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Genetic interactions between susceptibility loci reveal epistatic pathogenic networks in murine lupus

Genes & Immunity volume 4, pages 575–585 (2003)Cite this article

Abstract

Interactions between Sle1 and other susceptibility loci were required for disease development in the NZM2410 model of lupus. Sle1 corresponds to at least three subloci, Sle1a, Sle1b, and Sle1c, each of which independently causes loss of tolerance to chromatin, but displays a distinctive immune profile. We have used congenic strains to analyze the interactions between the Sle1 subloci and other lupus susceptibility loci using Y autoimmunity accelerator (Yaa) and Faslpr as sensitizing mutations. Sle1 coexpressed with either one of these single susceptibility alleles resulted in a highly penetrant nephritis, splenomegaly, production of nephrophilic antibodies, and increased expression of B- and T-cell activation markers. Here, we show that only Sle1b interacted with Yaa to produce these phenotypes, suggesting that Sle1b and Yaa belong to the same functional pathway. Interactions between the three Sle1 loci and lpr resulted in lymphocyte activation and lupus nephritis, but a significant mortality was observed only for the Sle1a.lpr combination. This suggests a major role for the FAS pathway in keeping in check the loss of tolerance mediated by the Sle1 loci, especially for Sle1a. Our results illustrate the complexity of interactions between susceptibility loci in polygenic diseases such as lupus and may explain the clinical heterogeneity of the disease.

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Acknowledgements

We thank Elisabeth Basco, Patrick Basco, Guangling Huang, and Keow Thavadahara for excellent technical help, and Eric Sobel and Kim Blenman for valuable discussions. This work was supported by a grant from the NIH (AI-54050) to L Morel and a VA Merit Review grant to G Gilkeson.

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Authors and Affiliations

  1. Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL, USA

    B P Croker & L Morel

  2. North Florida South George Veterans Health System, Gainesville, FL, USA

    B P Croker

  3. Medical Research Service, Ralph H Johnson Veterans Affairs Medical College and the Medical University of South Carolina, Charleston, SC, USA

    G Gilkeson

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  1. B P Croker
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Correspondence to L Morel.

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Croker, B., Gilkeson, G. & Morel, L. Genetic interactions between susceptibility loci reveal epistatic pathogenic networks in murine lupus. Genes Immun 4, 575–585 (2003). https://doi.org/10.1038/sj.gene.6364028

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