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© The Rockefeller University Press, 0022-1007/1996/12/2371/ $5.00
The Journal of Experimental Medicine, Volume 184, Number 6, December 1, 1996 2371-2384

Articles

Viral Infection of Transgenic Mice Expressing a Viral Protein in Oligodendrocytes Leads to Chronic Central Nervous System Autoimmune Disease

Claire F. Evans*, Marc S. Horwitz*, Monte V. Hobbs{ddagger}, and Michael B.A. Oldstone*

From the * Division of Virology, Department of Neuropharmacology; {ddagger} Department of Immunology, The Scripps Research Institute, La Jolla, California 92037

One hypothesis for the etiology of central nervous system (CNS) autoimmune disease is that infection by a virus sharing antigenic epitopes with CNS antigens (molecular mimicry) elicits a virus-specific immune response that also recognizes self-epitopes. To address this hypothesis, transgenic mice were generated that express the nucleoprotein or glycoprotein of lymphocytic choriomeningitis virus (LCMV) as self in oligodendrocytes. Intraperitoneal infection with LCMV strain Armstrong led to infection of tissues in the periphery but not the CNS, and the virus was cleared within 7–14 d. After clearance, a chronic inflammation of the CNS resulted, accompanied by upregulation of CNS expression of MHC class I and II molecules. A second LCMV infection led to enhanced CNS pathology, characterized by loss of myelin and clinical motor dysfunction. Disease enhancement also occurred after a second infection with unrelated viruses that cross-activated LCMV-specific memory T cells. These findings indicate that chronic CNS autoimmune disease may be induced by infection with a virus sharing epitopes with a protein expressed in oligodendrocytes and this disease may be enhanced by a second infection with the same or an unrelated virus. These results may explain the association of several different viruses with some human autoimmune diseases.

This work was supported by Public Health Service grants NS12428, AI09484 (M.B.A. Oldstone), AG09822 (M.V. Hobbs), postdoctoral training grants MH19185, GM07437 (M.S. Horowitz) and AG00080 (C.F. Evans), and by postdoctoral fellowships from the National Multiple Sclerosis Society (C.F. Evans and M.S. Horwitz). C.F. Evans is currently a scholar of the Leifer Trust Fund. This is publication no. 9765 from the Department of Neuropharmacology, The Scripps Research Institute.

Address correspondance to Claire F. Evans, Department of Neuropharmacology, Division of Virology, The Scripps Research Institute, 10550 North Torrey Pines Road, IMM6, La Jolla, California 92037.

1Abbreviations used in this paper: βgal, β-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.

C.F. Evans and M.S. Horwitz contributed equally to this work.


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