Lupus susceptibility loci in New Zealand mice.

Kono, Dwight H.; Burlingame, Rufus W.; Owens, Dan G.; Kuramochi, Akiko; Balderas, Robert; Balomenos, Dimitrios; Theofilopoulos, Argyrios N.

doi:10.1073/pnas.91.21.10168

Cited by 324 publications

(265 citation statements)

References 20 publications

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“…In addition to the MHC loci, several lupussusceptibility loci derived from the NZB and NZW strains have been identified, including Sle1-Sle6, Nba1-Nba4, Nwa1-Nwa2 and Lbw1-Lbw8. [38][39][40][41][42] However, the lpr mutation in an MRL susceptibility background is a key element in the penetrance of disease pathogenesis in the MRL/lpr strain.…”

Section: Discussionmentioning

confidence: 99%

Genomic view of IFN-α response in pre-autoimmune NZB/W and MRL/lpr mice

Shen

et al. 2007

Genes Immun

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Interferon (IFN)-a is involved in the pathogenesis of systemic lupus erythematosus. Studies in murine lupus models have revealed that type I IFN exerts either a protective effect in MRL/lpr, or can detrimentally impact disease progression, as in NZB/ W mice. To understand this paradox, we examined the kinetic global gene expression in pre-autoimmune NZB/W-, MRL/lprand normal BALB/c-derived splenic mononuclear cells following ex vivo IFN-a treatment. Analysis of IFN-a-induced gene expression patterns revealed genes associated with antiproliferative activity of IFN-a including CDKN1A, GADD45B, pituitary tumor-transforming 1, SCOTIN, ataxia telangiectasia-mutated homolog and calcyclin-binding protein were upregulated in MRL/ lpr and/or BALB/c mice. Of IFN-a-induced genes differentially expressed in NZB/W vs BALB/c and MRL/lpr mice at 3 h time point, enhanced expression of CCND1, cyclin D2, matrix metalloproteinase 13 and a panel of cytokines and chemokines and impaired expression of negative inflammatory regulators CD69 and an Src family kinase hemopoietic cell kinase were notable. Interestingly, the splenic mononuclear cells from the NZB/W not MRL/lpr lupus-prone mice at the pre-autoimmune stage before ex vivo IFN-a treatment, have increased expression of many known IFN-regulated genes. These results provide a unique genomic view of ex vivo IFN-a response in two lupus-prone models, and help to have an insight into the role of IFN-a in lupus pathogenesis Genes and Immunity (2007) IntroductionSystemic lupus erythematosus (SLE) is a prototypic systemic autoimmune disease characterized by a break of immune tolerance to self antigens, resulting in inflammation and damage to a range of organ systems. The exact pathoetiology of SLE remains elusive. Elevated serum levels of IFN-a have long been observed and correlated with disease activity. A series of studies using microarray gene expression analysis in patient peripheral blood cells demonstrated an 'IFN signature' in SLE, which correlated with renal and hematological involvement of phenotypes. [1][2][3][4][5][6] Supporting evidence has also come from studies on murine lupus. The (New Zealand Black (NZB) Â New Zealand White (NZW))F1 hybrid female mice (NZB/W) develop a disease closely resembling human SLE, characterized by the production of antinuclear antibodies, severe glomerulonephritis and early mortality. In the NZB parental strain, which also develops a lupus-like syndrome, homozygous IFN-a/b R-deleted NZB mice had significantly reduced antierythrocyte autoantibodies, erythroblastosis, hemolytic anemia, anti-DNA autoantibodies, kidney disease and mortality. 7 In contrast to normal BALB/c mice, continuous in vivo treatment of IFN-a in pre-autoimmune NZB/W mice from 8 weeks of age precipitates the autoimmune process and kidney damage, leading to premature death from severe immune complex glomerulonephritis. This result provides a direct evidence that IFN-a is implicated in the pathogenesis of SLE. 8 Thus, the type I IFNs have emerged as a dominant target in the path...

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Section: Discussionmentioning

confidence: 99%

Genomic view of IFN-α response in pre-autoimmune NZB/W and MRL/lpr mice

Shen

et al. 2007

Genes Immun

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“…In this study, we confirm that there is a 129-derived locus on proximal chromosome 7 linked to GN. 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.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2006

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“…This locus has been defined for initial spontaneous loss of immunologic tolerance because of its variety of associated traits and may implicate multiple coexisting mechanisms. [46][47][48][49][50][51] There are several immediately interesting candidates within the region. Among these is a downstream effector molecule of an established type I interferon pathway, RnaseL.…”

Section: Genetic Control Of Viral Myocarditis In Micementioning

confidence: 99%

Complex genetic control of host susceptibility to coxsackievirus B3-induced myocarditis

et al. 2007

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The pathogenesis of viral myocarditis is a multifactorial process involving host genetics, viral genetics and the environment in which they interact. We have used a model of infection with coxsackievirus B3 (CVB3) to characterize the contribution of host genetics to viral myocarditis in mice of different genetic backgrounds but with a common H2 haplotype: A/J and B10.A-H2 a .Here we have used Evans blue dye as a quantitative biomarker for susceptibility to CVB3-induced myocarditis in addition to histopathological semiquantitative measures. We have found evidence of linkage between susceptibility to viral myocarditis and three loci. A locus on chromosome 1 centered on D1Mit200 was linked to sarcolemmal disruption in males (P ¼ 0.00005), a second locus on chromosome 4 centered on D4Mit81 was also linked to sarcolemmal disruption in males (P ¼ 0.0022). A third locus on distal chromosome 3 centered on D3Mit19 was linked to myocardial infiltration, with a logarithm of odds (LOD) score of 4.7 (P ¼ 0.0045), as well as sarcolemmal disruption in females (P ¼ 0.0015). These results provide strong evidence for the presence of loci contributing to the susceptibility of mice to viral myocarditis.

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Lupus susceptibility loci in New Zealand mice.

Cited by 324 publications

References 20 publications

Genomic view of IFN-α response in pre-autoimmune NZB/W and MRL/lpr mice

Genomic view of IFN-α response in pre-autoimmune NZB/W and MRL/lpr mice

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

Complex genetic control of host susceptibility to coxsackievirus B3-induced myocarditis

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