title: T-cell tolerance induction is normal in the (NZB x NZW)F1 murine model of systemic lupus erythematosus.
abstract: The (New Zealand black (NZB) x New Zealand white (NZW))F1 (NZB/W) mouse strain spontaneously develops an autoimmune disease characterized by anti-dsDNA antibody production and glomerulonephritis. Although evidence suggests that production of pathogenic autoantibodies is T-cell dependent, the immunological defects that lead to activation of these autoreactive T cells are unknown. In particular, it has not been resolved whether autoreactive T cells become activated in these mice because of a generalized defect in T-cell tolerance induction. Previous work has demonstrated that thymic and peripheral tolerance to strongly deleting antigens are intact in NZB/W mice. In this study we investigate whether these mice possess a more subtle T-cell tolerance defect. To this end, we have produced NZB/W mice carrying a transgene encoding beef insulin (BI) which is expressed at levels close to the threshold for T-cell tolerance induction. In BALB/c mice this transgene produces a profound but incomplete state of BI-specific T-cell tolerance, mediated predominantly by clonal anergy. Comparison of BI-specific tolerance in NZB/W, major histocompatibility complex (MHC)-matched (BALB/c x NZW)F1, and BALB/c BI-transgenic mice clearly demonstrates that T-cell tolerance induction is normal in NZB/W mice. The data suggest that the loss of T-cell tolerance that ultimately supports nephritogenic autoantibody production in NZB/W mice does not result from a generalized defect in T-cell tolerance, and by extension likely results from aberrant activation of specific autoreactive T cells.
authors.affiliation: Departments of Medicine and Immunology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: J
authors.initials: J
authors.lastname: Wither
authors.forename: B
authors.initials: B
authors.lastname: Vukusic
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000276:immunology; D001324:Autoantigens / Q000276:immunology; D002417:Cattle; D017635:Clonal Anergy; D007108:Immune Tolerance; D007328:Insulin; D016753:Interleukin-10 / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D018709:Statistics, Nonparametric; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D007328:Insulin; D007376:Interleukin-2; D016753:Interleukin-10; D015847:Interleukin-4