Viral Infection of Transgenic Mice Expressing a Viral Protein in Oligodendrocytes Leads to Chronic Central Nervous System Autoimmune Disease

Evans, Claire F.; Horwitz, Marc S.; Hobbs, Monte V.; Oldstone, Michael B.A.

Enhancement of Autoimmune CNS Disease by Memory T Cell Stimulation. Since memory T cells require fewer activation signals and are potentially more aggressive than primary responding lymphocytes, the influence of a second viral infection on the immunohistochemical and clinical abnormalities in transgenic positive mice was examined. MBP-NP transgenic positive and negative mice previously infected with LCMV were reinfected with LCMV or a VV recombinant encoding the NP transgene (VV-NP) at 6 wk after primary infection. Immunohistochemical analysis of the CNS showed a three-to fivefold increase in CD8 Ï© lymphocytes in the transgenic positive mice at 4 wk after second infection with either LCMV or VV-NP, as compared with transgenic positive mice infected singly with LCMV at the same time after primary infection (10 wk). Additionally, a 10-fold increase in the number of CD4 Ï© T cells was 2376 Virus-induced Central Nervous System Autoimmune Disease detected compared with the number of cells observed after a single infection. The ratio of CD8 Ï© to CD4 Ï© cells in the doubly infected mice was 2:1 (Fig. 3, A and B) . The infiltrating cells in the doubly infected transgenic mice were found predominantly within white matter structures of the brain, and perivascular cuffs were observed. Coinciding with these increased levels of T cell infiltration, enhanced areas of F4/80 staining were observed (Fig. 3, C and D) . In addition, an upregulation of the astrocyte marker glial fibrillary acidic protein (GFAP) was observed. A marked increase in the expression of both MHC class I and II markers was observed in areas rich in myelin and coinciding with regions of T cell infiltration (Fig. 3, E-H) . Oligodendrocytes were again identified by confocal microscopy as expressing MHC class I.