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.

Two models of virus-induced insulin dependent diabetes mellitus (19, 47) used the rat insulin promoter to direct expression of the LCMV NP or GP to the ␤ cells in the islets of Langerhans of the pancreas. Upon infection with LCMV, immune-mediated destruction of the ␤ cells occurred, resulting in diabetes. Although the transgenes and the infecting virus are the same in the pancreatic and the CNS models, destruction of the transgene-expressing target cells was much more severe in the diabetic model. The primary difference between these models is the organ in which the transgene is expressed. The CNS is unique due to the blood-brain barrier, which restricts the entry of certain cells and molecules from the blood, and the low or nondetectable expression of both MHC class I and class II molecules. It is likely that the nature of the immune response in the target organs is influenced by several factors, including differences in permeability of the islet capillaries and blood-brain barrier to various immune cells, in expression of adhesion and MHC molecules on endothelial and target cells, in types of antigen-presenting cells present, and in the local cytokine milieu. Delineation of the factors that determine the outcome of the transgene-specific immune response should reveal important differences between autoimmune disease of a peripheral organ such as the pancreas, and the CNS.