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.

Mice expressing the LCMV NP or GP in their oligodendrocytes developed CNS autoimmune disease after a single infection with LCMV, and this disease was enhanced after a second infection with LCMV. This enhancement likely resulted from the activation of LCMV-specific memory T cells that traveled into the CNS, where they encountered transgene-expressing oligodendrocytes presenting LCMV peptides in association with MHC class I molecules. Increased levels of cytokines typically associated with activated CD8 ϩ / CD4 ϩ (Th1) cells were detected (IFN-␥, TNF-␣, and TNF-␤), as well as cytokines associated with activated macrophages/microglia (IL-1␣, IL-1␤, IL-12p40, and TNF-␣). IFN-␥ and TNF-␣ have been shown to increase MHC class I and/or class II molecules on a variety of cells (36) (37) (38) (39) , and thus the presence of these cytokines may account for the widespread upregulation of MHC class I and II molecules observed after double infection. In addition, TNF-␣ and TNF-␤ have been shown to be cytotoxic to oligodendrocytes in vitro (40, 41) . Damage to oligodendrocytes was demonstrated by confocal microscopic analyses of the lesions of infiltrating lymphocytes within the white matter. A number of observations were consistent with active myelin degradation, including the loss of MBP staining at the center of these lesions, the irregular shape of the lesions, the presence of activated microglia/macrophages in and around the lesions, and the uptake of MBP by these activated microglia/macrophages. The enhanced disease observed after a second LCMV infection shares several characteristics with the human CNS disease, MS, including chronic perivascular and parenchymal infiltration of autoreactive T cells in the brain and spinal cord, lesions in myelin tracts associated with the uptake of myelin components by activated macrophages/microglia, upregulation of MHC class I and class II molecules on resident CNS cells, activation of microglia and astrocytes, motor coordination dysfunction, and expression of cytokines in the CNS associated with cytotoxicity. MS is further characterized by the presence of plaques of demyelination in the CNS. These mice showed focal areas of demyelination consistent with sites of early plaque development. It is possible that additional environmental or genetic factors could influence further plaque development. Currently, studies are being done to manipulate the susceptibility of these mice to demyelination by evaluating the effects of genetic background, CNS cytokine expression, and TCR usage. Viruses have often been implicated in the etiology of MS (42, 43) , but it has not been possible to link just one virus with the disease. This model provides an opportunity to examine the roles of multiple viruses in inducing and potentiating CNS demyelinating disease, and will complement results from studies of the classical model of autoimmunity in MS, experimental allergic encephalomyelitis.