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.

To determine whether enhanced disease following stimulation of the LCMV memory response required that the second restimulating virus encoded the transgene, transgenic mice previously infected with LCMV were given a second infection with either VV, using a recombinant VV not encoding any LCMV genes, or PV, an arenavirus distantly related to LCMV but not sharing any of the defined LCMV CTL epitopes. MBP-NP transgenic positive and negative mice that had been infected with LCMV 6 wk previously were infected with either VV or PV. 4-8 wk later, the mice were killed and CNS tissues were examined. Stimulation of the memory response by these unrelated viruses resulted in enhanced pathology similar to that seen after a second infection with LCMV. This included greater numbers of infiltrating lymphocytes, an increase in the ratio of CD4 Ï© to CD8 Ï© lymphocytes, and a high preponderance of these infiltrates in white matter-rich areas (Fig. 6, A and B) . Additionally, activation of microglia and astrocytes, as measured by increased F4/80 and GFAP expression, were observed, as well as increased upregulation of the antigen presentation MHC class I and II molecules throughout the white matter regions. Infiltrating lymphocytes formed lesions within the white matter tracts of the CNS. These lesions showed a loss of MBP staining accompanied by uptake of MBP by activated microglia/macrophages similar to that observed after a second infection with LCMV.