Genetic dissection of vasculitis in MRL/lpr lupus mice: a novel susceptibility locus involving theCD72c allele

Qu, Wei Min; Miyazaki, Tatsuhiko; Terada, Miho; Lu, Ling; Nishihara, Masateru; Yamada, Akihiro; Mori, Shiro; Nakamura, Yusuke; Ogasawara, Haruhiko; Yazawa, Chie; Nakatsuru, Shuichi; Nose, Masato

doi:10.1002/1521-4141(200007)30:7<2027::aid-immu2027>3.0.co;2-s

Cited by 57 publications

(53 citation statements)

References 23 publications

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“…Considering our previous results with the same MCF 2 progenies of mice, Agnm1 and Agnm2 could share two susceptibility loci to systemic vasculitis, Arvm1 and Arvm2, respectively [8]. On the other hand, Agnm3 is a novel locus for susceptible to GN in an MRL allele.…”

Section: Allelic Differences Of Opn In Autoimmune Strains Of Micementioning

confidence: 65%

“…In the initial step of this study, three loci were found to be associated significantly with GN, and one of them, Agnm3, turned out to be a novel locus that did not share a chromosomal region with any lupus susceptibility loci reported previously [2][3][4][5][6]8], although some phenotypic loci referring to immune traits were reported such as Lprm4 (lymphoproliferation modifier 4, 54 cM) that was designated by spleen weight in MCN 2 mice [12] and Tsz1 (Thymus size 1, 56 cM) that was designated by thymus size [13]. It should be noted that another study using progenies from B6/lpr and MRL/lpr mice did not show any linkage of GN to Agnm3, even though we employed the same conditions for mouse breeding and histopathologic GN grading as in this study (Zhang et al, manuscript in preparation).…”

Section: Discussionmentioning

confidence: 99%

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Implication of allelic polymorphism of osteopontin in the development of lupus nephritis in MRL/lpr mice

Miyazaki

Ono

et al. 2005

Eur J Immunol

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Potentially, autoimmune diseases develop from a combination of multiple genes with allelic polymorphisms. An MRL/Mp-Fas lpr/lpr (MRL/lpr) strain of mice develops autoimmune diseases, including lupus nephritis, but another lpr strain, C3H/HeJFas lpr/lpr (C3H/lpr) does not. This indicates that MRL polymorphic genes are involved in the development of the diseases. By quantitative trait loci (QTL) analysis using 527 of the (MRL/lpr Â C3H/lpr)F 2 mice, we identified a novel locus for susceptibility to lupus nephritis at map position D5Mit115 on chromosome 5, the same alias of the osteopontin (Opn) gene (LOD score =4.0), susceptible in the MRL allele. In functional analyses of the MRL and C3H Opn alleles using synthetic osteopontin (OPN) made with a new method "cell-free system" with wheat germ ribosomes, the MRL-OPN induced higher expression and production of immunoglobulins as well as cytokines including TNF-a, IL-1b and IFN-c in splenocytes and/or macrophages than that of the C3H allele. These findings suggest that allelic polymorphism of OPN causes the functional differences in antibody production and macrophage activation between MRL and C3H strains, possibly involved in the development of lupus nephritis.

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Section: Allelic Differences Of Opn In Autoimmune Strains Of Micementioning

confidence: 65%

Section: Discussionmentioning

confidence: 99%

Implication of allelic polymorphism of osteopontin in the development of lupus nephritis in MRL/lpr mice

Miyazaki

Ono

et al. 2005

Eur J Immunol

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“…Marc4 and Marc7 overlap well with some of these loci associated with SpM [32,33], GN [34][35][36][37][38], vasculitis [39], anti-dsDNA [32,36,37], or mortality [33]. Sex-related preponderance was not examined for these loci.…”

Section: Discussionmentioning

confidence: 99%

Autosomal loci associated with a sex‐related difference in the development of autoimmune phenotypes in a lupus model

et al. 2007

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Sex-related differences (SrD) are a general characteristic of human autoimmune diseases. There is an increasing body of evidence that suggests a link between sexrelated hormones and autoimmune onsets. Here, through a genetic approach using a lupus mouse model, we attempted to show the involvement of genetic factors in the development of SrD in autoimmune diseases. Using MRL/lpr Â (MRL/lpr Â C57BL/ 6.Fas lpr )F1 (MBN2) mice, the whole genome was searched to identify linkage loci to autoimmune phenotypes inherited from a lupus MRL/Mp.Fas lpr (MRL/lpr) strain of mice, which exhibits glomerulonephritis, splenomegaly and antinuclear autoantibody. The genome-wide association study confirmed four linkage loci on chromosomes 4, 7, 13, and 17. Furthermore, differential analyses performed using male and female groups of MBN2 mice revealed that two loci located on chromosomes 4 (41-72 cM, MRL/lpr allele) and 7 (4-21 cM, B6/lpr allele) were male specific and suppressed autoimmune phenotypes. Notably, the sum effect of the two loci adequately explained a range of SrD developed in the MBN2 mice. Our present findings suggest the presence of a malepredominant mechanism underlying the development of SrD in autoimmunity, depending on the effects of autosomal loci under an undefined male-specific condition.

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“…To accomplish this, we and others mapped lupus-predisposing loci in F2 or N2 crosses of MRL-Fas lpr with several other strains, including CAST/Ei (2), C3H-Fas lpr (3)(4)(5)(6), and B6-Fas lpr (where B6 represents C57BL/6) (7). At least 15 loci located on eight of the 19 autosomal chromosomes were identified linked to various lupus-related manifestations.…”

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confidence: 99%

Characterization of Reciprocal Lmb1–4 Interval MRL-Fas lpr and C57BL/6-Fas lpr Congenic Mice Reveals Significant Effects from Lmb3

Santiago-Raber

Haraldsson

Theofilopoulos

et al. 2007

The Journal of Immunology

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Susceptibility to severe lupus in MRL-Faslpr mice requires not only the lpr mutation but also other predisposing genes. Using (MRL-Faslpr × B6-Faslpr)F2 (where B6 represents C57BL/6) intercrosses that utilize the highly susceptible MRL and poorly susceptible B6 backgrounds, we previously mapped CFA-enhanced systemic lupus-like autoimmunity to four loci, named Lmb1–4, on chromosomes 4, 5, 7, and 10. In the current study, we generated and analyzed reciprocal interval congenic mice for susceptibility to CFA-enhanced autoimmunity at all four Lmb loci. Although all loci had at least a slight effect on lymphoproliferation, only Lmb3 demonstrated a major effect on lymphoproliferation and anti-chromatin Ab levels. Further characterization of Lmb3, primarily by comparing MRL-Faslpr with MRL.B6-Lmb3 Faslpr congenic mice, revealed that it also played a significant role in spontaneous lupus, modifying lymphoproliferation, IgG and autoantibody levels, kidney disease, and survival. The less susceptible B6 Lmb3 locus was associated with a marked reduction in numbers of CD4+ and double-negative (CD4−CD8−) T cells, particularly in lymph nodes, as well as reduced T cell proliferation and enhanced T cell apoptosis, both in vivo and in vitro. IFN-γ-producing CD4+ T cells were also reduced in MRL.B6-Lmb3 Faslpr mice. Further mapping using subinterval congenic mice placed Lmb3 in the telomeric portion of chromosome 7. Thus, Lmb3, primarily through its effects on CD4+ and double-negative T cells, appears to be a highly penetrant lupus-modifying locus. Identification of the underlying genetic alteration responsible for this quantitative trait locus should provide new insights into lupus-modifying genes.

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Genetic dissection of vasculitis in MRL/lpr lupus mice: a novel susceptibility locus involving theCD72c allele

Cited by 57 publications

References 23 publications

Implication of allelic polymorphism of osteopontin in the development of lupus nephritis in MRL/lpr mice

Implication of allelic polymorphism of osteopontin in the development of lupus nephritis in MRL/lpr mice

Autosomal loci associated with a sex‐related difference in the development of autoimmune phenotypes in a lupus model

Characterization of Reciprocal Lmb1–4 Interval MRL-Fas lpr and C57BL/6-Fas lpr Congenic Mice Reveals Significant Effects from Lmb3

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