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

B. P. Croker, G. Gilkeson, L. Morel

Research output: Contribution to journalArticlepeer-review

48 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)575-585
Number of pages11
JournalGenes and Immunity
Issue number8
StatePublished - Dec 2003
Externally publishedYes


  • Clinical heterogeneity
  • Epistatis
  • Genetics
  • Lupus
  • Mice

ASJC Scopus subject areas

  • Immunology
  • Genetics
  • Genetics(clinical)


Dive into the research topics of 'Genetic interactions between susceptibility loci reveal epistatic pathogenic networks in murine lupus'. Together they form a unique fingerprint.

Cite this