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Enhancement of Virus-Induced CNS Autoimmune Disease by Expression of B7.1

C.F. Evans

Multiple sclerosis may be caused by infection with a virus that shares antigenic epitopes with proteins expressed in oligodendrocytes. To model this molecular mimicry, we generated transgenic mice that express the viral nucleoprotein from lymphocytic choriomeningitis virus (LCMV) as "self" in oligodendrocytes. Intraperitoneal inoculation of these mice with LCMV resulted in an acute infection of the periphery but not the CNS, and virus was cleared within 2 weeks by a vigorous cytotoxic T lymphocyte response. Subsequently, a chronic CNS disease developed that was characterized by infiltration of autoreactive T cells, microgliosis, and upregulation of MHC class I and class II molecules on microglia, oligodendrocytes, and endothelial cells.

In order to investigate the effects of CNS expression of costimulatory proteins, transgenic mice that expressed the LCMV nucleoprotein in oligodendrocytes were bred to other transgenic mice that expressed the costimulatory protein B7-1 in oligodendrocytes. No clinical or pathologic phenotypes developed spontaneously in transgenic mice with oligodendrocytes expressing B7-1 alone or B7-1 plus the LCMV nucleoprotein. However, when the mice were infected with LCMV, the kinetics and severity of the resulting CNS disease were greater in mice expressing both the LCMV nucleoprotein and the B7-1 transgenes than in mice expressing only the viral transgene.

Thus, CNS autoimmune disease can be induced by infection with a virus that shares epitopes with a protein expressed in oligodendrocytes, and localized expression of B7-1 results in more severe disease. These data suggest that CNS expression of costimulatory proteins enhances the activation of autoreactive T cells that have entered the CNS. Because expression of B7 is upregulated in lesions in multiple sclerosis, this mechanism may be one by which myelin-specific T cells are induced to cause damage within the CNS.