Genetic Contributions of Nonautoimmune SWR Mice Toward Lupus Nephritis

(SWR × New Zealand Black (NZB))F 1 (or SNF 1 ) mice succumb to lupus nephritis. Although several NZB lupus susceptibility loci have been identified in other crosses, the potential genetic contributions of SWR to lupus remain unknown. To ascertain this, a panel of 86 NZB × F 1 backcross mice was immunophenotyped and genome scanned. Linkage analysis revealed four dominant SWR susceptibility loci ( H2 , Swrl-1, Swrl-2 , and Swrl-3 ) and a recessive NZB locus, Nba1 . Early mortality was most strongly linked to the H2 locus on chromosome (Chr) 17 (log likelihood of the odds (LOD) = 4.59 − 5.38). Susceptibility to glomerulonephritis was linked to H2 (Chr 17, LOD = 2.37 − 2.70), Swrl-2 (Chr 14, 36 cM, LOD = 2.48 − 2.71), and Nba1 (Chr 4, 75 cM, LOD = 2.15 − 2.23). IgG antinuclear autoantibody development was linked to H2 (Chr 17, LOD = 4.92 − 5.48), Swrl-1 (Chr 1, 86 cM, colocalizing with Sle1 and Nba2 , LOD = 2.89 − 2.91), and Swrl-3 (Chr 18, 14 cM, LOD = 2.07 − 2.13). For each phenotype, epistatic interaction of two to three susceptibility loci was required to attain the high penetrance levels seen in the SNF 1 strain. Although the SWR contributions H2, Swrl-1 , and Swrl-2 map to loci previously mapped in other strains, often linked to very similar phenotypes, Swrl-3 appears to be a novel locus. In conclusion, lupus in the SNF 1 strain is truly polygenic, with at least four dominant contributions from the SWR strain. The immunological functions and molecular identities of these loci await elucidation.