Genetic origin of lupus in NZB/SWR hybrids: Lessons from an intercross study

• Published in: Arthritis and rheumatism 2005-02, Vol.52 (2), p.659-667
• Main Authors: Xie, Shangkui, Li, Li, Chang, SoogHee, Sharma, Ruchi, Kaliyaperumal, Arunan, Datta, Syamal K., Mohan, Chandra
• Format: Article
• Language: English
• Subjects: Animals; Antibodies, Antinuclear - blood; Biological and medical sciences; Chimera; Chromosome Mapping; Crosses, Genetic; Dermatology; DNA - immunology; DNA, Single-Stranded - immunology; Genetic Linkage; Genotype; Immunoglobulin G - analysis; Lupus Nephritis - genetics; Medical sciences; Mice; Mice, Inbred NZB; Skin involvement in other diseases. Miscellaneous. General aspects
• ISSN: 0004-3591; 1529-0131
• DOI: 10.1002/art.20786

Objective (SWR × NZB)F1 (or SNF1) hybrid mice succumb to lupus nephritis. A previous analysis of SNF1 × 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 SNF1 × 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 × NZB)F2 offspring. Methods A panel of (NZB × SWR)F2 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. Conclusion 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.