovirus
Neurologic Manifestations
T-Lymphocytes
Fas Ligand Protein
Nervous System Diseases
Genotype
Viruses
Mutation
Exocytosis
Delayed Hypersensitivity
Haplotypes
Epitopes
Spinal Cord
Pathology
Antigens

Keywords

  • Cytotoxic T lymphocyte
  • Granule exocytosis
  • MHC class I
  • Perforin
  • Picornavirus
  • Theiler's murine encephalomyelitis virus

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Murray, P. D., McGavern, D. B., Lin, X., Njenga, M. K., Leibowitz, J., Pease, L. R., & Rodriguez, M. (1998). Perforin-dependent neurologic injury in a viral model of multiple sclerosis. Journal of Neuroscience, 18(18), 7306-7314.

Perforin-dependent neurologic injury in a viral model of multiple sclerosis. / Murray, Paul D.; McGavern, Dorian B.; Lin, Xiaoqi; Njenga, M. Kariuki; Leibowitz, Julian; Pease, Larry R.; Rodriguez, Moses.

In: Journal of Neuroscience, Vol. 18, No. 18, 15.09.1998, p. 7306-7314.

Research output: Contribution to journalArticle

Murray, PD, McGavern, DB, Lin, X, Njenga, MK, Leibowitz, J, Pease, LR & Rodriguez, M 1998, 'Perforin-dependent neurologic injury in a viral model of multiple sclerosis', Journal of Neuroscience, vol. 18, no. 18, pp. 7306-7314.
Murray PD, McGavern DB, Lin X, Njenga MK, Leibowitz J, Pease LR et al. Perforin-dependent neurologic injury in a viral model of multiple sclerosis. Journal of Neuroscience. 1998 Sep 15;18(18):7306-7314.
Murray, Paul D. ; McGavern, Dorian B. ; Lin, Xiaoqi ; Njenga, M. Kariuki ; Leibowitz, Julian ; Pease, Larry R. ; Rodriguez, Moses. / Perforin-dependent neurologic injury in a viral model of multiple sclerosis. In: Journal of Neuroscience. 1998 ; Vol. 18, No. 18. pp. 7306-7314.
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