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.

The nucleoprotein (NP) and glycoprotein (GP) of lymphocytic choriomeningitis virus (LCMV) were selected as transgenes and cloned under the control of the myelin basic protein (MBP) promoter. These viral genes were chosen for the following reasons. First, the immune response to LCMV has been well characterized (13, 14) . After peripheral (i.p.) infection of mice with LCMV strain Armstrong, a vigorous CD8 ϩ CTL response is generated that clears the virus from all tissues by 7-10 d after infection (13, 14) . CTL epitopes of LCMV have been defined on several MHC backgrounds, including H-2 d and H-2 b (15, 16) . Second, i.p. infection of immunocompetent mice with LCMV results in the infection of many tissues but not cells of the CNS. Thus, in this system it is possible to test whether the generation of an immune response against a 1 Abbreviations used in this paper: ␤ gal, ␤ -galactosidase; BHK, baby hamster kidney; CNS, central nervous system; GFAP, glial fibrillary acidic protein; GP, glycoprotein; i.p., peripheral; LCMV, lymphocytic choriomeningitis virus; MBP, myelin basic protein; MS, multiple sclerosis; NP, nucleoprotein; PLP, proteolipid protein; PV, Pichinde virus; TAL-H, human transaldolase; VV, vaccinia virus. In this report, we present the results of peripheral infection of these transgenic mice by LCMV. We found that the LCMV infection was efficiently cleared, but a chronic CNS autoimmune disease developed and was enhanced by a second infection with LCMV or with unrelated viruses that stimulated LCMV-specific memory immune responses. This disease was characterized by T cell inflammatory lesions in the brain and spinal cord that included areas indicative of myelin loss, marked upregulation of CNS expression of MHC class I and class II molecules, and clinical motor dysfunction. This model establishes that an immune response to a peripheral viral infection can recognize identical antigens presented as self in the CNS, resulting in chronic CNS autoimmune disease.