Sle Susceptibility Loci on Mouse Chromosome 1

Morel, Laurence

Abstract

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 with significant pathological consequences. 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; 2) Sle1 engages in epistatic interactions with the NZB genome, and with the BXSB-derived Yaa locus, resulting in synergetic phenotypes that are different from those mediated the single loci, or the NZB genome alone; and 3) Sle1 phenotype expression is stronger in females than in males, suggesting that estrogens act as positive modifiers of this locus. 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 and their contribution to the Sle1 phenotypes. We will produce congenic strains containing each of the 3 loci singly, and in combination, and determine the corresponding in vivo and in vitro phenotypes by comparison to that of B6.NZMc1 mice where all 3 loci are expressed. 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 other models of SLE, the Yaa locus and the NZB genome. We will characterize in details the autoimmune phenotypes resulting from the interactions of Sle1 loci and a) the Yaa locus in B6.NZMc1.Yaa bicongenics, and b) the NZB genome in (B6.NZMc1 x NZB)F1 hybrids. We will investigate the contribution of each of the 3 Sle1 loci to these interactions, and map the number and genomic locations of NZB loci involved. 3. To investigate the interactions between estrogen and Sle1 loci. We will first assess whether the sexual dimorphism observed in Sle1 phenotypic expression is due to estrogen. We will then investigate the possible mechanisms of this interaction, by focusing on altered cytokine profiles and estrogen receptor expression. Finally, we will explore the contribution of the sexual dimorphism of a simple system, the Sle1 cluster, to the increased female susceptibility in a polygenic system. The long term of this proposal is a detailed functional and genetic characterization of the contribution of the telomeric chr.1 to SLE pathogenesis, to be conducted in parallel with our ongoing efforts to clone and identify the corresponding genes.