Spontaneous Autoimmunity in 129 and C57BL/6 Mice—Implications for Autoimmunity Described in Gene-Targeted Mice

Abstract

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 × 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.

Identification of chromosome intervals from 129 and C57BL/6 mouse strains linked to the development of systemic lupus erythematosus

“…jax.org). This is in agreement with our previous study, 6 in which SLE traits were mapped in (129 Â C57BL/6)F2 wild-type and (129 Â C57BL/6)F2.ApcsÀ/À mice. The linkages were markedly increased when we enlarged the sample size by combining data from the 21 The autoimmune-associated haplotype of the lupus-prone NZM2410 (NZW) strain, named the Slam/Cd2 haplotype 2, is also present in the 129/SvJ mice, 21 indicating that these two strains may share the same pathways leading to loss of peripheral tolerance when in combination with one or more polymorphic genes in the B6 genome.…”

“…In addition, we combined the data from this cohort with data from a previously published cohort of (129 Â B6)F2 wild-type mice, 6 in order to expand the sample size and confirm our observations. We show here that a number of genetic loci outside the C1q locus on distal chromosome 4 are linked to autoimmunity, both confirming previously described loci and identifying novel regions in this strain combination.…”

“…6 In order to increase the power of our study, we repeated the QTL analysis in a larger data set, obtained by combining data from the (129 Â B6)F2.C1qa À/À mice presented in this study with data from a previously reported (129 Â B6)F2 intercross, 6 resulting in 297 female mice. In this analysis, the medial and distal regions of chromosome 4 were not included.…”

“…We have previously shown that a number of genetic loci, derived from both 129 and B6, are linked to the development of disease in the (129 Â B6) mice, with the most statistically significant of these being a 129-derived interval on distal chromosome 1 linked to increased autoantibody production. 6 This region has been consistently linked to autoimmune traits in a number of lupus-prone strains, including NZB (Nba2), 7,8 NZM2410 (Sle1) 9 and BXSB (Bxs3). 10,11 A congenic strain, comprising the 129-derived locus on distal chromosome 1 on a B6 background, a combination commonly created by backcrossing onto B6 a knockout strain in which the gene located in that region has been inactivated in 129 embryonic stem cells, also developed an autoimmune phenotype.…”

“…The humoral autoimmunity in this congenic strain was indistinguishable to that observed in a mouse carrying a deletion of the Apcs gene, located within the lupus-linked genomic region on distal chromosome 1 and considered as a candidate gene for murine SLE. 6 Therefore, backgroundderived genes can significantly contribute to the phenotype observed in knockout strains even when the mice have been extensively backcrossed onto the B6 strain, greatly complicating the interpretation of the phenotypic analysis of gene-targeted animals.…”