Arthritis in MRL/lpr mice is under the control of multiple gene loci with an allelic combination derived from the original inbred strains

Kamogawa, Junji; Terada, Miho; Mizuki, Shinichi; Nishihara, Masateru; Yamamoto, Haruyasu; Mori, Shiro; Abe, Yoriko; Morimoto, Koji; Nakatsuru, Shuichi; Nakamura, Yusuke; Nose, Masato

doi:10.1002/art.10193

Cited by 49 publications

(40 citation statements)

References 27 publications

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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.…”

mentioning

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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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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“…enitis, and arthritis, were genetically segregated by the allelic combinations of these loci (6)(7)(8)(9).…”

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confidence: 99%

Accelerating effect of an MRL gene locus on the severity and onset of arthropathy in DBA/1 mice

Oishi¹,

Miyazaki²,

Mizuki³

et al. 2005

Arthritis & Rheumatism

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Objective. To analyze the influence of the genetic background of an arthritis-prone strain of mice, MRL, on the spontaneous development of arthropathy in DBA/1 mice, which histopathologically resembles enthesopathy in humans, and to clarify the strain-specific gene loci and their interactions that confer susceptibility to arthropathy.Methods. MRL, DBA/1, (MRL ؋ DBA/1)F 1 , and (MRL ؋ DBA/1)F 2 intercross mice were prepared, and the severity and onset of arthropathy of the ankle joints in individual mice were quantified (0-3 and 0-5 scale, respectively). A genome-wide scan of 271 male F 2 intercross mice with polymorphic microsatellite markers was performed.Results. Only male DBA/1, (MRL ؋ DBA/1)F 1 , and (MRL ؋ DBA/1)F 2 mice developed arthropathy. The macroscopic and histopathologic findings of arthropathy in the F 2 mice were similar to those in the parental DBA/1 mice, but the onset was significantly earlier. In the quantitative trait locus analysis of male F 2 mice, 1 susceptibility locus for both the severity and early onset of the disease in the region of an MRL allele, Amd1, was located at marker D10Mit259 (map position 40.0 cM), which was common to 1 of the sialadenitis susceptibility loci in MRL mice, Asm1. Another susceptibility locus for the severity and early onset of arthropathy in the region of a DBA allele, Amd2, was located at D3Mit46 (29.5 cM). These loci manifested an additive effect on the development of arthropathy.Conclusion. Arthropathy in DBA/1 mice is under the control of an allelic combination of gene loci, one of which is common to the locus for sialadenitis in MRL/ MpJ-lpr/lpr mice.

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“…5). A previous study (Kamogawa et al 2002) suggested that arthritis in MRL/lpr mice is under the control of multiple gene loci with an allelic combination derived from the original inbred strains by chromosomal mapping of the susceptibility loci to arthritis by using the backcross progeny of MRL/lpr × (MRL/lpr × C3H/lpr) F1 mice. The present results verified this proposed concept more clearly by using RI strains on the ground of the reason as described below.…”

Section: Discussionmentioning

confidence: 99%

“…The lesions, including the calcaneus bone and anterior and posterior synovial tissue at the ankle joints, were evaluated histopathologically. To evaluate the severity of synovitis, the following grading was used: normal, grade 0; thickening and proliferation of synovial lining, grade 1; and grade 1 with granulomatous and/or fibrous lesions in synovial sublining tissue, grade 2 (Kamogawa et al 2002). Pannus formation was categorized as follows: normal, grade 0, extending to bone cortex, grade 1; and further to bone marrow, grade 2.…”

Section: Histopathology Of Arthritismentioning

confidence: 99%

“…MXH/lpr mice were established by intercrosses between MRL/lpr and C3H/lpr strains of mice, among which genetic dissociation of arthritis might be generated due to genome recombination between the parental stains, based on a previous study of chromosomal mapping of the susceptibility loci to arthritis (Nose et al 1989;Kamogawa et al 2002). Expectedly, genetic dissociation of arthritis was observed among the MXH/lpr mice (Fig.…”

Section: Genetic Dissociation Of Rf Activity From the Severity Of Artmentioning

confidence: 99%

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Evaluating the Role of Rheumatoid Factors for the Development of Rheumatoid Arthritis in a Mouse Model with a Newly Established ELISA System

Tanaka

Komori

Mori

et al. 2010

Tohoku J. Exp. Med.

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Arthritis in MRL/lpr mice is under the control of multiple gene loci with an allelic combination derived from the original inbred strains

Cited by 49 publications

References 27 publications

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

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

Accelerating effect of an MRL gene locus on the severity and onset of arthropathy in DBA/1 mice

Evaluating the Role of Rheumatoid Factors for the Development of Rheumatoid Arthritis in a Mouse Model with a Newly Established ELISA System

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