The Roles of Ly108, the Genetic Susceptibility Loci Sle3, and CXCR4/CXCL12 in Systemic Lupus Erythematosus



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Ly108, in the NZM2410-derived Sle1b locus, was identified to play a key role in thymic selection. B6.Sle1b thymocytes displayed aberrant cell-surface Ly108 expression and decreased sensitivity to CD3-induced cell-death. Significant V-ß usage was found in B6.Sle1b versus B6 thymocytes. Simultaneous administration of OVA and anti-Ly108 antibody led to complete protection of OVA-induced deletion in B6.Sle1b.OTII mice but not in B6.OTII controls. Significant differences between B6 and B6.Sle1b were found in the amount of Ly108 phosphorylation and subsequent SAP-binding. Calm2 was found to be differentially expressed in B6.Sle1b thymocytes following Ly108 cross-linking. B6.Sle1b thymocytes were shown to flux less calcium, as result of modulated intracellular stocks of calcium, and, be more arrested in G1-phase following Ly108 engagement compared to B6, leading to an overall reduction in thymic apoptosis. These data suggest that the autoimmune form of Ly108 impairs thymic tolerance by dampening CD3-signaling and disrupting a G1-S cell-cycle checkpoint. Sle3, an NZM2410-derived susceptibility locus, mediates transition from benign to fatal autoimmunity. Sle3 was mapped to two main sub-loci, Sle3a and Sle3b. Sle3b was mapped to a 3.4 Mb interval containing Klf13, which has a known role in regulating RANTES. We found that Klf13 mRNA expression was significantly increased and that B6.Sle3 macrophages secreted roughly 2-fold more RANTES compared to B6. Co- culture of B6.Sle3 macrophages with blocking antibody to RANTES reversed the hyperactivation phenotype to B6 levels, indicating that increased RANTES secretion due to a genetic lesion in Klf13 could be responsible for the hyperactivation of macrophages seen in B6.Sle3. Polymorphisms in Klf13 were shown to be associated with human SLE. A significant dysregulation of the CXCR4/CXCL12 axis was observed in multiple murine models of spontaneous lupus. Increased CXCR4 expression in lupus mice led to functional differences, including increased migration to positive CXCL12 gradients. Simultaneously, the ligand for CXCR4, CXCL12, was significantly upregulated in the nephritic kidneys. To assess the contribution of CXCR4/CXCL12 upregulation on lupus pathogenesis, mice were treated with a peptide antagonist of CXCR4. Both preventive and therapeutic administration of CXCR4 blockade resulted in reduced renal infiltration by inflammatory myeloid cells and prolonged survival. Finally, increased renal CXCL12 expression and increased immune-cell CXCR4 expression was also observed in human SLE. These findings underscore the pathogenic role of CXCR4/CXCL12 in lupus nephritis and highlight this axis as a new and promising therapeutic target in this disease.

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