Genetic contributions of nonautoimmune SWR mice toward lupus nephritis.
(SWR x 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 x 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.
Xie
S
S
Simmon's Arthritis Research Center and Center for Immunology, University of Texas Southwestern Medical School, Dallas, TX 75390, USA.
Chang
S
S
Yang
P
P
Jacob
C
C
Kaliyaperumal
A
A
Datta
S K
SK
Mohan
C
C
D000818:Animals; D001323:Autoantibodies / Q000097:blood / Q000235:genetics; D002874:Chromosome Mapping; D004843:Epistasis, Genetic; D020022:Genetic Predisposition to Disease; D007074:Immunoglobulin G / Q000097:blood / Q000235:genetics; D016130:Immunophenotyping; D008181:Lupus Nephritis / Q000175:diagnosis / Q000235:genetics* / Q000276:immunology; D051379:Mice; D008814:Mice, Inbred NZB; D008815:Mice, Inbred Strains; D019683:Penetrance; D016019:Survival Analysis
D001323:Autoantibodies; D007074:Immunoglobulin G