Demyelinated axons and motor function are protected by genetic deletion of perforin in a mouse model of multiple sclerosis

Chandra Deb, Reghann G. LaFrance-Corey, Laurie Zoecklein, Louisa Papke, Moses Rodriguez, Charles L. Howe

Research output: Contribution to journalArticlepeer-review

37 Scopus citations

Abstract

Axon injury is a major determinant of the loss of neurological function in patients with multiple sclerosis. It is unclear, however, whether damage to axons is an obligatory consequence of demyelination or whether it is an independent process that occurs in the permissive environment of demyelinated lesions. Previous investigations into the role of CD8+ T cells and perforin in the Theiler murine encephalomyelitis virus model of multiple sclerosis have used mouse strains resistant to Theiler murine encephalomyelitis virus infection. To test the role of CD8+ T cells in axon injury, we established a perforin-deficient mouse model on the H-2q major histocompatibility complex background thereby removing confounding factors related to viral biology in this Theiler murine encephalomyelitis virusYsusceptible strain. This permitted direct comparison of clinical and pathological parameters between perforin-competent and perforin-deficient mice. The extent of demyelination was indistinguishable between perforin-competent and perforin-deficient H-2q mice, but chronically infected perforin-deficient mice exhibited preservation of motor function and spinal axons despite the presence of spinal cord demyelination. Thus, demyelination is necessary but insufficient for axon injury in this model; the absence of perforin protects axons without impacting demyelination. These results suggest that perforin is a key mediator of axon injury and lend additional support to the hypothesis that CD8+ T cells are primarily responsible for axon damage in multiple sclerosis.

Original languageEnglish (US)
Pages (from-to)1037-1048
Number of pages12
JournalJournal of Neuropathology and Experimental Neurology
Volume68
Issue number9
DOIs
StatePublished - Sep 1 2009

Keywords

  • Axon injury
  • CD8 T cell
  • CNS inflammation
  • MHC class I
  • Multiple sclerosis
  • Perforin
  • Theiler murine encephalomyelitis virus

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Neurology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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