Spontaneous autoimmunity in 129 and C57BL/6 mice-implications for autoimmunity described in gene-targeted mice

• Published in: PLoS biology 2004-08, Vol.2 (8), p.E243-E243
• Main Authors: Bygrave, Anne E, Rose, Kirsten L, Cortes-Hernandez, Josefina, Warren, Joanna, Rigby, Robert J, Cook, H Terence, Walport, Mark J, Vyse, Timothy J, Botto, Marina
• Format: Article
• Language: English
• Subjects: Animals; Autoimmune diseases; Autoimmunity - genetics; Autoimmunity - immunology; Cell Nucleus - metabolism; Chromosome Mapping; Cohort Studies; Disease Models, Animal; Epistasis, Genetic; Female; Gene Targeting; Genes; Genetic Linkage; Genetic Predisposition to Disease; Genetics; Genetics/Genomics/Gene Therapy; Genome; Genomics; Genotype; Immunology; Lupus; Lupus Erythematosus, Systemic - genetics; Mice; Mice, Inbred C57BL; Mice, Transgenic; Microsatellite Repeats; Models, Genetic; Mus (Mouse); Mutation; Quantitative Trait Loci; Species Specificity
• ISSN: 1545-7885; 1544-9173; 1545-7885
• DOI: 10.1371/journal.pbio.0020243

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disorder in which complex genetic factors play an important role. Several strains of gene-targeted mice have been reported to develop SLE, implicating the null genes in the causation of disease. However, hybrid strains between 129 and C57BL/6 mice, widely used in the generation of gene-targeted mice, develop spontaneous autoimmunity. Furthermore, the genetic background markedly influences the autoimmune phenotype of SLE in gene-targeted mice. This suggests an important role in the expression of autoimmunity of as-yet-uncharacterised background genes originating from these parental mouse strains. Using genome-wide linkage analysis, we identified several susceptibility loci, derived from 129 and C57BL/6 mice, mapped in the lupus-prone hybrid (129 x C57BL/6) model. By creating a C57BL/6 congenic strain carrying a 129-derived Chromosome 1 segment, we found that this 129 interval was sufficient to mediate the loss of tolerance to nuclear antigens, which had previously been attributed to a disrupted gene. These results demonstrate important epistatic modifiers of autoimmunity in 129 and C57BL/6 mouse strains, widely used in gene targeting. These background gene influences may account for some, or even all, of the autoimmune traits described in some gene-targeted models of SLE.