In Vivo Identification of SLE1B: LY108 Mediates Autoantibody Production

In the NZM2410 model of murine lupus, Sle1b mediates anti-nuclear autoantibody (ANA) production. Our goal is to determine the causative gene in the Sle1b locus. Seven members of the SLAM/CD2 family are located within the Sle1b interval, and previous work has shown that structural and expression polymorphisms in lymphocytes distinguish two major SLAM/CD2 haplotypes. To further narrow the interval, we utilized a BAC transgenic rescue approach whereby BACs carrying the lupus-resistant B6 alleles were bred to B6.Sle1b mice to identify the region mediating ANA suppression. One BAC carrying Cd84 and Ly108 suppressed autoantibody production. We then generated BAC transgenic mice carrying the lupus-susceptible (129) and lupus-resistant (B6) alleles of Ly108 on the B6 and B6.Sle1b genetic background, respectively. The B6 allele of Ly108 suppresses ANA production on the lupus-susceptible B6.Sle1b background while the 129 allele induces ANA on the lupus-resistant B6 genome. Taken together, these data identify Ly108 as a causative gene in Sle1b. While Ly108 is needed to mediate the breach in tolerance, we have also identified other SLAM family members as genetic modifiers necessary to recapitulate fully penetrant, high titer ANA production as seen in Sle1b. We found that in vitro stimulation of B6.Sle1b CD4 T cells led to altered cytokine production, such as decreased IL4 production. Interestingly, these phenotypes have also been reported in knockouts of SLAM/CD2 family members as well as in the absence of the SLAM family adaptor, SAP. Our data indicates that the presence of the Sle1b haplotype, derived from either NZM2410 or 129, recapitulates these phenotypes, independent of the absence of these molecules. While recent reports have suggested a role for SAP in ANA development, we find that the breach in tolerance in Sle1b mice is SAP-independent. However, SAP is necessary to potentiate the autoantibody production. ANAs is an important biomarker for autoimmune diseases including, Systemic Lupus Erythematosus (SLE), and potentially identifies an autoimmune-prone state. We have identified genes which contribute to the production of ANAs. Elucidating the pathways these genes dysregulate will provide critical insight into our understanding of tolerance and how tolerance can be breached.