title: Self-reactive T cells in murine lupus: analysis of genetic contributions and development of self-tolerance.
abstract: Our understanding of the immune mechanisms that lead to systemic lupus erythematosus has been greatly advanced by the availability of murine models which display both serological and clinical features of the human disease. Studies have demonstrated that CD4+ T cells are required for the full expression of disease in these mice. (NZB X NZW)F1 mice exhibit a lupus-like disease (elevated levels of IgG antinuclear antibodies and a fatal glomerulonephritis) that is not characteristic of either parent. At least three gene loci have been identified in NZW mice that could potentially contribute to a T cell-dependent autoimmune disease, including the T cell receptor alpha- and beta-chain gene complexes and the major histocompatibility complex (MHC). The NZW T cell receptor beta-chain complex appeared to be particularly unusual in that the C beta 1, D beta 2, and J beta 2 gene segments have been deleted. However, an analysis of (NZB X NZW)F1 X NZB back-cross mice revealed no association of disease expression with the presence of this allele. There was also no correlation of disease incidence with the presence of the NZW T cell receptor alpha-chain allele. In contrast, nearly 90% of the backcross mice with the NZW MHC expressed severe autoimmune disease compared with 12% of the mice that did not carry this haplotype. Additional studies strongly suggested that the gene(s) within the NZW MHC is the only dominant NZW genetic contribution to F1 disease. We also determined if self-reactive T cells are able to escape thymic tolerance in autoimmune New Zealand and MRLlpr/lpr mice. In nonautoimmune mice expressing I-E, T cells utilizing V beta 17a and V beta 11 encoded domains have been shown to be clonally eliminated in the thymus. Similarly, V beta 8.1+ and V beta 6+ T cells are tolerized in nonautoimmune mice expressing Mls-1a. These T cell subsets were quantified in the lymph nodes and spleens of (NZB X NZW)F1, (NZB X SWR)F1, and MRL-lpr/lpr mice before and after the development of lupus-like disease. The results indicate that peripheral T cells in these mice, including the massive CD4-, CD8- T cell population in lpr mice, have been modified by normal mechanisms of tolerance such that potential self-reactive V beta specificities have been eliminated in the thymus.
authors.affiliation: Department of Pediatrics, National Jewish Center for Immunology and Respiratory Medicine, Denver, Colorado 80206.
authors.forename: B L
authors.initials: BL
authors.lastname: Kotzin
authors.forename: L R
authors.initials: LR
authors.lastname: Herron
authors.forename: S K
authors.initials: SK
authors.lastname: Babcock
authors.forename: J P
authors.initials: JP
authors.lastname: Portanova
authors.forename: E
authors.initials: E
authors.lastname: Palmer
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D005838:Genotype; D007108:Immune Tolerance; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008815:Mice, Inbred Strains / Q000235:genetics; D013601:T-Lymphocytes / Q000276:immunology*; D013950:Thymus Gland / Q000276:immunology
chemical_list: D001324:Autoantigens