Molecular and cellular mechanisms, pathogenesis, and treatment of insulin-dependent diabetes obtained through study of a transgenic model of molecular mimicry.
The portrait of autoimmune diabetes mellitus or type I diabetes can be copied by a transgenic model in which either the nucleoprotein (NP) or glycoprotein (GP) of lymphocytic choriomeningitis virus (LCMV) is expressed in beta cells of the islets of Langerhans. In the absence of further environmental insult, diabetes does not occur. However, when LCMV or a dissimilar virus that shares cross-reactive T cell epitopes with LCMV initiates infection, diabetes ensues. If the self "viral" transgene is expressed only in the beta cells, then diabetes occurs acutely within 8 to 12 days. Specific antiviral (self) CD8 T cells are mandatory for disease, but CD4 T cells are not. In this instance, diabetes can occur in the absence of infection if interferon gamma or B7.1 molecules are also expressed in the islets but not when IL-2, IL-4, IL-10, or IL-12 is similarly expressed. In contrast, both CD8 and CD4 antiviral (self) specific T cells are required when the self "viral" transgene is expressed concomitantly in beta cells and in the thymus. In this instance, infection by LCMV or cross-reacting virus is essential to cause diabetes. Further, the time from onset of infection until disease depends, in part, on the host's MHC background and its quantitative influence on negative selection of high-avidity antiviral (self) T cells. Knowledge of the cells, their numbers, and the molecules required to cause diabetes allows the design of successful strategies to treat and prevent the autoimmune disease.
Oldstone
M B A
MB
Division of Virology, Department of Neuropharmacology, The Scripps Research Institute, La Jolla, CA 92037, USA. mbaobo@scripps.edu
D000595:Amino Acid Sequence; D000818:Animals; D001324:Autoantigens / Q000235:genetics; D016207:Cytokines / Q000096:biosynthesis; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology* / Q000235:genetics / Q000276:immunology / Q000628:therapy; D004195:Disease Models, Animal; D006801:Humans; D007328:Insulin / Q000235:genetics; D008217:Lymphocytic choriomeningitis virus / Q000235:genetics / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D018716:Molecular Mimicry / Q000235:genetics / Q000276:immunology*; D011401:Promoter Regions, Genetic; D051381:Rats; D013601:T-Lymphocytes / Q000276:immunology
D001324:Autoantigens; D016207:Cytokines; D007328:Insulin