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.

Consequences of Chronic Immune Cell Infiltration. To characterize further the effects of the inflammatory cell infiltration of the CNS of transgenic positive and negative mice after LCMV infection, brain sections were stained with additional immunohistochemical markers. The presence of B cells in the infiltrating population was examined using antibody to the B cell marker, B220. Insignificant numbers of B220 ϩ cells were observed in both transgenic positive and negative mice. Antibody to F4/80, a cell surface marker found on microglia, monocytes, and macrophages, revealed an upregulation of this molecule in regions of infiltrating T cells in transgenic positive mice (Fig. 2, C and H) . Microglial activation was observed as long as 1 yr after infection in association with T cell infiltration. Antibodies to MHC class I and II molecules were used to determine whether an increase in these antigen presentation markers was observed in response to the immune cell infiltration (Fig. 2, D, E, I, J) . In uninfected and LCMV-infected nontransgenic mice, MHC class I antigen staining was limited to the leptomeninges, choroid plexus, and endothelial cells of blood vessels. MHC class II staining was confined to a few macrophage-like cells in the interstitium of the choroid plexus. Staining for MHC class I and class II molecules in the brains of transgenic positive mice revealed that by 6 wk after infection there was an upregulation of both of these antigens on CNS cells in the vicinity of the infiltrating T cells, particularly pronounced in white matter regions. Antibody to MHC class I detected a fine reticular staining pattern in white matter regions, as well as staining many distinct cell types including those with microglial, lymphocyte, and endothelial cell morphology. Oligodendrocytes expressing MHC class I were identified by laser scanning confocal microscopy by colocalizing antibody to 2Ј,3Ј-cyclic nucleotide 3Ј-phosphodiesterase (CNP) with antibody to MHC class I (Horwitz, M.S, C.F. Evans, and M.B.A. Oldstone, manuscript submitted for publication). Anti-MHC class II antibodies stained cells of different morphologies including cells similar to microglia. This upregulation of MHC class I and class II molecules was observed in association with infiltrating lymphocytes for at least 1 yr after infection with LCMV. Light and confocal microscopic analyses of sagittal brain sections stained with luxol fast blue or antibodies to myelin basic protein and CD8 failed to reveal any areas of myelin damage in the transgenic mice after a single LCMV infection.