Epistatic Interactions in the Suppression of Autoimmunity
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Sle1 is a susceptibility locus for autoimmunity derived from the lupus-prone NZM2410 mouse. The NZW-derived suppressive modifier Sles1 was identified as a specific modifier of Sle1 and prevents the development of anti-chromatin autoantibodies mediated by Sle1 on the B6 background. Fine-mapping of Sles1 with truncated congenic intervals localized it to a ~956 KB segment on mouse chromosome 17. Sles1 completely abrogated the development of activated lymphocyte populations in B6.Sle1, but splenic B cells from B6.Sle1|Sles1 still exhibited intrinsic ERK phosphorylation. Classic genetic complementation tests using the non-autoimmmune 129/SvJ mouse, suggests that this strain possesses a Sles1 allele complementary to NZW, as evidenced by the lack of autoimmunity in [129 XB6.Sle1|Sles1]F1s. These findings localized and characterized the suppressive properties of Sles1 and implicated 129 as a useful strain for aiding in the identification of this elusive epistatic modifier gene. In contrast, introduction of the suppressive modifiers Sles2 and Sles3 onto B6.Sle1 led to a decrease in the penetrance and mean titres of autoantibody production, but not complete suppression. These results suggested that genes, such as Sles1, which can specifically modify the effects of susceptibility alleles causing a breach in tolerance, could prevent systemic autoimmunity, even in the presence of additional susceptibility genes. To test this hypothesis we introduced the Sle1-specific suppressive locus Sles1 onto two different lupus-prone models: B6.Sle1|yaa and B6.Sle1|Sle2|Sle3/5, to determine whether and how Sles1 mediated suppression of Sle1 impacts the highly penetrant systemic autoimmunity characteristic of these two mouse strains. Comparing the development of a variety of pathological, immunological, functional and molecular phenotypes between the B6.Sle1|yaa and 6.Sle1|Sles1|yaa strains at different ages, revealed that Sles1 mediated a profound and complete suppression of systemic autoimmunity in this model. In contrast, the introduction of Sles1 onto the B6.Sle1|Sle2|Sle3/5 strain improved survival, and altered the kinetics of disease, but did not completely suppress disease in this model. These data suggest that the nature of the additional susceptibility loci interacting with Sle1 influences the degree of Sles1-mediated epistatic suppression of Sle1. Further characterization of these different models will help identify specific pathways Sles1 impacts, and provide insight into potential therapeutic strategies.