title: Demyelinated axons and motor function are protected by genetic deletion of perforin in a mouse model of multiple sclerosis.
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-2 major histocompatibility complex background thereby removing confounding factors related to viral biology in this Theiler murine encephalomyelitis virus-susceptible 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-2 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.
authors.affiliation: Departments of Neurology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Chandra
authors.initials: C
authors.lastname: Deb
authors.forename: Reghann G
authors.initials: RG
authors.lastname: Lafrance-Corey
authors.forename: Laurie
authors.initials: L
authors.lastname: Zoecklein
authors.forename: Louisa
authors.initials: L
authors.lastname: Papke
authors.forename: Moses
authors.initials: M
authors.lastname: Rodriguez
authors.forename: Charles L
authors.initials: CL
authors.lastname: Howe
mesh_terms: D000818:Animals; D001369:Axons / Q000276:immunology / Q000473:pathology*; D001921:Brain / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D018188:Cardiovirus Infections / Q000235:genetics / Q000276:immunology; D003711:Demyelinating Diseases / Q000235:genetics* / Q000276:immunology / Q000503:physiopathology; D004195:Disease Models, Animal; D005434:Flow Cytometry; D015870:Gene Expression; D020869:Gene Expression Profiling; D006183:H-2 Antigens / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D009103:Multiple Sclerosis / Q000235:genetics* / Q000276:immunology / Q000503:physiopathology*; D054353:Perforin / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013116:Spinal Cord / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D017945:Theilovirus / Q000235:genetics / Q000276:immunology
chemical_list: D006183:H-2 Antigens; D054353:Perforin
references.citation: Brain Pathol. 2003 Jul;13(3):291-308
references.pmid: 12946019
references.citation: Eur J Immunol. 1993 Sep;23(9):2287-93
references.pmid: 8370406
references.citation: Am J Pathol. 2001 Sep;159(3):809-15
references.pmid: 11549572
references.citation: J Clin Invest. 2008 Apr;118(4):1532-43
references.pmid: 18340379
references.citation: J Neurovirol. 2008 May;14(3):261-6
references.pmid: 18569460
references.citation: Brain Pathol. 1999 Jan;9(1):21-31
references.pmid: 9989447
references.citation: Am J Pathol. 2006 Sep;169(3):999-1011
references.pmid: 16936273
references.citation: J Neuroimmunol. 2007 Nov;191(1-2):79-85
references.pmid: 17920696
references.citation: Future Virol. 2008;3(6):579-593
references.pmid: 19079794
references.citation: J Neurosci. 1998 Sep 15;18(18):7306-14
references.pmid: 9736651
references.citation: Am J Pathol. 2003 Apr;162(4):1259-69
references.pmid: 12651618
references.citation: J Virol. 1993 Jan;67(1):589-92
references.pmid: 8416386
references.citation: Brain. 2000 Jun;123 ( Pt 6):1174-83
references.pmid: 10825356
references.citation: J Exp Med. 2000 Aug 7;192(3):393-404
references.pmid: 10934227
references.citation: J Neurovirol. 2001 Oct;7(5):409-20
references.pmid: 11582513
references.citation: Infect Immun. 1975 May;11(5):1147-55
references.pmid: 164412
references.citation: Brain Pathol. 2004 Jan;14(1):43-50
references.pmid: 14997936
references.citation: J Neuropathol Exp Neurol. 2007 Sep;66(9):828-37
references.pmid: 17805013
references.citation: Neurobiol Dis. 2007 Feb;25(2):354-9
references.pmid: 17112732
references.citation: Ann Neurol. 2008 Apr;63(4):428-35
references.pmid: 18438950
references.citation: J Virol. 2001 Aug;75(16):7420-8
references.pmid: 11462014
references.citation: Lab Invest. 1991 Mar;64(3):358-70
references.pmid: 2002654
references.citation: Nat Med. 1998 Feb;4(2):187-193
references.pmid: 9461192
references.citation: J Neuropathol Exp Neurol. 2007 Apr;66(4):295-304
references.pmid: 17413320
references.citation: Nat Rev Neurosci. 2006 Dec;7(12):932-41
references.pmid: 17115075
references.citation: Am J Pathol. 2008 Jul;173(1):93-105
references.pmid: 18535178
references.citation: Trends Immunol. 2008 Feb;29(2):54-60
references.pmid: 18182323
references.citation: Ann Neurol. 2006 Mar;59(3):478-89
references.pmid: 16392116
references.citation: J Neuroimmunol. 2007 Aug;188(1-2):13-21
references.pmid: 17493690
references.citation: J Neuroimmunol. 2001 Jun 1;116(2):125-35
references.pmid: 11438167
references.citation: Springer Semin Immunopathol. 2002;24(2):105-25
references.pmid: 12503060
references.citation: J Virol. 1998 Sep;72(9):7320-9
references.pmid: 9696828