Augmentation of NZB Autoimmune Phenotypes by the Sle1c Murine Lupus Susceptibility Interval

Abstract

The Sle1c lupus susceptibility interval spans a 7-Mb region on distal murine chromosome 1. Cr2 is the strongest candidate gene for lupus susceptibility in this interval, as its protein products are structurally and functionally altered. B6.Sle1c congenic mice develop Abs to chromatin by 9 mo of age with a 30% penetrance and do not develop GN. To determine whether the New Zealand White (NZW)-derived Sle1c interval would interact with New Zealand Black (NZB) genes to result in enhanced autoimmune phenotypes, NZB mice were bred with B6 or B6.Sle1c congenic mice and ∼20 female offspring were selected from each breeding for longitudinal study. These mice differ only at the Sle1c locus at which they have either a NZB/B6 or NZB/NZW genotype. NZB × B6.Sle1c mice had an accelerated onset of anti-chromatin Abs (100 vs 68% at 6 mo, p = 0.006) and anti-dsDNA Abs (45 vs 5% at 9 mo, p = 0.0048). Furthermore, median titers of anti-chromatin and anti-dsDNA Abs were significantly higher in the NZB × B6.Sle1c group compared with the NZB × B6 group. This corresponded with a higher prevalence of proliferative GN at 12 mo (55 vs 16%, p = 0.0214) as well as increased glomerular deposition of C3 (p = 0.0272) and IgG (p = 0.032), although blood urea nitrogen remained normal and significant proteinuria was not identified in either group. These data show that the Sle1c interval accelerates and augments the loss of tolerance to chromatin and dsDNA induced by NZB genes and induces significantly greater end-organ damage.

Murine lupus susceptibility locus Sle1a requires the expression of two sub-loci to induce inflammatory T cells

“…An outcross with NZB has however shown that Sle1c contributed to autoimmune pathology 23. Here, the same strategy showed that Sle1a augments the production of anti-chromatin IgG in (NZW × B6.…”

“…Sle1c by itself leads to a very modest autoAb production , but significantly increased autoAb production and renal pathology when expressed on a NZB heterozygous genome 23. Using the same strategy for Sle1a , we compared (NZB X B6.…”

Cyclin-Dependent Kinase Inhibitor Cdkn2c Regulates B Cell Homeostasis and Function in the NZM2410-Derived Murine Lupus Susceptibility Locus Sle2c1

“…This complementation analysis previously determined that Sle1 (22) and Sle1c (23) significantly enhanced the autoimmune phenotypes of the NZW and NZB heterozygous genomes, respectively. At 12 months of age, both NxSle2 and NxSle2c1 mice showed a significantly increased splenomegaly (Fig.…”

Linking complement and anti-dsDNA antibodies in the pathogenesis of systemic lupus erythematosus

“…Cr2 has also been implicated as a lupus susceptibility gene in the NZM2410 mouse model of lupus as it encodes a structurally altered and dysfunctional protein [137]. Inclusion of the genetic interval containing the dysfunctional Cr2 gene on a NZB background augmented autoimmunity, including autoantibody development and kidney disease [138]. However, the interval used in these studies contains other genes that may contribute to the observations of enhanced disease.…”