There is accumulating evidence that background genes may influence the expression of autoimmunity in gene-targeted mice. Here we report what is to our knowledge the first systematic study that has examined this in the 129 and C57BL/6 mouse strains, widely used for gene targeting. Our results demonstrate interacting loci between 129 and C57BL/6 mice that can cause the expression of a powerful autoimmune phenotype in these animals, in the absence of any gene-targeted mutations. We also developed a congenic mouse strain bearing a portion of 129 Chromosome 1 on a C57BL/6 background and showed that this wild-type congenic line expressed striking anti-nuclear autoimmunity. By comparing this Chromosome 1 congenic strain with matched congenic mice lacking the Apcs gene, we demonstrated that serum amyloid P component deficiency influences the severity of glomerulonephritis, but is not the prime mover in the induction of anti-nuclear autoimmunity, contrary to our own original interpretation of our data (Bickerstaff et al. 1999). The same consideration applies to other genes located in the same Chromosome 1 region that have been implicated in the development of SLE when inactivated by gene-targeting in 129 embryonic stem cells and then backcrossed onto a pure genetic background (Bolland and Ravetch 2000; Miwa et al. 2002; Wu et al. 2002). For each, there has to be a question as to whether the anti-nuclear autoimmunity is due to the gene-targeted mutant gene or to the normal 129 genes expressed in the same region as the targeted gene.