CD8+-dependent CNS demyelination following ocular infection of mice with a recombinant HSV-1 expressing murine IL-2.
Demyelinating diseases comprise a spectrum of immunopathologic syndromes in which myelin, the fatty covering of nerve cell fibers in the brain and spinal cord, is destroyed. In this study, we have shown for the first time that ocular infection of BALB/c mice with a recombinant herpes simplex virus type 1 (HSV-1) expressing IL-2 (HSV-IL-2) results in CNS demyelination as determined by light microscopy and EM. The demyelinated lesions involve periventricular white matter, brain stem, and spinal cord white matter. Demyelination was detected in the CNS of infected mice up to 75 days (the longest time point tested) post HSV-IL-2 infection. In contrast, mice infected with HSV-IFN-gamma or HSV-IL-4, which are identical to HSV-IL-2 but express IFN-gamma or IL-4 instead of IL-2, did not exhibit demyelination. Control mice infected with wild-type HSV-1 or parental virus also remained free of these symptoms. During early times (days 3-7), post-infection with HSV-IL-2 virus, a T(H)1 + T(H)2 pattern of cytokines was produced by lymphocytes of infected mice while mice infected with HSV-IFN-gamma or control viruses produced a T(H)1 pattern of cytokine. By day 21 post-infection, all infected groups exhibited a T(H)1 pattern of response. Immunohistochemistry and FACS analyses of infiltrates in the brains and spinal cords of HSV-IL-2-infected mice showed elevations in CD4+ and CD8+ T cells and macrophages. However, T cell depletion studies suggest that only central memory CD8+ T cells are directly involved in the demyelination process, with macrophages being involved through a bystander effect.
Osorio
Yanira
Y
Center for Neurobiology and Vaccine Development, Ophthalmology Research, Department of Surgery, Cedars-Sinai Burns and Allen Research Institute, CSMC-D2024, 8700 Beverly Boulevard, Los Angeles, CA 90048, USA.
La Point
Scott F
SF
Nusinowitz
Steve
S
Hofman
Florence M
FM
Ghiasi
Homayon
H
D000818:Animals; D000956:Antigens, Viral / Q000032:analysis; D001921:Brain / Q000276:immunology / Q000473:pathology / Q000648:ultrastructure; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology / Q000821:virology; D002465:Cell Movement / Q000276:immunology*; D020278:Demyelinating Autoimmune Diseases, CNS / Q000276:immunology* / Q000473:pathology* / Q000821:virology; D005260:Female; D018259:Herpesvirus 1, Human / Q000235:genetics / Q000276:immunology*; D007376:Interleukin-2 / Q000096:biosynthesis* / Q000235:genetics; D016849:Keratitis, Herpetic / Q000276:immunology* / Q000473:pathology* / Q000821:virology; D008264:Macrophages / Q000276:immunology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D013116:Spinal Cord / Q000276:immunology / Q000473:pathology / Q000648:ultrastructure
D000956:Antigens, Viral; D007376:Interleukin-2