An epistatic effect of the female specific loci on the development of autoimmune vasculitis and antinuclear autoantibody in murine lupus

Zhang, Mingcai; Misu, Naoko; Furukawa, Hiroshi; Watanabe, Yukihiko; Terada, Miho; Komori, H.; Miyazaki, Tatsuhiko; Nose, Masato; Ono, M.

doi:10.1136/ard.2005.040832

Cited by 6 publications

(4 citation statements)

References 39 publications

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“…Previous studies have suggested the lack of SrD in MRL/lpr mice [22][23][24][25]. In the early stage of this study, we carefully confirmed that MRL/lpr mice hardly display any SrD related to the severity of autoimmune phenotypes, including glomerulonephritis (GN), splenomegaly (SpM), and autoantibody to nuclear antigens (ANA).…”

Section: Introductionsupporting

confidence: 81%

“…There are inconsistent facts that MBN2 mice show remarkable SrD in autoimmune phenotypes, while their ancestral MRL/lpr mice do not show significant SrD. Past studies have readily confirmed little SrD in the autoimmune phenotypes of an MRL/lpr strain [22][23][24][25]. Here, a question that arose was why the male-specific suppression by Marc4 had attenuated in the male mice of this strain.…”

Section: Discussionmentioning

confidence: 89%

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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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Section: Introductionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 89%

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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“…In MRL-Fas lpr mice, the polymorphisms of Cd22, Fcgr2b, Spp1, IL10ra, and Coro1a were reported to be associated with autoimmune phenotypes (11,(38)(39)(40)(41). Of particular interest, the epistatic interaction between Cd72 and Fcgr2b in the development of autoimmune diseases has been observed in both humans and mice (42,43). The occurrence of polygenic diseases has been explained in a threshold-liability model, in which individuals develop the disease when the total number of disease-susceptibility genes exceeds a given threshold.…”

Section: Discussionmentioning

confidence: 99%

A Bacterial Artificial Chromosome Transgene with PolymorphicCd72Inhibits the Development of Glomerulonephritis and Vasculitis in MRL-FaslprLupus Mice

Oishi

Tsubaki

Miyazaki

et al. 2013

The Journal of Immunology

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Systemic lupus erythematosus is considered to be under the control of polygenic inheritance, developing according to the cumulative effects of susceptibility genes with polymorphic alleles; however, the mechanisms underlying the roles of polygenes based on functional and pathological genomics remain uncharacterized. In this study, we substantiate that a CD72 polymorphism in the membrane-distal extracellular domain impacts on both the development of glomerulonephritis and vasculitis in a lupus model strain of mice, MRL/MpJ-Faslpr, and the reactivity of BCR signal stimulation. We generated mice carrying a bacterial artificial chromosome transgene originating from C57BL/6 (B6) mice that contains the Cd72b locus (Cd72B6 transgenic [tg]) or the modified Cd72b locus with an MRL-derived Cd72c allele at the polymorphic region corresponding to the membrane-distal extracellular domain (Cd72B6/MRL tg). Cd72B6 tg mice, but not Cd72B6/MRL tg mice, showed a significant reduction in mortality following a marked improvement of disease associated with decreased serum levels of IgG3 and anti-dsDNA Abs. The number of splenic CD4−CD8− T cells in Cd72B6 tg mice was decreased significantly in association with a reduced response to B cell receptor signaling. These results indicate that the Cd72 polymorphism affects susceptibility to lupus phenotypes and that novel functional rescue by a bacterial artificial chromosome transgenesis is an efficient approach with wide applications for conducting a genomic analysis of polygene diseases.

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“…An MRL/lpr strain carries a loss‐of‐function mutation of Fas gene ( lpr ) which encodes an apoptosis receptor on lymphocytes [5]. The lpr mutation is necessary for the onset of autoimmune diseases in MRL/lpr; however, the other lpr ‐congenic strains, including C3H/He.Fas lpr (C3H/lpr), C57BL/6.Fas lpr and AKR.Fas lpr , barely develop autoimmune diseases [6–9]. The strain difference in the lpr constraint also influences the longevity of mice.…”

Section: Introductionmentioning

confidence: 99%

A Genetic Locus Controlling Aging‐sensitive Regression of B Lymphopoiesis in an Autoimmune‐prone MRL/lpr Strain of Mice

Nakatani

Zhang

et al. 2007

Scand J Immunol

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Aging readily affects immune system under the influence of environmental and/or intrinsic factors while accelerating the development of various immune disorders including autoimmune diseases. Little is known about molecular and cellular mechanisms connecting between immune senescence and development of autoimmune diseases. Here, we first show strain‐specific and aging‐sensitive onset of B‐cell abnormality in a lupus‐prone MRL/Mp.Faslpr (MRL/lpr) strain of mice. This abnormality was characterized by the regression of B lymphopoiesis in the bone marrow of this strain. We next examined the association between the B‐cell regression and onset of autoimmune diseases in aged (MRL/lpr × C3H/He.Faslpr) F2 mice, in which pathologic phenotypes, such as glomerulonephritis, vasculitis, sialoadenitis and arthritis, variously developed. We also searched whole genome to identify genetic loci linked to the B‐cell regression by using the same F2 mice. The B‐cell regression manifested in the spleen of F2 mice was retrospectively evaluated by reverse transcriptase‐based PCR quantification. The results demonstrated that the onset of autoimmune diseases in the F2 mice was not associated with the aging‐sensitive B‐cell regression. The genetic study identified a significant locus responsible for the B‐cell regression in the vicinity of D5Mit233 (29 cM). This is first evidence for the presence of a genetic locus that affects B lymphopoiesis in an aging‐sensitive manner.

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An epistatic effect of the female specific loci on the development of autoimmune vasculitis and antinuclear autoantibody in murine lupus

Cited by 6 publications

References 39 publications

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

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

A Bacterial Artificial Chromosome Transgene with PolymorphicCd72Inhibits the Development of Glomerulonephritis and Vasculitis in MRL-FaslprLupus Mice

A Genetic Locus Controlling Aging‐sensitive Regression of B Lymphopoiesis in an Autoimmune‐prone MRL/lpr Strain of Mice

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