品系特点
自发突变
  
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品系详情
淋巴细胞增殖自发突变 (Faslpr) 纯合小鼠表现出全身自身免疫、异常 T 细胞增殖相关巨大淋巴结病、关节炎和免疫复合物肾小球肾炎。从大约三月龄起,MRL-lpr/lpr 小鼠的循环免疫复合物水平显著升高,而野生型MRL 小鼠无此表型 (Hewicker 1990)。Faslpr 基因相关症状的发作和严重程度呈品系依赖性。例如,与对照品系的淋巴结重量相比,同源品系 C57BL/6J-Faslpr/Faslpr 的淋巴结重量为对照品系的 24 倍,MRL/Mp-Faslpr/Faslpr 为对照品系的 75 倍,同源品系 C3H/HeJ-Faslpr/Faslpr 的淋巴结重量增幅最高,为对照品系的 116 倍,由此可见,淋巴细胞增殖差异非常大 (Morse et al 1985)。 在肾脏病理差异方面,4-7 月龄 MRL/Mp-Faslpr/Faslpr 小鼠的差异非常大,而在 14-16 月龄 C57BL/6J 和 C3H/HeJ 遗传背景下的 Faslpr 纯合小鼠中可忽略不计 (Kelley and Roths 1985)。抗 dsDNA 自身抗体的自发产生同样受到影响,C57BL/6J、C3H/HeJ 和 MRL/Mp 遗传背景下 Faslpr/Faslpr 小鼠的放射性标记 dsDNA 结合百分比分别为 5%、26% 和 49% (Izui et al 1984)。MRL/Mp-Faslpr 雌鼠和雄鼠的平均寿命分别为 17 周和 22 周。与之相比,C57BL/6J 或 C3H/HeJ 遗传背景下雌鼠的平均寿命为 42 周 至 52 周 (Roths 1987)。MRL/Mp-Faslpr/Faslpr 小鼠品系已建立胚胎干细胞系 (Kawase et al 1994)。这种小鼠适合用作系统性红斑狼疮样自身免疫综合征模型。
与一组其他近交系相比,MRL/MpJ 及其祖先品系之一 LG/J 表现出更高的伤口愈合率。伤后 4 周,MRL/MpJ 背景小鼠的 2 mm 耳洞伤口愈合至 0-0.4 mm,而 C57BL/6 背景小鼠的伤口大小仍有 1.2-1.6 mm。伤后 15 天,C57BL/6 小鼠的耳洞伤口大小最多愈合 30%,而 MRL 小鼠愈合 85%。MRL/MpJ 小鼠的愈合过程更快、更完全,表现为肿胀增加、血管生成、成纤维细胞迁移、细胞外基质沉积以及瘢痕和纤维化减少。此外,毛囊及其伴生的皮脂腺再生程度也更高。MRL/MpJ 的其他祖先品系(C3H、C57BL/6 和 AKR)未表现出这种促进愈合的情况。骨髓移植显示,MRL/MpJ 愈合表型不易随骨髓转移,而是保留在经过辐照的宿主组织中。MRL/MpJ 小鼠中还报告过促进心脏伤口愈合的现象。此模型的有丝分裂指数非常高 (10-20%),与在非哺乳动物组织再生中观察到的值相似。McBrearty 等人使用 F2 代并与 MRL/MpJ-Faslpr x B6 后代进行回交定位作图,鉴定出伤口愈合的以下 QTL:在 MRL/MpJ 13 号染色体上的 D13Mit115 和 D13Mit129 区域分别鉴定出 heal2 和 heal3 基因座;在 MRL/MpJ 12 号染色体上的 D12Mit233 区域鉴定出 heal5 基因座;在 C57BL/6 8 号染色体上的 D8Mit211 区域鉴定出 heal1 基因座;在 MRL/MpJ 7 号染色体上的 D7Mit220 区域鉴定出高度提示性基因座。(Clark et al., 1998; Leferovich et al., 2001; Kench et al., 1999; McBrearty et al., 1998.)
通过微阵列分析和 SELDI ProteinChip 分析鉴定出多个基因和蛋白在 MRL/MpJ-Faslpr 与 C57BL/6 小鼠的耳洞伤口中有差异表达。表达模式的变化表明,与 C57BL/6 小鼠相比,MRL/MpJ 小鼠的炎症反应较少,转入组织修复阶段的时间较早。(Li et al., 2000 and 2001.)
Blankenhorn 等人发现,MRL/MpJ 雌鼠比雄鼠的伤口愈合更快、更完全。有些愈合 QTL 具有性别二态性,如 heal 2、3、7、8、10、11 对雄鼠的影响较大,heal 4、5、9 则对雌鼠的影响较大。MRL/MpJ 雄鼠去势后能改善伤口愈合程度,使之接近雌鼠,而 MRL/MpJ 雌鼠进行卵巢切除术后不会改善伤口愈合程度。(Blankenhorn et al., 2003)
与 B10.D2nSnJ 小鼠相比,MRL/MpJ 小鼠对 LPS 输注的反应表现为中性粒细胞在细支气管灌洗液中的蓄积减少,且骨髓嵌合体试验显示肺部炎症反应会随骨髓转移。在 MRL/MpJ 小鼠的脾细胞中,转化生长因子 β1 自体诱导减少;而在巨噬细胞中,转化生长因子 β1 对白介素 1β 和肿瘤坏死因子 α 的产生诱导虽有减少,但转化生长因子 β1 的产生并无明显减少。(Kench et al., 1999.)MRL-Faslpr 小鼠对麻风分枝杆菌也高度易感 (Yogi et al., 1989)。
品系建立
杰克森实验室通过品系 LG、AKR、C3H 和 C57BL/6 的杂交获得 MRL/Mp 品系,并在第 12 代近亲交配后首次观察到大量淋巴细胞增殖。到第 13 代时,可以同时选择淋巴细胞增殖阳性和阴性亚系,估计其基因组存在89% 一致型。通过 5 次杂交-互交循环,残留杂合性估计值从 11% 降至 1%,从而将突变基因 Faslpr 转移至 MRL 阴性品系 (Murphy and Roth 1978 58:51)。
参考文献
精选参考文献
当使用该小鼠品系发表文献时,请引用原始文献,并在材料方法中提供该品系的品系货号:JAX stock#000485


2001

Fas/fas ligand deficiency results in altered localization of anti-double-stranded dna b cells and dendritic cells.

Fields ML , et al.

PubMed:11490027

MGI:J:70822

J Immunol 167(4):2370-8

2001

Heart regeneration in adult MRL mice.

Leferovich JM , et al.

PubMed:11493713

MGI:J:109867

Proc Natl Acad Sci U S A 98(17):9830-5

2001

Analysis of gene expression in the wound repair/regeneration process.

Li X , et al.

PubMed:11178744

MGI:J:68684

Mamm Genome 12(1):52-9

2001

Fas ligand (CD95L) protects neurons against perforin-mediated T lymphocyte cytotoxicity.

Medana I , et al.

PubMed:11441070
MGI:J:109872
J Immunol 167(2):674-81
2000

Differential protein profile in the ear-punched tissue of regeneration and non-regeneration strains of mice: a novel approach to explore the candidate genes for soft-tissue regeneration

Li X , et al.

PubMed:11113556
MGI:J:66437
Biochim Biophys Acta 1524(2-3):102-9
1999

Aberrant wound healing and TGF-beta production in the autoimmune-prone MRL/+ mouse.

Kench JA , et al.

PubMed:10479535
MGI:J:57718
Clin Immunol 92(3):300-10
1998

A new murine model for mammalian wound repair and regeneration.

Clark LD , et al.

PubMed:9683548
MGI:J:48937
Clin Immunol Immunopathol 88(1):35-45
1998

Genetic determinants of autoimmune disease and coronary vasculitis in the MRL-lpr/lpr mouse model of systemic lupus erythematosus.

Gu L , et al.

PubMed:9862736
MGI:J:52131
J Immunol 161(12):6999-7006
1998

Genetic analysis of a mammalian wound-healing trait.

McBrearty BA , et al.

PubMed:9751744
MGI:J:50111
Proc Natl Acad Sci U S A 95(20):11792-7
1994

Strain difference in establishment of mouse embryonic stem (ES) cell lines.

Kawase E , et al.

PubMed:7981049
MGI:J:19823
Int J Dev Biol 38(2):385-90
1994

Comparative influence of steroid hormones and immunosuppressive agents on autoimmune expression in lacrimal glands of a female mouse model of Sjogren's syndrome.

Sato EH , et al.

PubMed:8163351
MGI:J:18512
Invest Ophthalmol Vis Sci 35(5):2632-42
1993

The Fas protein is expressed at high levels on CD4+CD8+ thymocytes and activated mature lymphocytes in normal mice but not in the lupus-prone strain, MRL lpr/lpr.

Drappa J , et al.

PubMed:7694292
MGI:J:15429
Proc Natl Acad Sci U S A 90(21):10340-4
1992

Lacrimal and salivary gland inflammation in the C3H/Ipr autoimmune strain mouse: a potential mode for Sjogren's syndrome.

Johnson BC , et al.

PubMed:1565490
MGI:J:1028
Otolaryngol Head Neck Surg 106(4):394-9
1992

Lymphoproliferation disorder in mice explained by defects in Fas antigen that mediates apoptosis.

Watanabe-Fukunaga R , et al.

PubMed:1372394
MGI:J:1181
Nature 356(6367):314-7
1990

Detection of circulating immune complexes in MRL mice with different forms of glomerulonephritis.

Hewicker M , et al.

PubMed:2238887
MGI:J:109933
Z Versuchstierkd 33(4):149-56
1989

The experimental inoculation with Mycobacterium leprae in autoimmune mice: results of MRL/lpr mice inoculated into the right hind foot (continued).

Yogi Y , et al.

PubMed:2489281
MGI:J:27853
Nippon Rai Gakkai Zasshi 58(4):235-40
1985

Abnormalities induced by the mutant gene, lpr. Patterns of disease and expression of murine leukemia viruses in SJL/J mice homozygous and heterozygous for lpr.

Morse HC 3rd , et al.

PubMed:2982991
MGI:J:7745
J Exp Med 161(3):602-16
1982

Abnormalities induced by the mutant gene Ipr: expansion of a unique lymphocyte subset.

Morse HC 3rd , et al.

PubMed:6815273
MGI:J:6902
J Immunol 129(6):2612-5
1978

Spontaneous murine lupus-like syndromes. Clinical and immunopathological manifestations in several strains.

Andrews BS , et al.

PubMed:309911
MGI:J:27634
J Exp Med 148(5):1198-215
1978

Autoimmunity and lymphoproliferation: Induction by mutant gene lpr, and acceleration by a male-associated factor in strain BXSB mice

Murphy ED , et al.

其他参考文献
2004

Negative role of colony-stimulating factor-1 in macrophage, T cell, and B cell mediated autoimmune disease in MRL-Fas(lpr) mice.

Lenda DM , et al.

PubMed:15383612
MGI:J:93714
J Immunol 173(7):4744-54
2004

Regulation of NF-kappaB, Th activation, and autoinflammation by the forkhead transcription factor Foxo3a.

Lin L , et al.

PubMed:15308101
MGI:J:93593
Immunity 21(2):203-13
2004

Fas ligation on macrophages enhances IL-1R1-Toll-like receptor 4 signaling and promotes chronic inflammation.

Ma Y , et al.

PubMed:15004557
MGI:J:89208
Nat Immunol 5(4):380-7
2004

CD1d deficiency exacerbates inflammatory dermatitis in MRL-lpr/lpr mice.

Yang JQ , et al.

PubMed:15162443
MGI:J:90394
Eur J Immunol 34(6):1723-32
2003

Sexually dimorphic genes regulate healing and regeneration in MRL mice.

Blankenhorn EP , et al.

PubMed:12682777
MGI:J:82708
Mamm Genome 14(4):250-60
2003

Effect of genetic deficiency of terminal deoxynucleotidyl transferase on autoantibody production and renal disease in MRL/lpr mice.

Molano ID , et al.

PubMed:12804532
MGI:J:83942
Clin Immunol 107(3):186-97
2003

Genetic basis of tissue specificity of vasculitis in MRL/lpr mice.

Yamada A , et al.

PubMed:12746919
MGI:J:83832
Arthritis Rheum 48(5):1445-51
2002

Unusual expression of LINE-1 transposable element in the MRL autoimmune lymphoproliferative syndrome-prone strain.

Benihoud K , et al.

PubMed:12165858
MGI:J:78714
Oncogene 21(36):5593-600
2002

Anti-DNA autoreactivity in C4-deficient mice.

Paul E , et al.

PubMed:12207352
MGI:J:78993
Eur J Immunol 32(9):2672-9
2002

Role of RANTES in the development of autoimmune tissue injuries in MRL-Fas lpr mice.

Tsukahara T , et al.

PubMed:11987989
MGI:J:76389
Clin Immunol 103(1):89-97
2002

Impaired apoptosis, extended duration of immune responses, and a lupus-like autoimmune disease in IEX-1-transgenic mice.

Zhang Y , et al.

PubMed:11782530
MGI:J:73983
Proc Natl Acad Sci U S A 99(2):878-83
2001

Cytokines in autoimmune lacrimal gland disease in MRL/MpJ mice.

Jabs DA , et al.

PubMed:11581200
MGI:J:72054
Invest Ophthalmol Vis Sci 42(11):2567-71
2001

Treatment of MRL/lpr mice, a genetic autoimmune model, with the Ras inhibitor, farnesylthiosalicylate (FTS).

Katzav A , et al.

PubMed:11737078
MGI:J:73395
Clin Exp Immunol 126(3):570-7
2001

Spontaneous formation of germinal centers in autoimmune mice.

Luzina IG , et al.

PubMed:11590194
MGI:J:72513
J Leukoc Biol 70(4):578-84
2001

Fas-FasL interaction modulates nitric oxide production in Trypanosoma cruzi-infected mice.

Martins GA , et al.

PubMed:11380700
MGI:J:69492
Immunology 103(1):122-9
2000

Autoantibody responses and pathology regulated by B7-1 and B7-2 costimulation in MRL/lpr lupus

Liang B , et al.

PubMed:10975864
MGI:J:64568
J Immunol 165(6):3436-43
2000

Confounding influences on phenotype expression in MRL/lpr mice

Reuter JD , et al.

PubMed:10894502
MGI:J:62934
Comp Med 50(3):329-32
1995

Spontaneous development of corneal crystalline deposits in MRL/Mp mice.

Verhagen C , et al.

PubMed:7843914
MGI:J:24024
Invest Ophthalmol Vis Sci 36(2):454-61
1985

Interaction of mutant lpr gene with background strain influences renal disease.

Kelley VE , et al.

PubMed:4042431
MGI:J:109439
Clin Immunol Immunopathol 37(2):220-9
等位基因参考文献
基因分型和繁育
Allele Symbol Fas<lpr>
Allele Specific Protocols
  
由于具有 MRL 遗传背景的小鼠伤口愈合率较高,因此识别此品系个体小鼠时,不建议使用耳洞标记法。繁育对生产2窝幼崽后即会发展出疾病表型。
繁育策略
纯合子雌性 x 纯合子雄性
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Related Genotype: a/a Tyrc/Tyrc

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000485
MRL-Ipr
免疫学研究,器官研究,凋亡研究,肿瘤研究