Abrogation of resistance to Theiler's virus-induced demyelination in H-2b mice deficient in beta 2-microglobulin.
Intracerebral infection of susceptible strains of mice with Theiler's virus, a picornavirus, results in central nervous system demyelination, which is similar to multiple sclerosis. Immunogenetic experiments indicate that the MHC (H-2) and, in particular, the D region that controls class I-restricted immune responses, is an important determinant to development of demyelination. We tested whether disruption of beta 2-microglobulin (beta 2-m) would abrogate resistance to demyelinating disease normally observed in H-2b mice. All (C57BI/6 x 129)F3 mice transgenic for homozygous beta 2-m gene disruption (-/-) developed chronic demyelination after Theiler's murine encephalomyelitis virus infection, whereas none of the infected littermates with normal expression of class I MHC (beta 2-m, +/+) developed demyelination. Demyelinated lesions showed class II MHC expression, macrophages, and TNF but no class I MHC expression or CD8+ T cells. No correlation was observed between development of demyelination and delayed-type hypersensitivity responses to virus Ag. Despite the presence of demyelinating lesions, none of the infected beta 2-m (-/-) mice developed neurologic deficits. Infectious virus and virus Ag persisted in the central nervous systems of infected beta 2-m (-/-) mice but not in beta 2-m (+/+) mice. These experiments support the hypothesis that a class I immune response mediated by CD8+ T cells is important in resistance to Theiler's murine encephalomyelitis virus-induced demyelination. Development of chronic neurologic deficits as observed in immunocompetent susceptible strains of mice may be dependent on the presence of class I MHC and CD8+ T cells.
Rodriguez
M
M
Department of Neurology, Mayo Clinic, Rochester, MN 55901.
Dunkel
A J
AJ
Thiemann
R L
RL
Leibowitz
J
J
Zijlstra
M
M
Jaenisch
R
R
D000818:Animals; D000914:Antibodies, Viral / Q000096:biosynthesis; D000938:Antigen-Presenting Cells / Q000276:immunology; D000956:Antigens, Viral / Q000276:immunology; D003711:Demyelinating Diseases / Q000276:immunology* / Q000473:pathology; D004769:Enterovirus Infections / Q000276:immunology*; D015870:Gene Expression; D005805:Genes, MHC Class I; D005802:Genes, MHC Class II; D006968:Hypersensitivity, Delayed / Q000276:immunology; D004680:Maus Elberfeld virus / Q000276:immunology*; D051379:Mice; D008822:Mice, Transgenic; D016254:Mutagenesis, Insertional; D012867:Skin / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D001613:beta 2-Microglobulin / Q000172:deficiency*
D000914:Antibodies, Viral; D000956:Antigens, Viral; D001613:beta 2-Microglobulin