Browsing by Subject "Polymorphism, Genetic"
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Item Defining How Polymorphisms at the Slam Family Locus Affect NK and T Cell Function(2006-05-15) Mooney, Jill Marie; Schatzle, JohnSequence analysis of the SLAM family of receptors identified two stable haplotypes found in common laboratory strains of mice. The b haplotype is found in all C57-derived mouse strains, and the z haplotype is found in all non-C57 derived mouse strains, including many autoimmune mouse strains. The SLAM family of receptors, which includes CD244, Ly108, CD84, CD48, CD229, and Cs1, are involved in regulating several immune functions such as cellular activation, cytokine secretion, cytotoxicity, and apoptosis. Thus, it is not surprising that dysregulation of this family of receptors is associated with disease states such as systemic lupus erythematosus (SLE) and X-linked lymphoproliferative disease (XLP). The antinuclear autoantibody (ANA) causative locus, Sle1b, in the NZM2410 mouse model of lupus has been shown to contain the entire SLAM family (SF) locus. Whereas, XLP is caused by mutations in a critical adaptor protein, SAP, leading to defective SF signaling. This dissertation is based on the premise that polymorphisms at the SF locus alter SF function in lymphocytes. To address this, we compared lymphocyte function in B6 mice, which contain the b haplotype of the SF, and B6.Sle1b mice that are congenic for the 900 kb interval surrounding the z haplotype of the SF. Thus, differences in lymphocyte function can be directly attributed to polymorphism at the SF locus. These congenic mouse strains were used in two studies: 1) to characterize the function of CD244 in NK cells, and 2) to characterize CD4+ T cell function. We show that polymorphisms in CD244 alter receptor function, where engagement of the z allele of CD244 results in increased cytotoxicity dependent on SAP expression. In contrast, engagement of the b allele of CD244 predominately results in inhibition of cytotoxicity, independent of SAP expression. These studies may explain previously conflicting data describing CD244 function. Our studies characterizing CD4+ T cell function determined that polymorphisms at the SF locus result in altered SF expression, decreased IFN-gamma , IL-4, IL-5, IL-6, and IL-10 secretion, increased and prolonged CD40L expression, and altered SAP expression. In conclusion, we show that polymorphisms at the SF locus alter NK and T cell lymphocyte function.Item The Roles of Ly108, the Genetic Susceptibility Loci Sle3, and CXCR4/CXCL12 in Systemic Lupus Erythematosus(2011-08-10) Wang, Andrew; Wakeland, Edward K.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.