title: An Lck-cre transgene accelerates autoantibody production and lupus development in (NZB × NZW)F1 mice.
abstract: Lupus is an autoimmune disease characterized by the development of antinuclear autoantibodies and immune complex-mediated tissue damage. T cells in lupus patients appear to undergo apoptosis at an increased rate, and this enhanced T cell apoptosis has been postulated to contribute to lupus pathogenesis by increasing autoantigen load. However, there is no direct evidence to support this hypothesis. In this study, we show that an Lck-cre transgene, which increases T cell apoptosis as a result of T cell-specific expression of cre recombinase, accelerates the development of autoantibodies and nephritis in lupus-prone (NZB × NZW)F1 mice. Although the enhanced T cell apoptosis in Lck-cre transgenic mice resulted in an overall decrease in the relative abundance of splenic CD4(+) and CD8(+) T cells, the proportion of activated CD4(+) T cells was increased and no significant change was observed in the relative abundance of suppressive T cells. We postulate that the Lck-cre transgene promoted lupus by enhancing T cell apoptosis, which, in conjunction with the impaired clearance of apoptotic cells in lupus-prone mice, increased the nuclear antigen load and accelerated the development of anti-nuclear autoantibodies. Furthermore, our results also underscore the importance of including cre-only controls in studies using the cre-lox system.
authors.affiliation: Department of Genetics, Cell Biology & Anatomy, Nebraska Medical Center, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: R K
authors.initials: RK
authors.lastname: Nelson
authors.affiliation: Department of Genetics, Cell Biology & Anatomy, Nebraska Medical Center, University of Nebraska Medical Center, Omaha, NE, USA kagould@unmc.edu.
authors.forename: K A
authors.initials: KA
authors.lastname: Gould
mesh_terms: D000483:Alleles; D000818:Animals; D000936:Antigen-Antibody Complex / Q000276:immunology; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D001323:Autoantibodies / Q000096:biosynthesis* / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D019426:Integrases / Q000378:metabolism; D008181:Lupus Nephritis / Q000235:genetics* / Q000276:immunology*; D008297:Male; D051379:Mice; D008814:Mice, Inbred NZB; D008822:Mice, Transgenic; D017421:Sequence Analysis; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology; D019076:Transgenes
chemical_list: D000936:Antigen-Antibody Complex; D001323:Autoantibodies; C045073:Cre recombinase; D019426:Integrases
keywords: (NZB × NZW)F1 mice; T cell apoptosis; autoantibodies; cre toxicity; lupus