Genetic Dissection of SLE

Shi, Xiaoyan; Xie, Chun; Kreska, Desi; Richardson, James A.; Mohan, Chandra

doi:10.1084/jem.20010955

Cited by 68 publications

(22 citation statements)

References 47 publications

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“…1F-G). Most importantly, all parameters of renal disease were reversed to normal, similar to the phenotypes see in healthy B6 mice previously reported (16). …”

Section: Resultssupporting

confidence: 87%

“…The activation status of the B-cells, as gauged by surface CD86 expression was also markedly reduced following CDDO-Me treatment (6.48±0.42 vs 8.72±0.45 MFI units, P < 0.002; data not plotted). Importantly, after CDDO-Me treatment, the cell number and activation status of splenic B cells and T cells and their subsets were reversed to normal, similar to the phenotypes seen in healthy B6 mice previously reported (16). …”

Section: Resultssupporting

confidence: 85%

“…The anti-dsDNA, anti-histone, and anti-histone/DNA ELISA assays were carried out as described before (16). Raw OD was converted to Units/ml (U/ml), using a positive control serum derived from a B6.…”

Section: Methodsmentioning

confidence: 99%

“…Test sera with reactivity stronger than the standard were diluted further and re-assayed. The glomerular-binding ELISA was performed as described previously (16), using sonicated rat glomeruli as the substrate.…”

Section: Methodsmentioning

confidence: 99%

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Prevention of Murine Lupus Nephritis by Targeting Multiple Signaling Axes and Oxidative Stress Using a Synthetic Triterpenoid

Min

et al. 2014

Arthritis & Rheumatology

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Objective Current treatment options for lupus are far from optimal. Previously, we reported that PI3K/AKT/mTOR, MEK1/Erk1,2, p38, STAT3, STAT5, NF-κB, multiple Bcl-2 family members, and various cell cycle molecules were over-expressed in splenic B-cells in an age-dependent and gene-dose-dependent manner in mouse strains with spontaneous lupus. As the synthetic triterpenoid methyl-2-cyano-3,12-dioxooleana-1,9-dien-28-oate (CDDO-Me) has been shown to inhibit AKT, MEK1/2, and NF-κB, and to induce caspase-mediated apoptosis, we tested the therapeutic potential of this agent in murine lupus nephritis. Methods The synthetic triterpenoid CDDO-Me, or placebo, was administered to two month old B6.Sle1.Sle3 mice or MRL.lpr mice, which develop spontaneous lupus. All mice were phenotyped for disease. Results CDDO-Me-treated mice exhibited significantly reduced splenic cellularity, with decreased CD4+ T-cells and activated CD69+/CD4+ T-cells compared to the placebo-treated mice. These mice also exhibited significant reduction in serum autoantibody levels, including anti-dsDNA and anti-glomerular antibodies. Finally, CDDO-Me treatment attenuated renal disease in mice, as marked by reduced 24-hour proteinuria, blood urea nitrogen, and glomerulonephritis. At the mechanistic level, CDDO-Me treatment dampened MEK1/2, ERK, and STAT3 signaling within lymphocytes and oxidative stress. Importantly, the NF-E2-Related Factor 2 (Nrf2) pathway was activated after CDDO-Me treatment, indicating that CDDO-Me may be modulating renal damage in lupus via the inhibition of oxidative stress. Conclusion These findings underscore the importance of AKT/MEK1/2/NF-κB signaling in engendering murine lupus. Our studies reveal that the blockade of multiple signaling nodes and oxidative stress may effectively prevent and reverse the hematological, autoimmune and pathological manifestations of lupus.

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“…1F-G). Most importantly, all parameters of renal disease were reversed to normal, similar to the phenotypes see in healthy B6 mice previously reported (16). …”

Section: Resultssupporting

confidence: 87%

Section: Resultssupporting

confidence: 85%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

See 2 more Smart Citations

Prevention of Murine Lupus Nephritis by Targeting Multiple Signaling Axes and Oxidative Stress Using a Synthetic Triterpenoid

Min

et al. 2014

Arthritis & Rheumatology

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“…B6.Sle1yaa T cells at this stage of disease also had a replicative senescent phenotype, which is commonly a consequence of the chronic activation associated with severe autoimmunity in lupusprone mouse strains (Fig. 9, which is published as supporting information on the PNAS web site) (8,(40)(41)(42).…”

Section: Functional Changes Associated With the Tlr7 Translocation Inmentioning

confidence: 99%

ATlr7translocation accelerates systemic autoimmunity in murine lupus

Subramanian

Tus

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

580

485

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The y-linked autoimmune accelerating (yaa) locus is a potent autoimmune disease allele. Transcription profiling of yaa-bearing B cells revealed the overexpression of a cluster of X-linked genes that included Tlr7. FISH analysis demonstrated the translocation of this segment onto the yaa chromosome. The resulting overexpression of Tlr7 increased in vitro responses to Toll-like receptor (TLR) 7 signaling in all yaa-bearing males. B6.yaa mice are not overtly autoimmune, but the addition of Sle1, which contains the autoimmune-predisposing Slam͞Cd2 haplotype, causes the development of fatal lupus with numerous immunological aberrations. B6.Sle1yaa CD4 T cells develop the molecular signature for T FH cells and also show expression changes in numerous cytokines and chemokines. Disease development and all component autoimmune phenotypes were inhibited by Sles1, a potent suppressor locus. Sles1 had no effect on yaa-enhanced TLR7 signaling in vitro, and these data place Sles1 downstream from the lesion in innate immune responses mediated by TLR7, suggesting that Sles1 modulates the activation of adaptive immunity in response to innate immune signaling.Sle1 ͉ Sles1 ͉ Toll-like receptor 7 ͉ yaa

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Enhanced susceptibility to end‐organ disease in the lupus‐facilitating NZW mouse strain

Xie¹,

Zhou²,

Liu³

et al. 2003

Arthritis & Rheumatism

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106

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Objective. Although the NZW mouse strain is phenotypically normal, fulminant lupus glomerulonephritis (GN) develops when NZW mice are bred to several other strains, such as NZB, BXSB, B6.Sle1, and B6.Yaa. Based on the observation that aging NZW mice exhibit histologic evidence of GN, we sought to test our hypothesis that NZW mice may be more susceptible to immune-mediated renal damage.Methods. NZW mice, as well as C57BL/6 (B6) and BALB/c control mice, were challenged with rabbit antiglomerular basement membrane nephrotoxic sera (NTS), to induce renal disease. The different mouse strains were monitored for the degree of clinical disease, renal pathology, chemokine profiles, and cellular infiltrates.Results. Although the NZW and control strains showed similar glomerular deposits of rabbit Ig and exhibited similar levels of anti-rabbit xenogeneic immune response, the NZW mice had significantly worse pathologic changes and disease. Compared with the control strains, the NTS-injected NZW mice demonstrated significantly increased proteinuria, elevated blood urea nitrogen levels, more severe histologic GN and tubulointerstitial nephritis, increased glomerular crescent formation with macrophage and neutrophil infiltrates, elevated expression of CC and CXC chemokines (monocyte chemoattractant protein 1, RANTES, KC), and significantly accelerated mortality. Importantly, these changes occurred within a few days after NTS administration. Finally, (B6 ؋ NZW)F 1 mice were as susceptible as the NZW parents, which indicates dominant NZW contributions.Conclusion. Collectively, these findings support the notion that a lupus-facilitating genome may contribute to disease susceptibility by modulating the degree of immune-mediated end-organ damage. The availability of B6-based congenic strains bearing individual NZWderived lupus susceptibility loci will permit future genetic dissection of end-organ susceptibility in murine lupus.Over the last 4 decades, studies with the New Zealand strains of mice have contributed significantly to our understanding of the pathogenesis of lupus. Of particular interest are the specific genetic and immunologic contributions of the NZW and NZB strains to disease. The NZW strain is fairly healthy, but contributes to lupus nephritis, in epistasis with several other strains. When NZW mice are bred to the NZB strain, either as an F 1 hybrid or as a recombinant inbred strain, this leads to highly penetrant lupus nephritis (1-3). Likewise, when NZW mice are bred to the BXSB strain, the F 1 offspring exhibit lupus nephritis and coronary vascular disease (4). Moreover, when NZW mice are bred to B6 mice, either in the context of the lupus susceptibility locus Sle1 (5) or the Yaa locus (6), the F 1 offspring also exhibit severe proliferative glomerulonephritis (GN) and accelerated mortality. Thus, although the NZW genome by itself does not lead to the development of clinical nephritis, it clearly has the capacity to interact with several other genomes to precipitate endorgan disease.Although NZW mice are clinicall...

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Genetic Dissection of SLE

Cited by 68 publications

References 47 publications

Prevention of Murine Lupus Nephritis by Targeting Multiple Signaling Axes and Oxidative Stress Using a Synthetic Triterpenoid

Prevention of Murine Lupus Nephritis by Targeting Multiple Signaling Axes and Oxidative Stress Using a Synthetic Triterpenoid

ATlr7translocation accelerates systemic autoimmunity in murine lupus

Enhanced susceptibility to end‐organ disease in the lupus‐facilitating NZW mouse strain

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