Sle3 and Sle5 can independently couple with Sle1 to mediate severe lupus nephritis

Abstract

Genetic analyses of the lupus-prone NZM2410 mouse have identified multiple susceptibility loci on chromosome 7, termed Sle3 and Sle5. Both of these loci were contained within a large congenic interval, originally termed as Sle3 that strongly impacts a variety of myeloid and T-cell phenotypes and mediates fatal lupus nephritis when combined with Sle1. We have now produced two subcongenic strains, B6.Sle3 and B6.Sle5, carrying the Sle3 and Sle5 intervals separately and characterized their phenotypes as monocongenic strains and individually in combination with Sle1. Neither B6.Sle3 nor B6.Sle5 monocongenic strain develop severe autoimmunity; however, both of these intervals cause the development of severe glomerulonephritis when combined with Sle1. Thus, B6.Sle1Sle3 and B6.Sle1Sle5 exhibit splenomegaly, expansion of activated B and CD4 þ T-cell populations and high levels of IgG and IgM autoantibodies targeting multiple nuclear antigens, intact glomeruli and various other autoantigens. In addition, B6.Sle1Sle3 mice also produced higher levels of IgA antinuclear autoantibodies, which were implicated in the development of IgA nephropathy. Our results indicate that Sle3 and Sle5 can independently complement with Sle1, through shared and unique mechanisms, to mediate the development of severe autoimmunity.

The lupus phenotype in B6.NZBc1 congenic mice reflects interactions between multiple susceptibility loci and a suppressor locus

“…Thus, the NZB chromosome 1 interval joins a growing number of congenic intervals that based upon mapping studies were thought to contain a single susceptibility locus, but upon further dissection were found to contain multiple susceptibility loci. [15][16][17] These findings are consistent with the concept that the original mapping studies were underpowered to detect individual genetic loci, that in general have relatively small effects, and therefore only detected regions where multiple loci interacted additively or multiplicatively to produce a stronger signal.…”

CD22 × Siglec-G Double-Deficient Mice Have Massively Increased B1 Cell Numbers and Develop Systemic Autoimmunity

“…Chromosome intervals from the 129 mouse that contribute to systemic autoimmunity in mixed C57BL/6 3 129 background have been identified, and one of these intervals, called Sle3 lies on chromosome 7 and overlaps with the Siglec gene cluster (43,44). It is therefore conceivable that autoimmune phenotypes are caused by interacting loci between 129 and C57BL/6 mice, without involvement of the targeted genes.…”

Modelling clinical systemic lupus erythematosus: similarities, differences and success stories

“…NZM2410-derived Sle3 on chromosome 7 is responsible for generalized T cell activation and development of nephritis [44, 45]. The kallikrein genes within this region were associated with nephritis in both mice and humans [46].…”