Effects of MHC and Gender on Lupus-Like Autoimmunity inNba2Congenic Mice

Abstract

The lupus-like disease that develops in hybrids of NZB and NZW mice is genetically complex, involving both MHC- and non-MHC-encoded genes. Studies in this model have indicated that the H2d/z MHC type, compared with H2d/d or H2z/z, is critical for disease development. C57BL/6 (B6) mice (H2b/b) congenic for NZB autoimmunity 2 (Nba2), a NZB-derived susceptibility locus on distal chromosome 1, produce autoantibodies to nuclear Ags, but do not develop kidney disease. Crossing B6.Nba2 to NZW results in H2b/z F1 offspring that develop severe lupus nephritis. Despite the importance of H2z in past studies, we found no enhancement of autoantibody production or nephritis in H2b/z vs H2b/b B6.Nba2 mice, and inheritance of H2z/z markedly suppressed autoantibody production. (B6.Nba2 × NZW)F1 mice, compared with MHC-matched B6.Nba2 mice, produced higher levels of IgG autoantibodies to chromatin, but not to dsDNA. Although progressive renal damage with proteinuria only occurred in F1 mice, kidneys of some B6.Nba2 mice showed similar extensive IgG and C3 deposition. We also studied male and female B6.Nba2 and F1 mice with different MHC combinations to determine whether increased susceptibility to lupus among females was also expressed within the context of the Nba2 locus. Regardless of MHC or the presence of NZW genes, females produced higher levels of antinuclear autoantibodies, and female F1 mice developed severe proteinuria with higher frequencies. Together, these studies help to clarify particular genetic and sex-specific influences on the pathogenesis of lupus nephritis.

Type I interferon signaling is involved in the spontaneous development of lupus-like disease in B6.Nba2 and (B6.Nba2 × NZW)F1 mice

“…8,10,13 We analyzed the serum levels of total IgM and IgG in 3-month-old IFNAR þ / þ , IFNAR þ /À and IFNAR À/À B6.Nba2 mice to address whether IFNab signaling plays a role in early antibody production. There was a trend toward reduced levels of both total serum IgM and total serum IgG in IFNAR þ /À and IFNAR À/À B6.Nba2 mice, as compared with IFNAR þ / þ B6.Nab2 mice.…”

“…8 This locus has been associated with increased autoantibody production, and B6.Nba2 mice resemble NZB mice in their development of elevated levels of ANA directed against ssDNA, double-stranded DNA (dsDNA), total histones and chromatin. [8][9][10] Neither NZB nor B6.Nba2 mice, however, develop fatal kidney disease. 9 NZW mice do not develop elevated levels of ANA, but have been found to show increased susceptibility to anti-glomerular autoantibodyinduced kidney disease.…”

“…11 In addition, the female F1 offspring of NZW crossed with B6.Nba2 (but not B6) develops severe proteinuria and dies from kidney failure within 1 year of age as do female (NZB Â NZW)F1 mice. [8][9][10] Thus, the combination of Nba2-dependent autoantibody production and NZW-derived kidney susceptibility may be important for full disease development in the (B6.Nba2 Â NZW)F1 model of lupus-like disease.…”

Stimulation of T cells up-regulates expression of Ifi202, an interferon-inducible lupus susceptibility gene, through activation of JNK/c-Jun pathway

“…Interestingly, a recent study [47] has noted differences between male and female B6.Nba2 mice with respect to production of autoantibodies, raising the possibility that expression of Ifi202 gene in the B6.Nba2 mice is regulated by gender-dependent factors. Consistent with this idea, we noted that steady-state levels of Ifi202 mRNA were relatively low in male mice as compared to age-matched female NZB mice (Fig.…”

Three checkpoints in lupus development: central tolerance in adaptive immunity, peripheral amplification by innate immunity and end-organ inflammation

“…Indeed, the MHC locus has consistently emerged as the strongest susceptibility factor for murine lupus in multiple murine models. 48,49 Though this locus (referred to Sle4 or Sles1 in NZM2410 mice) has been phenotypically very well characterized, definitive evidence indicating that the H2 genes are indeed the disease genes within this locus is still elusive.…”