MHC class I expression regulates susceptibility to spontaneous autoimmune disease in (NZBxNZW)F1 mice.
(NZBxNZW)F1 mice spontaneously develop with age an autoimmune disease that resembles the human disease, systemic lupus erythematosus (SLE). Previous studies have demonstrated that susceptibility to experimentally induced SLE depended on the expression of MHC class I molecules: mice deficient in beta2-microglobulin did not express cell surface class I and were resistant to the induction of experimental SLE. Furthermore, the spontaneous SLE-like disease of (NZBxNZW)F1 mice was ameliorated by treatment with an agent that reduces MHC class I expression, methimazole (MMI). In the present study, the role of MHC class I has been examined in (NZBxNZW)F1 mice deficient in beta2-microglobulin expression. Homozygous (NZBxNZW)F1 beta2m-/- mice do not express class I or develop CD8+ T cells. Surprisingly, they show an increased susceptibility to disease. In sharp contrast, heterozygous (NZBxNZW)F1 beta2m+/- express class I, albeit at reduced levels, develop normal levels of CD8+ T cells and are less susceptible to autoimmune disease, relative to their wild-type litter mates. Taken together, these findings suggest that class I expression regulates the development of disease, both positively and negatively. We speculate that MHC class I expression itself confers susceptibility to disease through presentation of self-peptides, while also selecting for a CD8+ suppressor T cell population that mitigates disease.
Mozes
E
E
Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel.
Lovchik
J
J
Zinger
H
H
Singer
D S
DS
D000818:Animals; D000974:Antibodies, Antinuclear / Q000097:blood; D017951:Antigen Presentation; D001324:Autoantigens; D001327:Autoimmune Diseases / Q000235:genetics* / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D005260:Female; D015870:Gene Expression; D005805:Genes, MHC Class I; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D006824:Hybridization, Genetic; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology; D008297:Male; D051379:Mice; D008814:Mice, Inbred NZB; D018345:Mice, Knockout; D001613:beta 2-Microglobulin / Q000172:deficiency / Q000235:genetics
D000974:Antibodies, Antinuclear; D001324:Autoantigens; D001613:beta 2-Microglobulin