Sle1 on murine chr. 1 is a key locus to SLE pathogenesis in the NZM2410 model. This locus mediates the loss of tolerance to H2A/H2B/DNA subnucleosomes, an early step in the pathogenetic cascade. In addition, Sle1 participates in recessive epistatic interactions with other NZW-derived loci resulting in amplified autoimmune phenotypes and end-organ disease. We have discovered that 1) Sle1 corresponds to 3 loci, Sle1a, b, and -c, with Sle1a, and Sle1b linked within 2.4 cM in a location corresponding to the initial mapping of Sle1, and Sle1c located at the very telomeric end of chr. 1; and 2) Sle1 engages in epistatic interactions with the BXSB-derived Yaa locus, resulting in synergetic phenotypes that are different from those mediated the single loci. Based on this new information on Sle1, we now propose to functionally and genetically characterize the contribution of telomeric chr. 1 to SLE pathogenesis with 3 specific aims: 1. To assess the autoimmune phenotypes specific to each of the 3 loci located on NZM2410 telomeric chr. 1. We will determine the in vivo and in vitro phenotypes of congenic strains containing each of the 3 loci singly, and in combination, by comparison to that of B6.NZMc1 mice where all 3 loci are expressed. We will assess in vivo the role of apoptosis in Sle1 phenotypes using immunization with apoptotic cells. We will also determine the cell lineage in which each of the 3 loci is expressed. 2. To characterize the interactions of the Sle1 loci with Yaa locus, as a model of their interactions with other SLE-susceptibility genes. We will characterize in detail the autoimmune phenotypes resulting from the interactions of Sle1 loci and Yaa in B6.NZMc1.Yaa sub-strains, with specially emphasis on events leading to renal injury. We will also determine whether these interactions require the Sle1 loci and Yaa to be expressed in the same cells. 3. To assess the effects of each of the Sle1 loci on the gene expression of a large number of known genes with cDNA microarrays. We will delineate functional pathways of genes whose expression is directly affected by the expression of the Sle1 loci, providing a global picture of the genetic networks leading to the loss of tolerance to chromatin, the initiating event in SLE pathogenesis. Our goal is a characterization of the contribution of the telomeric chr. 1 to SLE pathogenesis, which will be achieved with a combination of techniques to assess the immunological defects, the cell lineages in which they are expressed, and to map functional pathways of genes affected by Sle1 loci. These experiments will to be conducted in parallel with our ongoing efforts to clone and identify the corresponding genes.
Showing the most recent 10 out of 31 publications
