Differential Role of Three Major New Zealand Black-Derived Loci Linked with Yaa-Induced Murine Lupus Nephritis

Abstract

By assessing the development of Y-linked autoimmune acceleration (Yaa) gene-induced systemic lupus erythematosus in C57BL/6 (B6) × (New Zealand Black (NZB) × B6.Yaa)F1 backcross male mice, we mapped three major susceptibility loci derived from the NZB strain. These three quantitative trait loci (QTL) on NZB chromosomes 1, 7, and 13 differentially regulated three different autoimmune traits: anti-nuclear autoantibody production, gp70-anti-gp70 immune complex (gp70 IC) formation, and glomerulonephritis. Contributions to the disease traits were further confirmed by generating and analyzing three different B6.Yaa congenic mice, each carrying one individual NZB QTL. The chromosome 1 locus that overlapped with the previously identified Nba2 (NZB autoimmunity 2) locus regulated all three traits. A newly identified chromosome 7 locus, designated Nba5, selectively promoted anti-gp70 autoantibody production, hence the formation of gp70 IC and glomerulonephritis. B6.Yaa mice bearing the NZB chromosome 13 locus displayed increased serum gp70 production, but not gp70 IC formation and glomerulonephritis. This locus, called Sgp3 (serum gp70 production 3), selectively regulated the production of serum gp70, thereby contributing to the formation of nephritogenic gp70 IC and glomerulonephritis, in combination with Nba2 and Nba5 in NZB mice. Among these three loci, a major role of Nba2 was demonstrated, because B6.Yaa Nba2 congenic male mice developed the most severe disease. Finally, our analysis revealed the presence in B6 mice of an H2-linked QTL, which regulated autoantibody production. This locus had no apparent individual effect, but most likely modulated disease severity through interaction with NZB-derived susceptibility loci.

Autosomal loci associated with a sex‐related difference in the development of autoimmune phenotypes in a lupus model

“…These loci also overlap with previously defined loci in other autoimmune models [33,34,36,37,48]. Past studies have highly implicated the chromosome 17 interval because it includes the H-2 region.…”

ATlr7translocation accelerates systemic autoimmunity in murine lupus

“…Previous studies found that yaa dysregulated the B cell lineage and that CD4 T cells were necessary for disease but need not carry the yaa mutation (16)(17)(18). Introgression of yaa onto the nonautoimmune C57BL͞6J (B6) background revealed that yaa could produce disease only when combined with other autoimmune-promoting genes (3,8,(19)(20)(21). In our B6 congenic system we found that the bicongenic B6.Sle1yaa strain developed severe disease, indicative of strong epistatic interactions between these two susceptibility loci (8).…”

Identification of chromosome intervals from 129 and C57BL/6 mouse strains linked to the development of systemic lupus erythematosus

“…6 Furthermore, this locus colocalizes with a number of loci from various lupusprone mouse strains, including Sle3 (NZM2401 locus linked to GN and ANA); 20,22 Lbw5 (NZW locus linked to mortality), 23 Lmb3 (MRL locus linked to splenomegaly, lymphadenopathy, anti-dsDNA Abs), 24 Nba3 (NZB locus linked to GN) 25 and Nba5. 26 As this is an analogous situation to that on distal chromosome 1, a similar haplotype-based candidate gene identification strategy could be applied, especially as murine single nucleotide polymorphism (SNP) databases continue to increase in both SNP density and the number of typed strains. The presence of a 129-derived lupus locus on proximal chromosome 7 also has impact on the phenotype of any targeted gene in this region -it is conceivable that the 129 gene(s) that predispose to GN in the (129 Â B6)F2 strain could modify or augment the GN observed in a knockout strain.…”