Problem: Systemic lupus erytromatosus is a multi-step autoimmune disease, that arises from a suite of genetic aberrations. In particular, in the NZM21410 murine model, susceptibility to lupus nephritis maps to at least 4 non-MHC loci: Sle1, Sle2., Sle3, and Sle5. The respective functions of these different loci have been ascertained by expressing them as congenic intervals on the normal B6 genetic background. In particular, Sle2 leads to generalized B-cell hyperactivity. In epistasis with other loci, Sle2 also augments the production of pathogenic ANAs. and fatal nephritis. However, the genetic identity of Sle2 remains unknown. This proposal explores the candidacy of a gene located within the Sle2 interval. Research Design: B6.Sle2 mice, as well control strains (136, NZM, NZB, NZW, and several others) will be examined in order to define: 1. the sequences of the coding, 5' untranslated, and 3' untranslated regions of the candidate gene 2. the expression profiles of the candidate gene by measuring the levels of RNA (by RTPCR), and protein, in spleens, BM, and PerC 3. whether augmentation of the level of expression of the candidate gene can lead to any lupus-related phenotypes. Significance: These experiments have the potential to uncover the identity of a lupus susceptibility gene on murine chromosome 4, that potentially impacts B-cell hyperactivity, pathogenic ANA formation. and end-organ disease.
