Genetic contributions of nonautoimmune SWR mice toward lupus nephritis

(SWR X New Zealand Black (NZB))F-1 (or SNF1) mice succumb to lupus nephriti s. Although several NZB lupus susceptibility loci have been identified in o ther crosses, the potential genetic contributions of SWR to lupus remain un known. To ascertain this, a panel of 86 NZB X F-1 backcross mice was immuno phenotyped and genome scanned. Linkage analysis revealed four dominant SWR susceptibility loci (H2, Swrl-1, Swrl-2, and Swrl-3) and a recessive NZB lo cus, Nba1. Early mortality was most strongly linked to the H2 locus on chro mosome (Chr) 17 (log likelihood of the odds (LOD) = 4.59 - 5.38). Susceptib ility to glomerulonephritis was linked to H2 (Chr 17, LOD = 2.37 - 2.70), S wrl-2 (Chr 14, 36 cM, LOD = 2.48 - 2.71), and Nba1 (Chr 4, 75 cM, LOD = 2.1 5 - 2.23). IgG antinuclear autoantibody development was linked to H2 (Chr 1 7, 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 re quired to attain the high penetrance levels seen in the SNF1 strain. Althou gh the SWR contributions H2, Swrl-1, and Swrl-2 map to loci previously mapp ed in other strains, often linked to very similar phenotypes, Swrl-3 appear s to be a novel locus. In conclusion, lupus in the SNF1 strain is truly pol ygenic, with at least four dominant contributions from the SWR strain. The immunological functions and molecular identities of these loci await elucid ation.