Sles1^NZW
QTL Variant Detail

Summary

• QTL variant: Sles1^NZW
• Name: systemic lupus erythmatosus suppressor 1; NZW
• MGI ID: MGI:2155791
• QTL: Sles1 Location: Chr17:34219890-35175937 bp Genetic Position: Chr17, cM position of peak correlated region/allele: 18.31 cM
• QTL Note: genome coordinates based on the marker associated with the peak LOD score

Variant origin

• Strain of Specimen: NZW

Variant description

• Allele Type: QTL
• Mutation: Undefined
• This allele confers resistance to systemic lupus erythematosus compared to C57BL/6. (J:57246)
• Inheritance: Recessive

Notes

Sles1 interacts with Sles2, Sles3, and Sles4 in a cumulative fashion.

NZW-derived alleles at Sles1 suppress the anti-nuclear autoantibody producing phenotype in animals with NZW-derived alleles at Sle1.

Mapping and Phenotype information for this QTL, its variants and associated markers

J:57246

To determine the number and locations of epistatic modifiers interacting with Sle1 homozygosity to mediate severe autoimmunity in B6 X NZW hybirds this study presents a genetic analysis of the espistatic suppression in NZW mice and presents the locations of 4 SLE supperssor loci that account for the absence of the fatal disease in NZW.

272 (B6.NZMc1[Sle1] x NZW) x NZW backrcoss progeny were assessed for autoimmune phenotypes at 12 months. B6.NZMc1 congenic mice do not exhibit fatal lupus and are Sle1 homozygous. Positions of loci contributing to the phenotypes were determined via genome scan using 122 informatives microsatellite markers distributed throughout the autosomal genome. Six intervals were identified with either significant or suggestive linkage to fatal lupus or high titered anti-dsDNA autoanitbody. The intervals could be organized into 2 groups based on whether homozygosity or herteozygosity for NZW-derived alleles were associated with disease.

Disease susceptibility was enhanced by homozygosity in 2 NZW-derived genomic intervals.

One was centered on D7Mit158, which coincided with the location of Sle3, systemic lupus erythmatosus susceptibility 3 orginally identified in 1994 in J:25006. The interval spanned markers D7Mit178 and tyr. Homozygosity for NZW at this interval was significantly associated with both lupus nephritis (LOD=8.16) and humoral autoimmunity (LOD =6.85) at peak marker D7Mit158. [Table 1].

A second locus was identified in the centromeric region of Chromosome 5, peaking with marker D5Mit4. The locus, designated Sle6, systemic lupus erythematosus susceptibility 6, was significantly associated with lupus nephritis (LOD=3.63) and only weakly associated with humoral autoimmunity (LOD=1.47). The genomic interval for Sle6 spans markers D5Mit146 and D5Mit12. [Table 1].

Four intervals were identified in which heterozygosity was associated with disease susceptibility in the (B6.NZMc1 x NZW) x NZW backcross. These loci were designated with Sles, for SLE suppressor, based on the diminuation of autoimmunity by homozygosity for NZW-derived alleles at these loci.

Sles1, systemic lupus erythmatosus suppressor 1, was identified on Chromosome 17 mapping with markers H2, D17Mit34 and D17Mit10. Sles1 maps in the S (complement) region of the murine MHC. Heterozygosity for this interval was stongly associated with with both lupus nephritis (LOD=10.90) and humoral autoimmunity (LOD=8.54). [Table 1].

Sles2, systemic lupus erythmatosus suppressor 2, was identified on Chromosome 4 mapping with markers D4Mit9, D4Mit12, D4Mit54 and D4Mit33. Sles2 was more strongly associated with humoral autoimmunity (LOD=3.07) than lupus nephritis (LOD=2.15), centered with marker D4Mit12. [Table 1].

Sles3, systemic lupus erythmatosus suppressor 3, was indentified on Chromosome 3 peaking at marker D3Mit137, and spanning markers IL2, D3Mit137, D3Mit100, and D3Mit17. Heterozygosity at this locus acheived suggestive linkage for humoral autoimmunity (LOD=2.9) and weaker linkage with lupus nephritis (LOD=1.76).[Table 1]. Sle3 is near IL2 in a region of Chromosome 3 that has been associated with susceptibility to both diabetes and EAE in other murine models.

Sles4, systemic lupus erythmatosus suppressor 4, was identified in the centromeric region of Chromosome 9 peaking near D9Mit249. The interval spanned markers D9Mit59, D9Mit249, D9Mit42, D9Mit90 amd D9Mit2. Heterozygosity for this interval reached suggestive linkage for lupus nephritis (LOD=2.27) and showed no linkage with humoral autoimmunity (LOD=0.59). [Table 1].Sle4 was stongly gender biased in that the entire effect was male specific (LOD=2.14 for 35 males vs LOD=0.72 for 50 affected females.)

Multivariate analysis of disease penetrance as a function of suppressive Sles alleles carried supports the hypothesis that the cumulative effect of these four loci is sufficient to account for the suppression of severe autoimmunity in NZW. The number of active Sles loci were negatively correlated with the penetrance of GN and anti-dsDNA (p=0.0067 and p=0.0076, respecively.)

J:100678

The Sles1 (systemic lupus erythematosus suppressor 1) QTL interval was localized to a 956 kb segment of mouse Chromosome 17 using linkage analysis of subcongenic lines. Six different subcongenic lines carrying segments of NZW-derived donor DNA spanning the Sles1 locus on a C57BL/6 genetic background were constructed. These subcongenics also carry an NZW-derived Sle1 locus. Suppression of anti-nuclear antibody production mapped between D17Mit28 (18.44 cM) and D17Mit83 (18.9 cM) in one of the subcongenic lines. There are 69 potential candidate genes mapping to the refined Sles1 interval. Potential candidate genes with known autoimmune involvement include H2-Aa, H2-Eb2, Notch4, H2-Bf, Daxx, H2-Ab1, H2-Eb1, H2-Ea, C4, C2, and Hspa1a.

A recombination hotspot was detected upstream of Sles1 between D17Mit146 (17.1 cM) and D17Mit175 (17.7 cM).

Sle1 increases the percentages of CD3+ T cells and CD69 cell-surface expression. These effects were suppressed by the presence of Sles1 in bicongenic animals. Complementation analysis suggests that the 129-derived allele of Sles1 is similar to NZW in suppressing anti-dsDNA autoantibody production and glomerulonephritis in Sle1 animals.

References

• Original: J:57246 Morel L, et al., Epistatic modifiers of autoimmunity in a murine model of lupus nephritis. Immunity. 1999 Aug;11(2):131-9
• All: 4 reference(s)