Genetic origin of lupus in NZB/SWR hybrids: lessons from an intercross study.
OBJECTIVE
(SWR x NZB)F(1) (or SNF(1)) hybrid mice succumb to lupus nephritis. A previous analysis of SNF(1) x NZB backcross mice revealed the existence of 4 SWR loci (H2 on chromosome 17, Swrl-1 on chromosome 1, Swrl-2 on chromosome 14, and Swrl-3 on chromosome 18) and 2 NZB loci (Nba1 and Lbw2/Sbw2, both on chromosome 4). A second study focusing on SNF(1) x SWR backcross offspring uncovered 5 suggestive loci for antinuclear antibody formation, consisting of 3 dominant NZB contributions (Nba4 on chromosome 5, Lbw4 on chromosome 6, and Nba5 on chromosome 7) and 2 recessive SWR contributions (Swrl-1 on chromosome 1 and Swrl-4 on chromosome 10). The present intercross study was executed to replicate the earlier findings, using an independent panel of (SWR x NZB)F(2) offspring.


METHODS
A panel of (NZB x SWR)F(2) hybrids were phenotyped (for renal disease, early mortality, and a variety of autoantibodies) and genotyped (using 95 microsatellite primers positioned across all 19 autosomes and the X chromosome). Linkage analysis was conducted using the derived phenotype and genotype data, with the interval-mapping program MapManager.


RESULTS
Four suggestive loci were mapped: Swrl-5 on chromosome 1 (peak at 106 cM), linked to hypergammaglobulinemia; an NZB locus on chromosome 5 (Nba4; peak at 15 cM), linked to IgG anti-single-stranded DNA (anti-ssDNA) antibodies, IgG anti-doubled-stranded DNA (anti-dsDNA) antibodies, and glomerulonephritis; an NZB locus on chromosome 13 (Nba6; peak at 28 cM), linked to IgG anti-dsDNA antibodies; and an SWR locus on chromosome 14 (Swrl-2; peak at 30 cM), linked to IgG anti-ssDNA antibodies. Eight additional loci revealed linkage at P < 0.01, of which 7 co-mapped with lupus susceptibility loci previously identified in other models.


CONCLUSIONS
Considering all 3 mapping studies together, lupus in SWR/NZB hybrids appears to be the epistatic end product of several distinct loci, of which 3 SWR-derived loci (Swrl-1, Swrl-2, and Swrl-3) and 5 NZB-derived loci (Nba1, Nba3, Nba4, Nba5, and Lbw4) have been independently confirmed. The immunologic functions and molecular identities of these loci await elucidation.
Xie
Shangkui
S
Simmons Arthritis Research Center, University of Texas Southwestern Medical School, Dallas 75390-8884, USA.
Li
Li
L
Chang
Sooghee
S
Sharma
Ruchi
R
Kaliyaperumal
Arunan
A
Datta
Syamal K
SK
Mohan
Chandra
C
D000818:Animals; D000974:Antibodies, Antinuclear / Q000097:blood; D002678:Chimera; D002874:Chromosome Mapping; D003433:Crosses, Genetic; D004247:DNA / Q000276:immunology; D004277:DNA, Single-Stranded / Q000276:immunology; D008040:Genetic Linkage; D005838:Genotype; D007074:Immunoglobulin G / Q000032:analysis; D008181:Lupus Nephritis / Q000235:genetics*; D051379:Mice; D008814:Mice, Inbred NZB
D000974:Antibodies, Antinuclear; D004277:DNA, Single-Stranded; D007074:Immunoglobulin G; D004247:DNA