Overview

Also Known As:lymphoproliferation, MRL-lpr

This strain is commonly known as MRL-lpr or lpr mutant. Mice are homozygous for the lymphoproliferation spontaneous mutation (Fas^lpr), and show systemic autoimmunity, massive lymphadenopathy associated with proliferation of aberrant T cells, arthritis, and immune complex glomerulonephrosis. Mice are useful as a model to determine the etiology of systemic lupus erythematosus (SLE) and Sjorgren (Sicca) syndrome and to evaluate therapies.
Information about lupus disease phenotypes in MRL-lpr is available here.

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Genetic overview

Genetic Background	Generation
	F5pF13 (2014-08-05 00:00:00)

Fas^lpr

Allele Type	Gene Symbol	Gene Name
Spontaneous (Hypomorph)	Fas	Fas (TNF receptor superfamily member 6)

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Research Applications

Immunology, Inflammation and Autoimmunity Research
Internal/Organ Research
Apoptosis Research
Cancer Research
Mouse/Human Gene Homologs

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Base Price

Starting at:

$135.41 Domestic price for female 3-week

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Details

Important Note

July 2007: This strain has been recovered from cryopreservation and the original phenotype was observed: The sixteen-week old mice have lymph nodes that were 4.5 (females) to 10.1 times (male) larger than age and sex matched individuals from the former colony. Splenomegaly is 3 to 6 times greater and their life spans were also greatly reduced. The former version of this line, which displayed a loss of lymphoproliferative phenotype, has been renamed MRL/MpJ-Fas^lpr/2J and is available as Stock No.
006825.

Detailed Description

Mice homozygous for the lymphoproliferation spontaneous mutation (Fas^lpr) show systemic autoimmunity, massive lymphadenopathy associated with proliferation of aberrant T cells, arthritis, and immune complex glomerulonephrosis. Starting at about three months of age, levels of circulating immune complexes rise greatly in the MRL-lpr/lpr mouse but not the MRL normal (Hewicker 1990). Onset and severity of symptoms associated with the Fas^lpr gene is strain-dependent. For example, lymphoproliferation varies greatly with congenic strain C57BL/6J-Fas^lpr/Fas^lpr at a 24 fold increase over control lymph node weight, MRL/Mp-Fas^lpr/Fas^lpr at 75 fold and congenic strain C3H/HeJ-Fas^lpr/Fas^lpr highest at 116 fold increase over control lymph node weight (Morse et al 1985). Variance in renal pathology ranks from extensive in MRL/Mp-Fas^lpr/Fas^lpr at 4 to 7 months to negligible at 14 to 16 months in mice with C57BL/6J and C3H/HeJ backgrounds and homozygous for the Fas^lpr (Kelley and Roths 1985). Spontaneous production of anti-dsDNA autoantibodies is likewise affected with percentage binding of radiolabeled dsDNA in Fas^lpr/Fas^lpr mice varying from 5 percent on C57BL/6J to 26 percent on C3H/HeJ to as high as 49 percent on MRL/Mp (Izui et al 1984). Female MRL/Mp-Fas^lpr mice die at an average age of 17 weeks of age and males at 22 weeks. This compares to between 42 and 52 weeks in females on the C57BL/6J or C3H/HeJ background (Roths 1987). Embryonic stem cell lines have been established with MRL/Mp-Fas^lpr/Fas^lpr mouse strains (Kawase et al 1994). This mouse is a model for systemic lupus erythematosus-like autoimmune syndromes.

MRL/MpJ and one of its ancestral strains LG/J display heightened wound healing relative to a panel of other inbred strains. At 4 weeks post-injury, 2mm ear punch wounds healed to 0-0.4mm in MRL/MpJ mice but were still 1.2-1.6mm in C57BL/6 mice. At 15 days post-injury C57BL/6 showed a maximal closure of 30% reduction in ear hole size while MRL showed 85% reduction. The process of healing in MRL/MpJ mice was faster, more complete, showed increased swelling, angiogenesis, fibroblast migration, extracellular matrix deposition, and decreased scarring and fibrosis. Additionally, hair follicles and accompanying sebaceous glands were regenerated to a much greater degree. The other ancestral strains of MRL/MpJ (C3H, C57BL/6, and AKR) do not display this enhanced healing. Bon e marrow transplantation showed that the MRL/MpJ healing phenotype did not readily transfer with bone marrow and did remain in the irradiated host tissues. Enhanced healing of cardiac wounds has also been reported in MRL/MpJ mice. In this model a very high mitotic index (10-20%) was found, similar to that seen in non-mammalian tissue regeneration. Using F2 and backcross mapping of MRL/MpJ-Fas^lpr x B6 progeny McBrearty et al. identified wound healing QTLs: the heal2 and heal3 loci were identified on MRL/MpJ Chromosome 13 in the region of D13Mit115 and D13Mit129 respectively; the heal5 locus was identified on MRL/MpJ chromosome 12 in the region of D12Mit233; the heal1 locus was identified on chromosome 8 of C57BL/6 in the region of D8Mit211; and a highly suggestive locus was found on MRL/MpJ Chromosome 7 in the region of D7Mit220. (Clark et al., 1998; Leferovich et al., 2001; Kench et al., 1999; McBrearty et al., 1998.)

Microarray analysis and SELDI ProteinChip analysis have identified multiple genes and proteins that have varied expression in the ear punch wounds of MRL/MpJ-Fas^lpr versus C57BL/6. The changes in expression patterns suggest that in MRL/MpJ mice there is less of an inflammatory response and an earlier transition into tissue repair than is seen in C57BL/6. (Li et al., 2000 and 2001.)

Blankenhorn et al. found that MRL/MpJ females heal faster and more completely than males. Some heal QTL are sexually dimorphic with heal 2, 3, 7, 8, 10, and 11 having greater effect in males and heal 4, 5, and 9 having greater effect in females. Castration improves wound healing in MRL/MpJ males to nearly the degree seen in females, but ovariectomy does not improve the degree of healing seen in MRL/MpJ females. (Blankenhorn et al., 2003)

Relative to B10.D2nSnJ mice, MRL/MpJ mice have decreased Neutrophil accumulation in the bronchiolar lavage in response to LPS infusion and tests using bone marrow chimeras revealed that the pulmonary inflammatory response transfers with bone marrow. Transforming growth factor beta 1 autologous induction is reduced in MRL/MpJ splenocytes while macrophages show a reduction in the transforming growth factor beta 1 induction of interleukin 1 beta and tumor necrosis factor alpha production but no significant reduction in transforming growth factor beta 1 production. (Kench et al., 1999.) MRL-Fas^lpr are also highly susceptible to Mycobacterium leprae (Yogi et al., 1989).

Development

The first observation of the massive lymphoproliferation occurred in the 12th generation of inbreeding of strain MRL/Mp derived from crosses among strains LG, AKR, C3H, and C57BL/6 at The Jackson Laboratory. At the 13th generation it was possible to select both lymphoproliferative positive and negative sublines which had an estimated 89% of their genomes in common. The mutant gene, Fas^lpr, was transferred to the MRL negative strain by 5 cycles of cross-intercross matings thus reducing the estimate of residual heterozygosity to 1% from 11% (Murphy and Roth 1978 58:51).

Control Suggestions

000486 MRL/MpJ

Additional Information

Considerations for Choosing Controls

Selected References

Andrews BS; Eisenberg RA; Theofilopoulos AN; Izui S; Wilson CB; McConahey PJ; Murphy ED; Roths JB; Dixon FJ. 1978. Spontaneous murine lupus-like syndromes. Clinical and immunopathological manifestations in several strains. J Exp Med 148(5):1198-215PubMed: 309911 MGI: J:27634
Clark LD; Clark RK; Heber-Katz E. 1998. A new murine model for mammalian wound repair and regeneration. Clin Immunol Immunopathol 88(1):35-45PubMed: 9683548 MGI: J:48937
Drappa J; Brot N; Elkon KB. 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. Proc Natl Acad Sci U S A 90(21):10340-4PubMed: 7694292 MGI: J:15429
Fields ML; Sokol CL; Eaton-Bassiri A; Seo Sj; Madaio MP; Erikson J. 2001. Fas/fas ligand deficiency results in altered localization of anti-double-stranded dna b cells and dendritic cells. J Immunol 167(4):2370-8PubMed: 11490027 MGI: J:70822
Gu L; Weinreb A; Wang XP; Zack DJ; Qiao JH; Weisbart R; Lusis AJ. 1998. Genetic determinants of autoimmune disease and coronary vasculitis in the MRL-lpr/lpr mouse model of systemic lupus erythematosus. J Immunol 161(12):6999-7006PubMed: 9862736 MGI: J:52131
Hewicker M; Kromschroder E; Trautwein G. 1990. Detection of circulating immune complexes in MRL mice with different forms of glomerulonephritis. Z Versuchstierkd 33(4):149-56PubMed: 2238887 MGI: J:109933
Johnson BC; Morton JI; Trune DR. 1992. Lacrimal and salivary gland inflammation in the C3H/Ipr autoimmune strain mouse: a potential mode for Sjogren's syndrome. Otolaryngol Head Neck Surg 106(4):394-9PubMed: 1565490 MGI: J:1028
Kawase E; Suemori H; Takahashi N; Okazaki K; Hashimoto K; Nakatsuji N. 1994. Strain difference in establishment of mouse embryonic stem (ES) cell lines. Int J Dev Biol 38(2):385-90PubMed: 7981049 MGI: J:19823
Kench JA; Russell DM; Fadok VA; Young SK; Worthen GS; Jones-Carson J; Henson JE; Henson PM; Nemazee D. 1999. Aberrant wound healing and TGF-beta production in the autoimmune-prone MRL/+ mouse. Clin Immunol 92(3):300-10PubMed: 10479535 MGI: J:57718
Leferovich JM; Bedelbaeva K; Samulewicz S; Zhang XM; Zwas D; Lankford EB; Heber-Katz E. 2001. Heart regeneration in adult MRL mice. Proc Natl Acad Sci U S A 98(17):9830-5PubMed: 11493713 MGI: J:109867
Li X; Mohan S; Gu W; Baylink DJ. 2001. Analysis of gene expression in the wound repair/regeneration process. Mamm Genome 12(1):52-9PubMed: 11178744 MGI: J:68684
Li X; Mohan S; Gu W; Miyakoshi N; Baylink DJ. 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 Biochim Biophys Acta 1524(2-3):102-9PubMed: 11113556 MGI: J:66437
McBrearty BA; Clark LD; Zhang XM; Blankenhorn EP; Heber-Katz E. 1998. Genetic analysis of a mammalian wound-healing trait. Proc Natl Acad Sci U S A 95(20):11792-7PubMed: 9751744 MGI: J:50111
Medana I; Li Z; Flugel A; Tschopp J; Wekerle H; Neumann H. 2001. Fas ligand (CD95L) protects neurons against perforin-mediated T lymphocyte cytotoxicity. J Immunol 167(2):674-81PubMed: 11441070 MGI: J:109872
Morse HC 3rd; Davidson WF; Yetter RA; Murphy ED; Roths JB; Coffman RL. 1982. Abnormalities induced by the mutant gene Ipr: expansion of a unique lymphocyte subset. J Immunol 129(6):2612-5PubMed: 6815273 MGI: J:6902
Morse HC 3rd; Roths JB; Davidson WF; Langdon WY; Fredrickson TN; Hartley JW. 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. J Exp Med 161(3):602-16PubMed: 2982991 MGI: J:7745
Murphy ED; Roths JB. 1978. Autoimmunity and lymphoproliferation: Induction by mutant gene lpr, and acceleration by a male-associated factor in strain BXSB mice:207-20MGI: J:28885
Sato EH; Sullivan DA. 1994. Comparative influence of steroid hormones and immunosuppressive agents on autoimmune expression in lacrimal glands of a female mouse model of Sjogren's syndrome. Invest Ophthalmol Vis Sci 35(5):2632-42PubMed: 8163351 MGI: J:18512
Watanabe-Fukunaga R; Brannan CI; Copeland NG; Jenkins NA; Nagata S. 1992. Lymphoproliferation disorder in mice explained by defects in Fas antigen that mediates apoptosis. Nature 356(6367):314-7PubMed: 1372394 MGI: J:1181
Yogi Y; Nakamura K; Suzuki A. 1989. The experimental inoculation with Mycobacterium leprae in autoimmune mice: results of MRL/lpr mice inoculated into the right hind foot (continued). Nippon Rai Gakkai Zasshi 58(4):235-40PubMed: 2489281 MGI: J:27853

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Genetics

Fas^lpr

Allele Symbol: Fas^lpr

Allele Name	lymphoproliferation
Allele Type	Spontaneous (Hypomorph)
Allele Synonym(s)	Fas-; Fas-def; lpr; MRL/lpr; Tnfrf6^lpr; Tnfrsf6^lpr; Tnfrsf6lpr
Gene Symbol and Name	Fas, Fas (TNF receptor superfamily member 6)
Gene Synonym(s)
Strain of Origin	MRL/Mp
Chromosome	19
General Note	Fas^lpr, lymphoproliferation, recessive. This mutation was found during inbreeding of a strain MRL/Mp derived from crosses among strains LG, AKR, C3H, and C57BL/6. The resemblance has led to extensive use of Fas^lpr mice in attempts to determine the etiology of SLE and to evaluate therapies. However, the human APT1 gene (OMIM 134637) encodes the FAS antigen; Tnfrsf6 is not the homolog of the human (SLE) gene.The Cd72^c haplotype is a modifier of Fas^lpr-induced autoimmune disease. J:204782
Molecular Note	Southern blotting experiments indicated that the mutation is a genomic rearrangement within the gene, probably within the second intron. Sequencing of genomic DNA and RT-PCR products from homozygous mutant mice revealed the insertion of an early transposable element (ETn) into intron 2. RT-PCR analysis of liver and thymus mRNA showed that the presence of the ETn leads to premature termination of transcription at the long terminal repeat (LTR) of the ETn and aberrant mRNA splicing. The mutation is "leaky," however, as full-length mRNA and a longer splice product incorporating a segment of the ETn as an extra intron are detected in the thymus at low levels.

Disease/Phenotype

Disease Terms

Model with phenotypic similarity to human disease where etiologies involve orthologs. Human genes are associated with this disease. Orthologs of those genes appear in the mouse genotype(s).

autoimmune lymphoproliferative syndrome

Model with phenotypic similarity to human disease where etiologies are distinct. Human genes are associated with this disease. Orthologs of these genes do not appear in the mouse genotype(s).

systemic lupus erythematosus

Models with phenotypic similarity to human diseases where etiology is unknown or involving genes where ortholog is unknown.

Sjogren's syndrome

Research Areas By Phenotype

This mouse can be used to support research in many areas including:

Immunology, Inflammation and Autoimmunity Research
- Immunodeficiency
  - Sjogren syndrome
- Autoimmunity
  - lupus erythematosus
Internal/Organ Research
- Wound Healing
  - enhanced

Genotype: Fas^lpr related

Immunology, Inflammation and Autoimmunity Research
- Autoimmunity
  - lupus erythematosus
  - lupus erythematosus: rheumatoid arthritis
- Inflammation
  - rheumatoid arthritis
Apoptosis Research
- Death Receptors
Cancer Research
- Genes Regulating Growth and Proliferation
Mouse/Human Gene Homologs
- autoimmune lymphoproliferative syndrome

Mammalian Phenotype Terms by Genotype

The following phenotype information is associated with a similar, but not exact match to this JAX^® Mice strain

Genotype: Fas^lpr/Fas^lpr
involves: C3H * MRL/Mp

cardiovascular system phenotype

abnormal stria vascularis vasculature morphology
- the stria capillaries often were larger than normal, and the endothelial cells were occasionally swollen or thickened due to hypertrophy and not hyperplasia

hematopoietic system phenotype

increased spleen weight
- at 2 months of age and on

immune system phenotype

autoimmune response
- characterized by elevated serum immune complexes, cryoglobulins, and antinuclear antibodies
- systemic autoimmune disease occurred at 2-3 months of age

increased anti-nuclear antigen antibody level
- beginning at 4 month of age

increased spleen weight
- at 2 months of age and on

increased susceptibility to systemic lupus erythematosus
- beginning at 4 month of age

increased susceptibility to type III hypersensitivity reaction
- beginning at 4 month of age

growth/size/body region phenotype

increased spleen weight
- at 2 months of age and on

hearing/vestibular/ear phenotype

abnormal stria vascularis morphology
- Normal - all sensorineural elements, inner and outer hair cells and spiral ganglion neurons appeared normal even in the 8-10 month-old mice with significant threshold shifts
- by 10 months of age, stria vascularis area was smaller
- degeneration of the stria vascularis was seen starting at 2 month and progressed throughout the lifespan
- early edema of the stria occurred in the apex and progressed basalward
- edematous areas in the stria vascularis primarily in the basal turns due to enlarged extracellular spaces filled with fluid
- Normal - no degeneration of hair cells was seen at any age

abnormal stria vascularis vasculature morphology
- the stria capillaries often were larger than normal, and the endothelial cells were occasionally swollen or thickened due to hypertrophy and not hyperplasia

increased or absent threshold for auditory brainstem response
- after onset of systemic autoimmune disease at 3-4 months of age, threshold at 6 months were significantly elevated at 24 and 32 kHz
- Normal - the 2- and 4-month-old mutant mice had normal auditory thresholds similar to control
- the ABR thresholds of the 10-month-old mutant mice were significantly higher than those of wild-type C3H/HeJ controls
- Normal - threshold at the low frequencies (4 and 8 kHz) did not change with progression of systemic disease
- threshold continued to rise and by 8 months 16 kHz was elevated as well

Genotype: Fas^lpr/Fas^lpr
B6.MRL-Fas/J

cellular phenotype

decreased B cell apoptosis
- after bile duct ligation (BDL), Peyer's patch B cells do not display evidence of apoptosis

decreased hepatocyte apoptosis
- hepatocyte cell death is reduced compared to controls after BDL

focal hepatic necrosis
- necroinflammatory foci after BDL are reduced in number compared to controls

increased renal glomerulus apoptosis
- higher numbers of apoptotic cells are detected in glomeruli compared to wild-type

immune system phenotype

abnormal NK cell physiology
- continuous treatment with recombinant murine IL12 results in sustained recruitment of NK cells to the liver

abnormal splenic cell ratio
- T1:follicular B cell ratio is higher than wild-type or Bcl2l11-deficient mice

brain inflammation
- by 7 days after TMEV infection, inflammation is present, decreasing slightly by 21 days, but widespread tissue damage is present, similar to controls (B6)
- tissue damage is less frequent at 45 days than in Prf-null mice

CNS inflammation

decreased B cell apoptosis
- after bile duct ligation (BDL), Peyer's patch B cells do not display evidence of apoptosis

enlarged lymph nodes
- mice develop less severe lymphadenopathy at later ages than the double mutant Igh-6/Fas mice

increased anti-double stranded DNA antibody level
- anti-ssDNA IgM and IgG antibodies are increased compared to wild-type

increased anti-histone antibody level
- increased compared to wild-type

increased anti-nuclear antigen antibody level
- anti-nuclear antibodies are increased compared to wild-type

increased anti-single stranded DNA antibody level
- anti-ssDNA IgM and IgG antibodies are increased compared to wild-type

increased autoantibody level
- total anti-IgM antibody levels are increased compared to wild-type

increased follicular B cell number
- higher in spleen relative to wild-type

increased immature B cell number
- plasmablast numbers in spleen are increased relative to wild-type

increased marginal zone B cell number
- higher in spleen relative to wild-type, Fas^lpr homozygotes, and Bcl2l11-deficient mice

increased splenocyte number
- total number of CD19+ splenocytes is higher than wild-type
- total number of splenocytes is increased relative to wild-type

increased susceptibility to bacterial infection
- mice infected with 500 CFU of S. aureus have drastically elevated number of S. aureus CFU compared to similarly-infected wild-type mice, but lower counts than infected Fasl^gld mice

increased susceptibility to Picornaviridae infection
- inflammation and tissue damage in the brain are slightly greater than in control, resistant mice at 45 and 180 days

increased susceptibility to viral infection
- inflammation and tissue damage in the brain are slightly greater than in control, resistant mice at 45 and 180 days

increased transitional stage B cell number
- higher numbers of T2 B cells in spleen relative to wild-type

lymph node hyperplasia
- total number of cells per lymph node is increased compared to wild-type

liver/biliary system phenotype

abnormal hepatocyte morphology
- confluent foci of feathery hepatocyte degeneration due to bile acid cytotoxicity are significantly reduced compared to controls hours after BDL

abnormal liver physiology
- after BDL, necroinflammatory foci and lymphocytic infiltration are obviously less than in controls
- treatment with Prf1-deficient HBsAg-specific Th1 cells and HBsAg induces liver injury as severe as that induced by wild-type HBsAg-specific Th1 cells
- when mice are recipients of wild-type hepatitis B surface antigen (HBsAg)-specific Th1 cells after treatment with HBsAg, severe liver injury is induced to similar extent as in wild-type mice

decreased hepatocyte apoptosis
- hepatocyte cell death is reduced compared to controls after BDL

focal hepatic necrosis
- necroinflammatory foci after BDL are reduced in number compared to controls

nervous system phenotype

brain inflammation
- by 7 days after TMEV infection, inflammation is present, decreasing slightly by 21 days, but widespread tissue damage is present, similar to controls (B6)
- tissue damage is less frequent at 45 days than in Prf-null mice

CNS inflammation

demyelination
- by 7 days after TMEV infection, inflammation is present in the meninges and gray matter of spinal cord, but decreases by 21 days, although not as much as in controls (B6)

renal/urinary system phenotype

abnormal kidney morphology
- number of macrophages surrounding glomeruli is increased compared to wild-type which have no macrophage index

abnormal renal glomerulus basement membrane morphology
- IgG deposits mainly localized to glomerular basement membrane are increased relative to wild-type

increased renal glomerulus apoptosis
- higher numbers of apoptotic cells are detected in glomeruli compared to wild-type

hematopoietic system phenotype

abnormal NK cell physiology
- continuous treatment with recombinant murine IL12 results in sustained recruitment of NK cells to the liver

abnormal splenic cell ratio
- T1:follicular B cell ratio is higher than wild-type or Bcl2l11-deficient mice

decreased B cell apoptosis
- after bile duct ligation (BDL), Peyer's patch B cells do not display evidence of apoptosis

increased follicular B cell number
- higher in spleen relative to wild-type

increased immature B cell number
- plasmablast numbers in spleen are increased relative to wild-type

increased marginal zone B cell number
- higher in spleen relative to wild-type, Fas^lpr homozygotes, and Bcl2l11-deficient mice

increased splenocyte number
- total number of CD19+ splenocytes is higher than wild-type
- total number of splenocytes is increased relative to wild-type

increased transitional stage B cell number
- higher numbers of T2 B cells in spleen relative to wild-type

Genotype: Fas^lpr/Fas^lpr
MRL.Cg-Irf1 Fas

cellular phenotype

epidermal necrosis
- by 24 weeks, ear necrosis is observed in some mice

homeostasis/metabolism phenotype

increased urine protein level
- by 24 weeks of age, 75% of mice have urine protein levels >200 mg/dl

immune system phenotype

glomerulonephritis
- at 26 weeks of age, mice show severe glomerulonephritis

increased anti-double stranded DNA antibody level
- at 26 weeks of age, levels are significantly higher relative to Fas^lpr, Irf1-null mice

integument phenotype

abnormal skin condition
- mice show characteristic signs of skin disease at 24 weeks of age

epidermal necrosis
- by 24 weeks, ear necrosis is observed in some mice

skin lesions

mortality/aging

premature death
- mice typically die by 26 weeks of age from renal failure; 50% of mice are dead by 22 weeks

renal/urinary system phenotype

glomerulonephritis
- at 26 weeks of age, mice show severe glomerulonephritis

increased urine protein level
- by 24 weeks of age, 75% of mice have urine protein levels >200 mg/dl

kidney failure
- occurs around 26 weeks, leading to death

renal glomerular immunoglobulin deposits
- mice show extensive glomerular deposition/staining of IgG and C3

Genotype: Fas^lpr/Fas^lpr
C3.MRL-Fas/J

cardiovascular system phenotype

lymph node hemorrhage
- larger lymph nodes often show extensive hemorrhage

cellular phenotype

increased apoptosis
- a trend toward increased apoptosis in airways is observed in anti-Il5 treated mutants after IP-IN OVA challenge

lymph node necrosis
- larger lymph nodes often show extensive necrosis

mammalian phenotype

immune system phenotype
- Normal - mice show normal spleen and lymph node cell cytotoxic T cell response to alloantigen

mortality/aging
- Normal - when placed under hyperoxic conditions for >5 days, mice do not show increased survival (resistance to hyperoxia) compared to wild-type mice

mortality/aging

premature death
- 50% mortality is observed at 11.5 months with 90% mortality at 14 months, significantly reduced from wild-type

renal/urinary system phenotype

abnormal renal glomerulus morphology
- nephritic changes consist of focal increase in mesangial substance and mild mesangial proliferation

expanded mesangial matrix
- focal increase in mesangial substance

glomerulonephritis
- Background Sensitivity - immune complex glomerulonephritis develops by 1 year of age but is much milder than in MRL homozygotes

mesangial cell hyperplasia
- mild mesangial proliferation

renal glomerular immunoglobulin deposits

respiratory system phenotype

abnormal airway responsiveness
- under same paradigm develop AHR at 48 hours but changes in airway resistance resolve by 96 hours
- mice intraperitoneally-injected (IP) with ovalbumin (OVA) and subsequently challenged intranasally (IN) with OVA develop airway hyperresponsiveness (AHR) at 48 hours and is significantly sustained at 96 hours but resolves at 6 days, whereas wild-type mice under same paradigm develop AHR at 48 hours but changes in airway resistance resolve by 96 hours
- treatment with anti-Il5 at 48 hours post-IP-IN challenge significantly attenuates AHR

hematopoietic system phenotype

abnormal B cell activation
- after 10 weeks of age, there is a 2-fold increase in frequency of immunoglobulin-containing and secreting cells in the spleen; this does not occur until abnormal T cells (Ly-5(B220⁺) cells) are found in the spleen

abnormal T cell morphology
- (sIg^-, Ly-5(B220⁺) are present at 4 weeks of age in spleen and by 16-20 weeks, represent 80% of cells

decreased eosinophil cell number
- airway eosinophils are decreased with anti-Il5 teatment compared to contol IgG-teated animals at 96 hours

increased immunoglobulin level
- IgG and IgM levels are increased in serum at 6 months

immune system phenotype

abnormal B cell activation
- after 10 weeks of age, there is a 2-fold increase in frequency of immunoglobulin-containing and secreting cells in the spleen; this does not occur until abnormal T cells (Ly-5(B220⁺) cells) are found in the spleen

abnormal lymph node morphology
- larger lymph nodes often show extensive hemorrhage and necrosis

abnormal T cell morphology
- (sIg^-, Ly-5(B220⁺) are present at 4 weeks of age in spleen and by 16-20 weeks, represent 80% of cells

decreased eosinophil cell number
- airway eosinophils are decreased with anti-Il5 teatment compared to contol IgG-teated animals at 96 hours

decreased interleukin-2 secretion
- after 6 weeks of age, spleen cells show significant decrease in ability to produce Il-2 induced by concanavalin A treatment

enlarged lymph nodes
- nodes are 29 times normal size

glomerulonephritis
- Background Sensitivity - immune complex glomerulonephritis develops by 1 year of age but is much milder than in MRL homozygotes

increased anti-double stranded DNA antibody level
- antibodies are increased relative to controls

increased anti-nuclear antigen antibody level
- mice have significantly increased levels of anti-ssDNA antibodies

increased autoantibody level
- marked increase in thymocytotoxic autoantibodies at 6 months is seen

increased immunoglobulin level
- IgG and IgM levels are increased in serum at 6 months

lymph node hemorrhage
- larger lymph nodes often show extensive hemorrhage

lymph node hyperplasia
- after 10 weeks of age, there is a 3- to 4-fold increase in numbers of B lymphocytes, and after 6 weeks of age, there is a 4- to 5-fold increase in number of null cells (sIg^-, Thy-1^-)

lymph node necrosis
- larger lymph nodes often show extensive necrosis

Genotype: Fas^lpr/Fas^lpr
B6.MRL-Fas

cardiovascular system phenotype

lymph node hemorrhage
- larger lymph nodes often show extensive hemorrhage

cellular phenotype

lymph node necrosis
- larger lymph nodes often show extensive necrosis

mortality/aging

premature death
- 50% mortality is observed at 13.5 months with 90% mortality at 16 months, significantly reduced from wild-type
- 64% survival at 24 weeks
- median survival is 284 days, compared to 795 days for controls

growth/size/body region phenotype

enlarged spleen

renal/urinary system phenotype

abnormal renal glomerulus morphology
- nephritic changes consist of focal increase in mesangial substance and mild mesangial proliferation

expanded mesangial matrix
- focal increase in mesangial substance

glomerulonephritis
- Background Sensitivity - immune complex glomerulonephritis develops by 1 year of age but is much milder than in MRL homozygotes
- interstitial lymphoid infiltration is observed at 6 months; glomerular IgG deposits that are exclusively mesangial are observed

mesangial cell hyperplasia
- mild mesangial proliferation

renal glomerular immunoglobulin deposits

hematopoietic system phenotype

enlarged spleen

increased double-negative T cell number

increased immunoglobulin level
- IgG and IgM levels are increased in serum at 6 months

immune system phenotype

abnormal lymph node morphology
- larger lymph nodes often show extensive hemorrhage and necrosis

decreased interleukin-2 secretion
- defect in Il2 activity begins during early life and worsens with age; spleen cells show no stimulated Il2 production upon stimulation with concanavalin A

enlarged lymph nodes
- by 4 months of age, lymph nodes are increased 10- to 20-fold
- generalized lymphadenopathy
- nodes are 13 times normal size

enlarged spleen

glomerulonephritis
- Background Sensitivity - immune complex glomerulonephritis develops by 1 year of age but is much milder than in MRL homozygotes
- interstitial lymphoid infiltration is observed at 6 months; glomerular IgG deposits that are exclusively mesangial are observed

increased anti-double stranded DNA antibody level
- antibodies are increased relative to controls

increased anti-nuclear antigen antibody level
- anti-nuclear antibodies are present at 6 months of age
- mice have elevated levels of anti-chromatin (anti-nucleosome) antibodies compared to double mutants

increased autoantibody level
- increase in thymocytotoxic autoantibodies at 6 months is seen
- mice have elevated levels of anti-chromatin antibodies compared to double mutants

increased double-negative T cell number

increased immunoglobulin level
- IgG and IgM levels are increased in serum at 6 months

lymph node hemorrhage
- larger lymph nodes often show extensive hemorrhage

lymph node necrosis
- larger lymph nodes often show extensive necrosis

Genotype: Fas^lpr/Fas^lpr
AK.MRL-Fas

cardiovascular system phenotype

lymph node hemorrhage
- larger lymph nodes often show extensive hemorrhage

renal/urinary system phenotype

abnormal renal glomerulus morphology
- nephritic changes consist of focal increase in mesangial substance and mild mesangial proliferation

expanded mesangial matrix
- focal increase in mesangial substance

glomerulonephritis
- Background Sensitivity - immune complex glomerulonephritis develops by 1 year of age but is much milder than in MRL homozygotes

mesangial cell hyperplasia
- mild mesangial proliferation

renal glomerular immunoglobulin deposits

cellular phenotype

lymph node necrosis
- larger lymph nodes often show extensive necrosis

hematopoietic system phenotype

increased immunoglobulin level
- IgG and IgM levels are modestly increased in serum at 6 months

immune system phenotype

abnormal lymph node morphology
- larger lymph nodes often show extensive hemorrhage and necrosis

enlarged lymph nodes
- nodes are 6 times normal size

glomerulonephritis
- Background Sensitivity - immune complex glomerulonephritis develops by 1 year of age but is much milder than in MRL homozygotes

increased anti-double stranded DNA antibody level
- antibodies are increased relative to controls

increased anti-nuclear antigen antibody level
- mice have significantly increased levels of anti-ssDNA antibodies

increased autoantibody level
- increase in thymocytotoxic autoantibodies at 6 months is seen

increased immunoglobulin level
- IgG and IgM levels are modestly increased in serum at 6 months

lymph node hemorrhage
- larger lymph nodes often show extensive hemorrhage

lymph node necrosis
- larger lymph nodes often show extensive necrosis

Genotype: Fas^lpr/Fas^lpr
C3.MRL-Fas

cellular phenotype

abnormal T cell proliferation
- cells do not proliferate in response to stimulation with alloantigens

decreased apoptosis
- unlike wild-type vaginal cells, vaginal cells derived from mutant mice do not undergo apoptosis after treatment with agonistic anti-mouse Fas antibody or mouse recombinant TNF antibody

decreased neuron apoptosis
- neuron viability is comparable to wild-type when grown in absence of Abeta or if treated with KCN which induces necrotic cell death
- very low levels of apoptosis (15%) compared to wild-type (60%) are seen when cortical neurons are treated with Abeta25-35 or Abeta1-40 peptides

hematopoietic system phenotype

abnormal T cell morphology
- lymph node cells (T cell origin) are abnormal; cells are Ly-2^-/L3T4^-/surface Ig^-

abnormal T cell physiology
- cells do not generate CTL in response to stimulation with alloantigens

abnormal T cell proliferation
- cells do not proliferate in response to stimulation with alloantigens

homeostasis/metabolism phenotype

abnormal interleukin level
- stimulation with concanavalin A does not induce cells to produce Il2

immune system phenotype

abnormal interleukin level
- stimulation with concanavalin A does not induce cells to produce Il2

abnormal T cell morphology
- lymph node cells (T cell origin) are abnormal; cells are Ly-2^-/L3T4^-/surface Ig^-

abnormal T cell physiology
- cells do not generate CTL in response to stimulation with alloantigens

abnormal T cell proliferation
- cells do not proliferate in response to stimulation with alloantigens

lacrimal gland inflammation
- at 2 months, glandular inflammation is neglible; at 5 months, nearly all mice exhibit lacrimal gland inflammation covering a larger area than in mutants at 2 months or controls at 5 months
- inflammation correlates with age, immune complex level and spleen weight; antinuclear antibody level correlation is greater than probability cutoff; controls do not show correlations with these factors and gland inflammation
- inflammatory infiltrates consist of mononuclear cells and occurs in a periductal or perivascular pattern
- scattered lobular atrophy with loss of secretory elements is seen in glands with multifocal infiltrates

salivary gland inflammation

mammalian phenotype

endocrine/exocrine gland phenotype
- Normal - in inflamed lacrimal glands, lobular boundaries are preserved with preservation of interlobular septae; lobular atrophy occurs with preservation of ductal epithelium; widely dilated ducts indicate that ductal obstruction is not observed
- Normal - no parotid gland inflammation is observed and only 1 animal showed sublingual gland inflammation at 5 months
- Normal - submandibular gland inflammation is observed in most mice at 5 months, but differences compared to wild-type are not significant

nervous system phenotype

decreased neuron apoptosis
- neuron viability is comparable to wild-type when grown in absence of Abeta or if treated with KCN which induces necrotic cell death
- very low levels of apoptosis (15%) compared to wild-type (60%) are seen when cortical neurons are treated with Abeta25-35 or Abeta1-40 peptides

reproductive system phenotype

abnormal vagina weight
- at 2 days after estrogen deprivation induced by gonadectomy, mutant females show no vaginal regression (measured by a decrease in vaginal organ weight), indicating no Fas-mediated vaginal cell death, in contrast to wild-type females that show >50% decrease in vaginal organ weight
- e in vaginal organ weight

vision/eye phenotype

lacrimal gland atrophy
- scattered lobular atrophy with loss of secretory elements is seen in glands with multifocal infiltrates

lacrimal gland inflammation
- at 2 months, glandular inflammation is neglible; at 5 months, nearly all mice exhibit lacrimal gland inflammation covering a larger area than in mutants at 2 months or controls at 5 months
- inflammation correlates with age, immune complex level and spleen weight; antinuclear antibody level correlation is greater than probability cutoff; controls do not show correlations with these factors and gland inflammation
- inflammatory infiltrates consist of mononuclear cells and occurs in a periductal or perivascular pattern
- scattered lobular atrophy with loss of secretory elements is seen in glands with multifocal infiltrates

digestive/alimentary phenotype

salivary gland inflammation

endocrine/exocrine gland phenotype

lacrimal gland atrophy
- scattered lobular atrophy with loss of secretory elements is seen in glands with multifocal infiltrates

lacrimal gland inflammation
- at 2 months, glandular inflammation is neglible; at 5 months, nearly all mice exhibit lacrimal gland inflammation covering a larger area than in mutants at 2 months or controls at 5 months
- inflammation correlates with age, immune complex level and spleen weight; antinuclear antibody level correlation is greater than probability cutoff; controls do not show correlations with these factors and gland inflammation
- inflammatory infiltrates consist of mononuclear cells and occurs in a periductal or perivascular pattern
- scattered lobular atrophy with loss of secretory elements is seen in glands with multifocal infiltrates

salivary gland inflammation

Genotype: Fas^lpr/Fas^lpr
involves: C57BL/6 * MRL/Mp

growth/size/body region phenotype

enlarged spleen
- at day 175 and 275 compared with wild-type mice

hematopoietic system phenotype

enlarged spleen
- at day 175 and 275 compared with wild-type mice

increased IgA level
- at day 175 and 275 compared with wild-type mice

increased IgG1 level
- at day 175 and 275 compared with wild-type mice

increased IgG2a level
- at day 175 and 275 compared with wild-type mice

increased IgG2b level
- at day 175 and 275 compared with wild-type mice

increased IgG3 level
- at day 175 and 275 compared with wild-type mice

increased IgM level
- at day 175 and 275 compared with wild-type mice

immune system phenotype

enlarged spleen
- at day 175 and 275 compared with wild-type mice

increased anti-double stranded DNA antibody level
- at day 275

increased anti-single stranded DNA antibody level
- at day 275

increased IgA level
- at day 175 and 275 compared with wild-type mice

increased IgG1 level
- at day 175 and 275 compared with wild-type mice

increased IgG2a level
- at day 175 and 275 compared with wild-type mice

increased IgG2b level
- at day 175 and 275 compared with wild-type mice

increased IgG3 level
- at day 175 and 275 compared with wild-type mice

increased IgM level
- at day 175 and 275 compared with wild-type mice

lymph node hyperplasia
- at day 175 and 275 compared with wild-type mice

Genotype: Fas^lpr/Fas^lpr
involves: 129P2/OlaHsd * MRL

hematopoietic system phenotype

increased double-negative T cell number
- develop massive lymphadenopathy due to alpha beta DN T cell accumulation

increased gamma-delta T cell number

mortality/aging

premature death
- about 10% of mice are moribund by 16 weeks of age

renal/urinary system phenotype

abnormal kidney morphology

abnormal renal glomerulus morphology
- glomerular hypercellularity

glomerulonephritis
- focal

increased urine protein level
- compared to age-matched B10.A mice

kidney inflammation
- periglomerular infiltration

homeostasis/metabolism phenotype

increased blood urea nitrogen level
- significantly elevated

increased urine protein level
- compared to age-matched B10.A mice

immune system phenotype

enlarged lymph nodes
- develop massive lymphadenopathy due to alpha beta DN T cell accumulation

glomerulonephritis
- focal

increased double-negative T cell number
- develop massive lymphadenopathy due to alpha beta DN T cell accumulation

increased gamma-delta T cell number

kidney inflammation
- periglomerular infiltration

The following phenotype relates to a compound genotype created using this strain

Genotype: Fas^lpr/Fas^lpr
MRL/Mp-Fas

cardiovascular system phenotype

abnormal cardiovascular system physiology
- 15-30% of mice suffer old and/or acute myocardial infarction involving either ventricle and judged severe enough to contribute to death

abnormal coronary artery morphology

abnormal glomerular capillary endothelium morphology
- proliferation of endothelial cells

abnormal glomerular capillary morphology
- granular deposits of immunoglobulins present in the capillary walls

lymph node hemorrhage
- in mice with lymph node hyperplasia, larger nodes show extensive hemorrhage

vascular inflammation
- arteritis is observed in a number of organs, and is associated with hemorrhage and infarcts in the lymph nodes

digestive/alimentary phenotype

abnormal submandibular gland morphology
- this treatment significantly decreases lymphocytic infiltration into submandibular glands
- treatment with androgens increases gland weight in mutants

salivary gland inflammation
- lymphocytic infiltration and lymphocytic foci are observed in mice 3.4-3.7 months of age
- treatment with danazol or Org 4094 sifnificantly lowers number of foci and percentage of lymphocyte infiltration, as well as other immune parameters compared to untreated controls

submandibular gland inflammation
- autoimmune sialodenitis with parenchymal destruction is observed in 4-6 month old mice in submandibular salivary glands of female mice
- most infiltrating cells are CD4⁺ and Vbeta8⁺ with a minority being CD4⁺ and Vbeta6⁺

integument phenotype

skin lesions
- erythemateous lesions of the ear often become necrotic
- lesions accompanied by hair loss and scab formation were common

endocrine/exocrine gland phenotype

abnormal gland morphology
- dexamethasone treatment increases weight of lacrimal tissue compared to untreated mice; treatment results in a reduction in tear volume

abnormal submandibular gland morphology
- this treatment significantly decreases lymphocytic infiltration into submandibular glands
- treatment with androgens increases gland weight in mutants

abnormal thymus medulla morphology
- increase in thymus weight restricted to the medulla

abnormal thyroid follicle morphology
- marked decrease in follicle size is noted proceeding from center of lobe toward periphery

abnormal thyroid gland morphology
- fibrosis is minimal, with only 1% of tissue displaying fibroblast growth; when detected, fibrosis is adjacent to atrophic follicles
- functional communication between cells in thyroid cell cultures is dramatically reduced
- inflamed tissue has massive infiltration organized into lymphoid follicle centers and extensive interstitially distributed lymphocytes

enlarged thymus
- slighlty enlarged

increased thymus weight
- doubling of thymus weight

lacrimal gland inflammation
- adult lacrimal glands show infiltration by lymphocytes
- Normal - treatment with steroids alleviates lymphocyte infiltration

salivary gland inflammation
- lymphocytic infiltration and lymphocytic foci are observed in mice 3.4-3.7 months of age
- treatment with danazol or Org 4094 sifnificantly lowers number of foci and percentage of lymphocyte infiltration, as well as other immune parameters compared to untreated controls

submandibular gland inflammation
- autoimmune sialodenitis with parenchymal destruction is observed in 4-6 month old mice in submandibular salivary glands of female mice
- most infiltrating cells are CD4⁺ and Vbeta8⁺ with a minority being CD4⁺ and Vbeta6⁺

thymus atrophy
- in 5-10% of animals, there is medullary or stromal hyperplasia that maintains or increases the size of the thymus
- initial lesion is loss of cortical thymocytes, with later degeneration (cystic) of thymocytes of medulla
- thymic atrophy is observed; severity is most severe in the cortex but usually involves the medulla in most animals

thymus cortex atrophy
- atrophic cortex

thyroid gland inflammation
- animals display thyroid gland infiltration (autoimmune thyroiditis)

mammalian phenotype

endocrine/exocrine gland phenotype
- Normal - lymphatic tissues that undergo age-related increase in weight due to lymphocytic accumulation are decreased in weight with cyclophosphamide treatment compared to placebo treated controls

mortality/aging

premature death
- 50% mortality is observed at 5 or 5.5 months for females and males with 90% mortality at 7.3 or 8.6 months in females and males
- life span of females is 120+/-4 days
- life span of males is 154+/-32 days
- mean age of death in females was 17 weeks of age
- mean age of death in males was 22 weeks of age

renal/urinary system phenotype

abnormal glomerular capillary endothelium morphology
- proliferation of endothelial cells

abnormal glomerular capillary morphology
- granular deposits of immunoglobulins present in the capillary walls

glomerular crescent
- capsular cell proliferation is seen in severe glomerular lesions

glomerulonephritis
- capsular cell proliferation, tubular damage, and casts were seen in severe lesions
- glomerular lesions involve proliferation of both endothelial and mesangial cells and basement membrane thickening
- granular deposits of immunoglobulins present in the capillary walls
- immune complex glomerulonephritis
- mice show a largely subacute proliferative form of disease; lesions involve proliferation of endothelial and mesangial cells

increased kidney cell proliferation
- glomerular lesions involve proliferation of endothelial and mesangial cells

increased renal glomerulus basement membrane thickness
- glomerular basement membrane thickening

increased urine protein level
- incomplete penetrance, 50% of females tested have a 9-fold increase over controls

mesangial cell hyperplasia
- proliferation of mesangial cells

renal cast
- casts were seen in severe glomerular lesions

renal glomerular immunoglobulin deposits

renal glomerular protein deposits
- between 2 and 5 months, granular IgG and C3 deposits increase in capillary wall and mesangium

skeleton phenotype

joint swelling
- 20-25% of old, diseased mice show joint swelling of the hind feet and lower legs; involving destruction of articular cartilage, proliferation of synovium, pannus formations, and sometimes joint effusions

vision/eye phenotype

lacrimal gland inflammation
- adult lacrimal glands show infiltration by lymphocytes
- Normal - treatment with steroids alleviates lymphocyte infiltration

growth/size/body region phenotype

enlarged spleen
- spleen is 7-fold larger than controls

hematopoietic system phenotype

abnormal B cell morphology
- frequency of C3d receptor bearing cells declines with age

abnormal B cell receptor editing
- Anti-dsDNA B cells escape receptor editing

abnormal cytotoxic T cell physiology
- 4-6 month old mice exhibit significantly depressed cytotoxic T cell response to alloantigens

abnormal marginal zone B cell morphology
- mice have a larger marginal zone B cell population (10.8% of splenic lymphocytes) compared to BALB/c controls (1.9%)

abnormal T cell morphology
- increase in T-cell frequencies and absolute numbers with advanced disease; however, the number of Ly123+ and Ly23+ T cells is markedly decreased in older mice compared to young mice
- lymph node cells (T cell origin) are abnormal; cells are Ly-2^-/L3T4^-/surface Ig^-

abnormal T cell physiology
- cells do not generate CTL in response to stimulation with alloantigens

abnormal T cell proliferation
- cells do not proliferate in response to stimulation with alloantigens

abnormal T-helper 2 physiology
- activity of helper T cells is enhanced in older mice relative to younger animals or normal controls

abnormal thymus medulla morphology
- increase in thymus weight restricted to the medulla

enlarged spleen
- spleen is 7-fold larger than controls

enlarged thymus
- slighlty enlarged

increased IgA level
- 2-fold increase

increased IgG level
- at 2-3 months, concentration are up to 5 times control and 8 times control at 5 months

increased IgG1 level
- 10-fold increase

increased IgG2a level
- 10-fold increase

increased IgG2b level
- 2-fold increase

increased IgM level
- 2-fold increase

increased immunoglobulin level
- hypergammaglobulinemia
- mice show 4- to 6-fold higher frequencies of immunoglobulin-secreting cells in spleens compared to normal controls

increased thymus weight
- doubling of thymus weight

thymus atrophy
- in 5-10% of animals, there is medullary or stromal hyperplasia that maintains or increases the size of the thymus
- initial lesion is loss of cortical thymocytes, with later degeneration (cystic) of thymocytes of medulla
- thymic atrophy is observed; severity is most severe in the cortex but usually involves the medulla in most animals

thymus cortex atrophy
- atrophic cortex

cellular phenotype

abnormal T cell proliferation
- cells do not proliferate in response to stimulation with alloantigens

increased kidney cell proliferation
- glomerular lesions involve proliferation of endothelial and mesangial cells

lymph node necrosis
- in mice with lymph node hyperplasia, larger nodes show extensive cystic necrosis

homeostasis/metabolism phenotype

abnormal circulating protein level
- high levels of cyroglobulins are found in mice at 5 months
- mice have high concentrations of circulating immune complex at 2-3 and 4-5 months

abnormal interleukin level
- stimulation with concanavalin A does not induce cells to produce Il2

increased circulating serum albumin level

increased circulating total protein level
- 2-fold increase in beta- and 5-fold increase in gamma-globulins
- total serum protein levels are slightly increased

increased urine protein level
- incomplete penetrance, 50% of females tested have a 9-fold increase over controls

joint swelling
- 20-25% of old, diseased mice show joint swelling of the hind feet and lower legs; involving destruction of articular cartilage, proliferation of synovium, pannus formations, and sometimes joint effusions

immune system phenotype

abnormal B cell morphology
- frequency of C3d receptor bearing cells declines with age

abnormal B cell receptor editing
- Anti-dsDNA B cells escape receptor editing

abnormal cytotoxic T cell physiology
- 4-6 month old mice exhibit significantly depressed cytotoxic T cell response to alloantigens

abnormal immune system organ morphology

abnormal immune system physiology

abnormal interleukin level
- stimulation with concanavalin A does not induce cells to produce Il2

abnormal lymph node cell ratio
- mice show 4- to 6-fold higher frequencies of immunoglobulin-secreting cells (IgSC) compared to normal controls

abnormal lymph node morphology
- in mice with lymph node hyperplasia, larger nodes show extensive hemorrhage and cystic necrosis, which results in clinically observed terminal reduction in size

abnormal marginal zone B cell morphology
- mice have a larger marginal zone B cell population (10.8% of splenic lymphocytes) compared to BALB/c controls (1.9%)

abnormal T cell morphology
- increase in T-cell frequencies and absolute numbers with advanced disease; however, the number of Ly123+ and Ly23+ T cells is markedly decreased in older mice compared to young mice
- lymph node cells (T cell origin) are abnormal; cells are Ly-2^-/L3T4^-/surface Ig^-

abnormal T cell physiology
- cells do not generate CTL in response to stimulation with alloantigens

abnormal T cell proliferation
- cells do not proliferate in response to stimulation with alloantigens

abnormal T-helper 2 physiology
- activity of helper T cells is enhanced in older mice relative to younger animals or normal controls

abnormal thymus medulla morphology
- increase in thymus weight restricted to the medulla

abnormal type III hypersensitivity reaction
- perivascular and peribronchial lymphoproliferation observed in lung reslting in patches of atelectasis and exudate containing patches
- perivascular infiltration of lymphocytes, plasma cells, and histiocytes in lung, kidney, salivary gland and liver

decreased interleukin-2 secretion
- early in life, mice show reduced Il2 production, that worsens with age, such that almost no Il2 activity is detected in culture supernatants from 2 month old animals; spleen cells show no stimulated Il2 production upon stimulation with concanavalin A
- mice have severe deficiency in Il-2 production

enlarged lymph nodes
- all mice begin to develop generalized lymph lymphadenopathy when >3 months of age; in about 33%. lymph nodes shrink markedly 7-10 days before death
- enlargement started at 8 weeks of age and progressed until lymph node weights were 100 times control lymph node weight by 16 weeks of age
- no evidence of malignancy was present, despite enlargement
- node architecture was blurred, with proliferation of lymphocytes with some admixture of plasma cells and histiocytes

enlarged Peyer's patches
- slight enlargement

enlarged spleen
- spleen is 7-fold larger than controls

enlarged thymus
- slighlty enlarged

glomerulonephritis
- capsular cell proliferation, tubular damage, and casts were seen in severe lesions
- glomerular lesions involve proliferation of both endothelial and mesangial cells and basement membrane thickening
- granular deposits of immunoglobulins present in the capillary walls
- immune complex glomerulonephritis
- mice show a largely subacute proliferative form of disease; lesions involve proliferation of endothelial and mesangial cells

increased anti-double stranded DNA antibody level
- 4-month old mice show around 4-fold higher number of spleen cells secreting autoantibodies to dsDNA compared to 8-month old wild-type controls.
- high levels detected at 4-5 months
- levels of these auto antibodies rise with age
- significant levels of IgM and IgG antibodies that bind dsDNA antibodies are detected in mice 6-8 weeks of age

increased anti-erythrocyte antigen antibody level
- levels reach 4 and 11% in males and females

increased anti-nuclear antigen antibody level
- antinuclear antibody titers are detectable at 8 weeks of age and increased rapidly
- anti-nuclear antigen antibody (ANA) activity in renal eluate Ig is much higher than activity in serum Ig for anti-ssDNA and anti-dsDNA
- anti-Sm antibodies are detected in males and females but not in controls

increased anti-single stranded DNA antibody level
- detected at significant levels at 2 months, with very high levels detected at 4-5 months

increased autoantibody level
- thymocytoxic autoantibodies are detected with aging

increased IgA level
- 2-fold increase

increased IgG level
- at 2-3 months, concentration are up to 5 times control and 8 times control at 5 months

increased IgG1 level
- 10-fold increase

increased IgG2a level
- 10-fold increase

increased IgG2b level
- 2-fold increase

increased IgM level
- 2-fold increase

increased immunoglobulin level
- hypergammaglobulinemia
- mice show 4- to 6-fold higher frequencies of immunoglobulin-secreting cells in spleens compared to normal controls

increased susceptibility to autoimmune disorder

increased thymus weight
- doubling of thymus weight

lacrimal gland inflammation
- adult lacrimal glands show infiltration by lymphocytes
- Normal - treatment with steroids alleviates lymphocyte infiltration

lymph node hemorrhage
- in mice with lymph node hyperplasia, larger nodes show extensive hemorrhage

lymph node hyperplasia
- lymph nodes are up to 100 times normal size

lymph node necrosis
- in mice with lymph node hyperplasia, larger nodes show extensive cystic necrosis

salivary gland inflammation
- lymphocytic infiltration and lymphocytic foci are observed in mice 3.4-3.7 months of age
- treatment with danazol or Org 4094 sifnificantly lowers number of foci and percentage of lymphocyte infiltration, as well as other immune parameters compared to untreated controls

submandibular gland inflammation
- autoimmune sialodenitis with parenchymal destruction is observed in 4-6 month old mice in submandibular salivary glands of female mice
- most infiltrating cells are CD4⁺ and Vbeta8⁺ with a minority being CD4⁺ and Vbeta6⁺

thymus atrophy
- in 5-10% of animals, there is medullary or stromal hyperplasia that maintains or increases the size of the thymus
- initial lesion is loss of cortical thymocytes, with later degeneration (cystic) of thymocytes of medulla
- thymic atrophy is observed; severity is most severe in the cortex but usually involves the medulla in most animals

thymus cortex atrophy
- atrophic cortex

thyroid gland inflammation
- animals display thyroid gland infiltration (autoimmune thyroiditis)

vascular inflammation
- arteritis is observed in a number of organs, and is associated with hemorrhage and infarcts in the lymph nodes

Genotype: Fas^lpr/Fas^lpr
MRL/MpJ-Fas/J

behavior/neurological phenotype

abnormal spatial learning
- mice show increased latency to locate hidden platform in water maze testing on days 2-5 of testing at 8 weeks of age; at 16 weeks in spatial bias testing, mutants spend less time and travel reduced distances in quadrant of platform's previous location compared to controls
- pared to controls

impaired coordination
- equilibrium is significantly impaired in mice at 18-20 weeks, as measured by performance in rotarod tests

hearing/vestibular/ear phenotype

abnormal stria vascularis morphology
- slight degenerative changes in the stria vascularis of both the apical and basal turns
- the basal infolding of strial marginal cells
- the basement membrane of the capillaries in the stria vascularis was thickened
- widened intercellular space in the stria vascularis

abnormal strial intermediate cell morphology
- thinned intermediate cell layer

increased or absent threshold for auditory brainstem response
- the ABR threshold f the 20-week-old mutant mice were significantly higher than those of the 4-week-old mutant mice and the 20-week-old wild-type BALB/c mice

vision/eye phenotype

abnormal conjunctival epithelium morphology

conjunctivitis

hematopoietic system phenotype

abnormal immunoglobulin level
- in vitro, splenic B cells produce significantly higher amounts of IgG1 in response to LPS and anti-CD40 plus Il4 stimulation, and higher amounts of IgG2a upon LPS stimulation

decreased IgG level
- production of anti-NP IgG is impaired in spleen cells

decreased immature B cell number
- CD19+IgM+ immature B cells are reduced in the spleen

decreased marginal zone B cell number
- numbers of marginal zone (MZ) B cells is reduced

decreased mature B cell number
- CD19+ IgD^high IgM^low B cells are severely reduced in the spleen

decreased spleen germinal center number
- staining intensity and number of germinal centers (GCs) is reduced 10 days post-challenge with NP-KLH antigen, compared to controls

decreased transitional stage B cell number
- numbers of the T1 subset of B cells is reduced

increased IgG level
- mice exhibit increased serum IgG levels and IgG deposits in the kidney unlike wild-type mice

increased immunoglobulin level
- IgG and IgM levels are increased in serum at 6 months
- mice display hypergammaglobulinemia; serum levels are comparable to Fas homozygotes

increased neutrophil cell number
- mild to moderated neutrophil accumulation is observed at 20 weeks

increased plasma cell number
- increased B220+IgM+ cells are observed in bone marrow; number of IgG-secreting cells are significantly increased compared to Fas^lpr homozygotes

homeostasis/metabolism phenotype

abnormal enzyme/coenzyme activity
- Background Sensitivity - 7-8 week old mice show 2-3 fold induction of Dnase1l3 in macrophages and 4-5 fold induction in splenocytes over C57BL/6; levels in other strains like BXSB/MpJ and (NZB x NZW)F1 are similarly elevated compared to B6
- Background Sensitivity - mice show a dramatic defect (~8-fold decrease) in macrophage-secreted Dnase1l3 barrier to liposomal (BT) activity compared to B6; (NZB x NZW)F1 mice show a similar defect in BT activity

albuminuria
- mice have excessive urinary albumin compared to wild-type (>10-fold) at 3-4 months

increased urine protein level

immune system phenotype

abnormal immunoglobulin level
- in vitro, splenic B cells produce significantly higher amounts of IgG1 in response to LPS and anti-CD40 plus Il4 stimulation, and higher amounts of IgG2a upon LPS stimulation

CNS inflammation
- at 20 weeks, all mice show mononuclear infiltrates in the choroid plexus; at 10 weeks, all mice display monuclear infiltrates

conjunctivitis

decreased IgG level
- production of anti-NP IgG is impaired in spleen cells

decreased immature B cell number
- CD19+IgM+ immature B cells are reduced in the spleen

decreased marginal zone B cell number
- numbers of marginal zone (MZ) B cells is reduced

decreased mature B cell number
- CD19+ IgD^high IgM^low B cells are severely reduced in the spleen

decreased spleen germinal center number
- staining intensity and number of germinal centers (GCs) is reduced 10 days post-challenge with NP-KLH antigen, compared to controls

decreased transitional stage B cell number
- numbers of the T1 subset of B cells is reduced

enlarged lymph nodes
- nodes are 62 times normal size

glomerulonephritis
- kidney lesions have lower scores than those in double mutants at 20 weeks
- mice show deposition of IgG or C3 in kidneys and inflammation, similar to Fas homozygotes
- Background Sensitivity - severe immune complex glomerulonephritis develops by 6 months

increased anti-double stranded DNA antibody level
- antibodies are increased relative to controls and other mutant strains with Fas^lpr mutations
- mice produce high titers of IgG1 and IgG2a anti-dsDNA antibodies, comparable to Fas homozygotes

increased anti-nuclear antigen antibody level
- at 16 weeks, anti-DNA titers are significantly higher than in wild-type controls
- by 5-6 months of age, Fas-deficient mice have antinuclear antibody (ANA) levels comparable to >50% of C4b-deficient females (on Igh^b haplotype homozygous background)
- DNA auto-antibodies are increased compared to in wild-type mice at 12 weeks
- mice have significantly increased levels of anti-ssDNA antibodies

increased autoantibody level
- at 16 weeks, levels of anti-cardiolipin antibodies are significantly higher than in wild-type controls; levels are significantly higher at 8 weeks
- mice exhibit increased serum levels of kappa-chain rheumatoid factor compared to in wild-type mice

increased IgG level
- mice exhibit increased serum IgG levels and IgG deposits in the kidney unlike wild-type mice

increased immunoglobulin level
- IgG and IgM levels are increased in serum at 6 months
- mice display hypergammaglobulinemia; serum levels are comparable to Fas homozygotes

increased neutrophil cell number
- mild to moderated neutrophil accumulation is observed at 20 weeks

increased plasma cell number
- increased B220+IgM+ cells are observed in bone marrow; number of IgG-secreting cells are significantly increased compared to Fas^lpr homozygotes

increased susceptibility to systemic lupus erythematosus
- mice exhibit increased serum levels of kappa-chain rheumatoid factor and DNA auto-antibodies, lymphadenopathy, glomerulonephritis, renal immunoglobulin deposits, proteinuria, and end organ disease compared to in wild-type mice

lymph node hemorrhage
- larger lymph nodes often show extensive hemorrhage

lymph node necrosis
- larger lymph nodes often show extensive necrosis

salivary gland inflammation

vasculitis

cardiovascular system phenotype

abnormal myocardium layer morphology
- myocardium neighboring the heart valves shows mononuclear infiltration of the vessels, but valves are normal

lymph node hemorrhage
- larger lymph nodes often show extensive hemorrhage

vasculitis

cellular phenotype

lymph node necrosis
- larger lymph nodes often show extensive necrosis

mammalian phenotype

vision/eye phenotype

mortality/aging

premature death
- 50% mortality is observed at 5 months with 90% mortality at 7.5 months, significantly reduced from wild-type

muscle phenotype

abnormal myocardium layer morphology
- myocardium neighboring the heart valves shows mononuclear infiltration of the vessels, but valves are normal

nervous system phenotype

CNS inflammation
- at 20 weeks, all mice show mononuclear infiltrates in the choroid plexus; at 10 weeks, all mice display monuclear infiltrates

pigmentation phenotype

abnormal strial intermediate cell morphology
- thinned intermediate cell layer

renal/urinary system phenotype

abnormal kidney physiology
- progressive decline in renal function is observed, during progression to end-stage renal disease

abnormal renal glomerulus morphology
- abnormalities due to severe glomerulonephritis
- at 20 weeks, lesions show some neutrophil infiltration and hypercellularity
- tuft necrosis, capsular proliferation and fibrosis are less common and less severe than observed in double mutants

albuminuria
- mice have excessive urinary albumin compared to wild-type (>10-fold) at 3-4 months

cortical renal glomerulopathies
- glomerulonephritic changes such as hypercellularity, lobularity, dilated capsules and crescent formation or enlarged glomeruli are observed in mice at 3-4 months

dilated renal glomerular capsule
- dilated capsules are observed in mice at 3-4 months

expanded mesangial matrix
- mild increase in mesangial matrix is seen at 20 weeks of age

glomerular crescent
- crescent formation is observed in mice at 3-4 months

glomerulonephritis
- kidney lesions have lower scores than those in double mutants at 20 weeks
- mice show deposition of IgG or C3 in kidneys and inflammation, similar to Fas homozygotes
- Background Sensitivity - severe immune complex glomerulonephritis develops by 6 months

increased urine protein level

mesangial cell hyperplasia
- mild increase in mesangial cells is seen at 20 weeks of age

podocyte foot process effacement
- foot processes are only focally effaced

renal glomerulus hypertrophy
- enlarged glomeruli are observed in mice at 3-4 months

digestive/alimentary phenotype

salivary gland inflammation

endocrine/exocrine gland phenotype

salivary gland inflammation

Genotype: Fas^lpr/Fas^lpr
MRL-Fas

cardiovascular system phenotype

vasculitis
- observed in kidneys with destruction of external elastic lamina common

immune system phenotype

abnormal T-helper 2 physiology
- enhanced T-helper cell activity is seen in vitro; removal of T cells from splenic cultures resulted in a significant reduction of the frequency of spontaneous immunoglobulin release in both autoimmune and normal spleen cell populations
- T cell-enriched populations from older animals provided twice the help offered by T cells of young syngeneic animals or T cells from young and older normal mice of the same H-2 haplotype

enlarged lymph nodes
- mean weight of axillary lymph nodes is 1.3 grams

glomerulonephritis
- lymphocyte infiltration, lobulation, and hyaline deposition noted in kidney

increased anti-double stranded DNA antibody level
- 30 fold higher than in mice without autoimmune disease

increased anti-nuclear antigen antibody level
- levels are elevated compared to wild-type mice

increased IgG level
- twice wild-type levels

increased IgM level
- about 1.7 fold higher than wild-type levels

increased immunoglobulin level
- splenic cells in culture show four- to sixfold higher frequencies of spontaneous immunoglobulin release than controls

increased spleen weight
- mean weight is 0.9 grams

vasculitis
- observed in kidneys with destruction of external elastic lamina common

growth/size/body region phenotype

increased spleen weight
- mean weight is 0.9 grams

renal/urinary system phenotype

glomerulonephritis
- lymphocyte infiltration, lobulation, and hyaline deposition noted in kidney

hematopoietic system phenotype

abnormal T-helper 2 physiology
- enhanced T-helper cell activity is seen in vitro; removal of T cells from splenic cultures resulted in a significant reduction of the frequency of spontaneous immunoglobulin release in both autoimmune and normal spleen cell populations
- T cell-enriched populations from older animals provided twice the help offered by T cells of young syngeneic animals or T cells from young and older normal mice of the same H-2 haplotype

increased IgG level
- twice wild-type levels

increased IgM level
- about 1.7 fold higher than wild-type levels

increased immunoglobulin level
- splenic cells in culture show four- to sixfold higher frequencies of spontaneous immunoglobulin release than controls

increased spleen weight
- mean weight is 0.9 grams

homeostasis/metabolism phenotype

increased blood urea nitrogen level
- mean levels are 52.4 mg/dl

Genotype: Fas^lpr/Fas^lpr
MRL/MpJ-Fas

cardiovascular system phenotype

vascular inflammation
- mice develop systemic necrotizing arteritis of small- and medium-sized arteries; frequently observed in kidneys

immune system phenotype

abnormal leukocyte adhesion
- significantly enhanced at 12 and 16 weeks

abnormal leukocyte morphology
- 46% of venules display leukocytes adjacent to endothelium, compared to only 145 in controls; in mutants and controls, 60-70% of these cells are mononuclear

autoimmune response
- mice develop anti-nuclear antibodies (ie. anti-dsDNA, anti-ssDNA, etc)

decreased activated T cell number

decreased B cell number

decreased CD4-positive, alpha beta T cell number
- reduced compared to wild-type MRL animals

decreased CD8-positive, alpha-beta T cell number
- reduced compared to wild-type MRL animals

enlarged lymph nodes
- severe

enlarged spleen
- severe

glomerulonephritis
- mice show deposition of IgG or C3 in kidneys and inflammation

impaired leukocyte tethering or rolling
- in mice chronically treated with anti-E-selectin antibodies, rolling is completely eliminated
- rolling is dramatically reduced, but not eliminated, in mutants compared to controls

increased anti-nuclear antigen antibody level
- levels of anti-dsDNA and anti-chromatin autoantibodies are elevated compared to wild-type

increased autoantibody level
- IgG3 anti-IgG2a rheumatoid factor (RF) levels are much higher than wild-type controls

increased double-negative T cell number
- significantly increased relative to controls

increased immunoglobulin level
- mice develop hypergammaglobulinemia

vascular inflammation
- mice develop systemic necrotizing arteritis of small- and medium-sized arteries; frequently observed in kidneys

cellular phenotype

abnormal leukocyte adhesion
- significantly enhanced at 12 and 16 weeks

impaired leukocyte tethering or rolling
- in mice chronically treated with anti-E-selectin antibodies, rolling is completely eliminated
- rolling is dramatically reduced, but not eliminated, in mutants compared to controls

mortality/aging

premature death
- 50% mortality by 20 weeks; <40% survival beyond 40 weeks
- animals start to die at 4.5 months, with >50% mortality observed at 7 months

renal/urinary system phenotype

glomerulonephritis
- mice show deposition of IgG or C3 in kidneys and inflammation

renal glomerular immunoglobulin deposits

growth/size/body region phenotype

enlarged spleen
- severe

hematopoietic system phenotype

abnormal leukocyte adhesion
- significantly enhanced at 12 and 16 weeks

abnormal leukocyte morphology
- 46% of venules display leukocytes adjacent to endothelium, compared to only 145 in controls; in mutants and controls, 60-70% of these cells are mononuclear

decreased activated T cell number

decreased B cell number

decreased CD4-positive, alpha beta T cell number
- reduced compared to wild-type MRL animals

decreased CD8-positive, alpha-beta T cell number
- reduced compared to wild-type MRL animals

enlarged spleen
- severe

impaired leukocyte tethering or rolling
- in mice chronically treated with anti-E-selectin antibodies, rolling is completely eliminated
- rolling is dramatically reduced, but not eliminated, in mutants compared to controls

increased double-negative T cell number
- significantly increased relative to controls

increased immunoglobulin level
- mice develop hypergammaglobulinemia

Genotype: Fas^lpr/Fas^lpr
involves: MRL/Mp

cellular phenotype

decreased macrophage apoptosis
- macrophages exhibit 60% less cholesterol-induced apoptosis compared with similarly treated wild-type cells

hematopoietic system phenotype

decreased macrophage apoptosis
- macrophages exhibit 60% less cholesterol-induced apoptosis compared with similarly treated wild-type cells

immune system phenotype

decreased macrophage apoptosis
- macrophages exhibit 60% less cholesterol-induced apoptosis compared with similarly treated wild-type cells

increased susceptibility to bacterial infection
- mice exhibit increased Pseudomonas aerugiosa exotoxin-induced mortality compared with similarly treated wild-type mice

mortality/aging

increased sensitivity to induced morbidity/mortality
- mice exhibit increased Pseudomonas aerugiosa exotoxin-induced mortality compared with similarly treated wild-type mice

Phenotype Information

Body Weight Information - JAX^® Mice Strain - MRL/MpJ-Fas^lpr/J (000485)

References

Andrews BS; Eisenberg RA; Theofilopoulos AN; Izui S; Wilson CB; McConahey PJ; Murphy ED; Roths JB; Dixon FJ. 1978. Spontaneous murine lupus-like syndromes. Clinical and immunopathological manifestations in several strains. J Exp Med 148(5):1198-215PubMed: 309911 MGI: J:27634
Clark LD; Clark RK; Heber-Katz E. 1998. A new murine model for mammalian wound repair and regeneration. Clin Immunol Immunopathol 88(1):35-45PubMed: 9683548 MGI: J:48937
Drappa J; Brot N; Elkon KB. 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. Proc Natl Acad Sci U S A 90(21):10340-4PubMed: 7694292 MGI: J:15429
Fields ML; Sokol CL; Eaton-Bassiri A; Seo Sj; Madaio MP; Erikson J. 2001. Fas/fas ligand deficiency results in altered localization of anti-double-stranded dna b cells and dendritic cells. J Immunol 167(4):2370-8PubMed: 11490027 MGI: J:70822
Gu L; Weinreb A; Wang XP; Zack DJ; Qiao JH; Weisbart R; Lusis AJ. 1998. Genetic determinants of autoimmune disease and coronary vasculitis in the MRL-lpr/lpr mouse model of systemic lupus erythematosus. J Immunol 161(12):6999-7006PubMed: 9862736 MGI: J:52131
Hewicker M; Kromschroder E; Trautwein G. 1990. Detection of circulating immune complexes in MRL mice with different forms of glomerulonephritis. Z Versuchstierkd 33(4):149-56PubMed: 2238887 MGI: J:109933
Johnson BC; Morton JI; Trune DR. 1992. Lacrimal and salivary gland inflammation in the C3H/Ipr autoimmune strain mouse: a potential mode for Sjogren's syndrome. Otolaryngol Head Neck Surg 106(4):394-9PubMed: 1565490 MGI: J:1028
Kawase E; Suemori H; Takahashi N; Okazaki K; Hashimoto K; Nakatsuji N. 1994. Strain difference in establishment of mouse embryonic stem (ES) cell lines. Int J Dev Biol 38(2):385-90PubMed: 7981049 MGI: J:19823
Kench JA; Russell DM; Fadok VA; Young SK; Worthen GS; Jones-Carson J; Henson JE; Henson PM; Nemazee D. 1999. Aberrant wound healing and TGF-beta production in the autoimmune-prone MRL/+ mouse. Clin Immunol 92(3):300-10PubMed: 10479535 MGI: J:57718
Leferovich JM; Bedelbaeva K; Samulewicz S; Zhang XM; Zwas D; Lankford EB; Heber-Katz E. 2001. Heart regeneration in adult MRL mice. Proc Natl Acad Sci U S A 98(17):9830-5PubMed: 11493713 MGI: J:109867
Li X; Mohan S; Gu W; Baylink DJ. 2001. Analysis of gene expression in the wound repair/regeneration process. Mamm Genome 12(1):52-9PubMed: 11178744 MGI: J:68684
Li X; Mohan S; Gu W; Miyakoshi N; Baylink DJ. 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 Biochim Biophys Acta 1524(2-3):102-9PubMed: 11113556 MGI: J:66437
McBrearty BA; Clark LD; Zhang XM; Blankenhorn EP; Heber-Katz E. 1998. Genetic analysis of a mammalian wound-healing trait. Proc Natl Acad Sci U S A 95(20):11792-7PubMed: 9751744 MGI: J:50111
Medana I; Li Z; Flugel A; Tschopp J; Wekerle H; Neumann H. 2001. Fas ligand (CD95L) protects neurons against perforin-mediated T lymphocyte cytotoxicity. J Immunol 167(2):674-81PubMed: 11441070 MGI: J:109872
Morse HC 3rd; Davidson WF; Yetter RA; Murphy ED; Roths JB; Coffman RL. 1982. Abnormalities induced by the mutant gene Ipr: expansion of a unique lymphocyte subset. J Immunol 129(6):2612-5PubMed: 6815273 MGI: J:6902
Morse HC 3rd; Roths JB; Davidson WF; Langdon WY; Fredrickson TN; Hartley JW. 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. J Exp Med 161(3):602-16PubMed: 2982991 MGI: J:7745
Murphy ED; Roths JB. 1978. Autoimmunity and lymphoproliferation: Induction by mutant gene lpr, and acceleration by a male-associated factor in strain BXSB mice:207-20MGI: J:28885
Sato EH; Sullivan DA. 1994. Comparative influence of steroid hormones and immunosuppressive agents on autoimmune expression in lacrimal glands of a female mouse model of Sjogren's syndrome. Invest Ophthalmol Vis Sci 35(5):2632-42PubMed: 8163351 MGI: J:18512
Watanabe-Fukunaga R; Brannan CI; Copeland NG; Jenkins NA; Nagata S. 1992. Lymphoproliferation disorder in mice explained by defects in Fas antigen that mediates apoptosis. Nature 356(6367):314-7PubMed: 1372394 MGI: J:1181
Yogi Y; Nakamura K; Suzuki A. 1989. The experimental inoculation with Mycobacterium leprae in autoimmune mice: results of MRL/lpr mice inoculated into the right hind foot (continued). Nippon Rai Gakkai Zasshi 58(4):235-40PubMed: 2489281 MGI: J:27853

Additional References

Abrego-Peredo A; Romero-Ramirez H; Espinosa E; Lopez-Herrera G; Garcia-Garcia F; Flores-Munoz M; Sandoval-Montes C; Rodriguez-Alba JC. 2020. Naringenin mitigates autoimmune features in lupus-prone mice by modulation of T-cell subsets and cytokines profile. PLoS One 15(5):e0233138PubMed: 32421738 MGI: J:288711
Benihoud K; Bonardelle D; Soual-Hoebeke E; Durand-Gasselin I; Emilie D; Kiger N; Bobe P. 2002. Unusual expression of LINE-1 transposable element in the MRL autoimmune lymphoproliferative syndrome-prone strain. Oncogene 21(36):5593-600PubMed: 12165858 MGI: J:78714
Blankenhorn EP; Troutman S; Clark LD; Zhang XM; Chen P; Heber-Katz E. 2003. Sexually dimorphic genes regulate healing and regeneration in MRL mice. Mamm Genome 14(4):250-60PubMed: 12682777 MGI: J:82708
Dai R; Cowan C; Heid B; Khan D; Liang Z; Pham CT; Ahmed SA. 2017. Neutrophils and neutrophil serine proteases are increased in the spleens of estrogen-treated C57BL/6 mice and several strains of spontaneous lupus-prone mice. PLoS One 12(2):e0172105PubMed: 28192517 MGI: J:245406
Edwards MR; Dai R; Heid B; Cecere TE; Khan D; Mu Q; Cowan C; Luo XM; Ahmed SA. 2017. Commercial rodent diets differentially regulate autoimmune glomerulonephritis, epigenetics and microbiota in MRL/lpr mice. Int Immunol 29(6):263-276PubMed: 28637300 MGI: J:249532
Edwards MR; Dai R; Heid B; Cowan C; Werre SR; Cecere T; Ahmed SA. 2020. Low-dose 17alpha-ethinyl estradiol (EE) exposure exacerbates lupus renal disease and modulates immune responses to TLR7/9 agonists in genetically autoimmune-prone mice. Sci Rep 10(1):5210PubMed: 32251357 MGI: J:286976
Goltsev Y; Samusik N; Kennedy-Darling J; Bhate S; Hale M; Vazquez G; Black S; Nolan GP. 2018. Deep Profiling of Mouse Splenic Architecture with CODEX Multiplexed Imaging. Cell 174(4):968-981.e15PubMed: 30078711 MGI: J:268649
Han X; Vesely MD; Yang W; Sanmamed MF; Badri T; Alawa J; Lopez-Giraldez F; Gaule P; Lee SW; Zhang JP; Nie X; Nassar A; Boto A; Flies DB; Zheng L; Kim TK; Moeckel GW; McNiff JM; Chen L. 2019. PD-1H (VISTA)-mediated suppression of autoimmunity in systemic and cutaneous lupus erythematosus. Sci Transl Med 11(522)PubMed: 31826980 MGI: J:283647
Hawley D; Tang X; Zyrianova T; Shah M; Janga S; Letourneau A; Schicht M; Paulsen F; Hamm-Alvarez S; Makarenkova HP; Zoukhri D. 2018. Myoepithelial cell-driven acini contraction in response to oxytocin receptor stimulation is impaired in lacrimal glands of Sjogren's syndrome animal models. Sci Rep 8(1):9919PubMed: 29967327 MGI: J:268474
Hiramatsu S; Watanabe KS; Zeggar S; Asano Y; Miyawaki Y; Yamamura Y; Katsuyama E; Katsuyama T; Watanabe H; Takano-Narazaki M; Matsumoto Y; Kawabata T; Sada KE; Wada J. 2019. Regulation of Cathepsin E gene expression by the transcription factor Kaiso in MRL/lpr mice derived CD4+ T cells. Sci Rep 9(1):3054PubMed: 30816218 MGI: J:275257
Jabs DA; Burns WH; Prendergast RA. 1996. Paradoxic effect of anti-CD4 therapy on lacrimal gland disease in MRL/Mp-lpr/lpr mice. Invest Ophthalmol Vis Sci 37(1):246-50PubMed: 8550330 MGI: J:280908
Jabs DA; Prendergast RA; Rorer EM; Hudson AP; Whittum-Hudson JA. 2001. Cytokines in autoimmune lacrimal gland disease in MRL/MpJ mice. Invest Ophthalmol Vis Sci 42(11):2567-71PubMed: 11581200 MGI: J:72054
Katzav A; Kloog Y; Korczyn AD; Niv H; Karussis DM; Wang N; Rabinowitz R; Blank M; Shoenfeld Y; Chapman J. 2001. Treatment of MRL/lpr mice, a genetic autoimmune model, with the Ras inhibitor, farnesylthiosalicylate (FTS). Clin Exp Immunol 126(3):570-7PubMed: 11737078 MGI: J:73395
Kelley VE; Roths JB. 1985. Interaction of mutant lpr gene with background strain influences renal disease. Clin Immunol Immunopathol 37(2):220-9PubMed: 4042431 MGI: J:109439
Lenda DM; Stanley ER; Kelley VR. 2004. Negative role of colony-stimulating factor-1 in macrophage, T cell, and B cell mediated autoimmune disease in MRL-Fas(lpr) mice. J Immunol 173(7):4744-54PubMed: 15383612 MGI: J:93714
Liang B; Kashgarian MJ; Sharpe AH; Mamula MJ. 2000. Autoantibody responses and pathology regulated by B7-1 and B7-2 costimulation in MRL/lpr lupus J Immunol 165(6):3436-43PubMed: 10975864 MGI: J:64568
Lin L; Hron JD; Peng SL. 2004. Regulation of NF-kappaB, Th activation, and autoinflammation by the forkhead transcription factor Foxo3a. Immunity 21(2):203-13PubMed: 15308101 MGI: J:93593
Luzina IG; Atamas SP; Storrer CE; daSilva LC; Kelsoe G; Papadimitriou JC; Handwerger BS. 2001. Spontaneous formation of germinal centers in autoimmune mice. J Leukoc Biol 70(4):578-84PubMed: 11590194 MGI: J:72513
Ma Y; Liu H; Tu-Rapp H; Thiesen HJ; Ibrahim SM; Cole SM; Pope RM. 2004. Fas ligation on macrophages enhances IL-1R1-Toll-like receptor 4 signaling and promotes chronic inflammation. Nat Immunol 5(4):380-7PubMed: 15004557 MGI: J:89208
Martins GA; Petkova SB; MacHado FS; Kitsis RN; Weiss LM; Wittner M; Tanowitz HB; Silva JS. 2001. Fas-FasL interaction modulates nitric oxide production in Trypanosoma cruzi-infected mice. Immunology 103(1):122-9PubMed: 11380700 MGI: J:69492
Molano ID; Redmond S; Sekine H; Zhang XK; Reilly C; Hutchison F; Ruiz P; Gilkeson GS. 2003. Effect of genetic deficiency of terminal deoxynucleotidyl transferase on autoantibody production and renal disease in MRL/lpr mice. Clin Immunol 107(3):186-97PubMed: 12804532 MGI: J:83942
Mu Q; Tavella VJ; Kirby JL; Cecere TE; Chung M; Lee J; Li S; Ahmed SA; Eden K; Allen IC; Reilly CM; Luo XM. 2017. Antibiotics ameliorate lupus-like symptoms in mice. Sci Rep 7(1):13675PubMed: 29057975 MGI: J:255507
Nowling TK; Rodgers J; Thiyagarajan T; Wolf B; Bruner E; Sundararaj K; Molano I; Gilkeson G. 2020. Targeting glycosphingolipid metabolism as a potential therapeutic approach for treating disease in female MRL/lpr lupus mice. PLoS One 15(3):e0230499PubMed: 32187230 MGI: J:286783
Paul E; Pozdnyakova OO; Mitchell E; Carroll MC. 2002. Anti-DNA autoreactivity in C4-deficient mice. Eur J Immunol 32(9):2672-9PubMed: 12207352 MGI: J:78993
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Reuter JD; Zeiss CJ. 2000. Confounding influences on phenotype expression in MRL/lpr mice Comp Med 50(3):329-32PubMed: 10894502 MGI: J:62934
Spurney RF; Onorato JJ; Ruiz P; Pisetsky DS; Coffman TM. 1993. Characterization of glomerular thromboxane receptors in murine lupus nephritis. J Pharmacol Exp Ther 264(2):584-90PubMed: 8437109 MGI: J:281065
Sundararaj K; Rodgers JI; Marimuthu S; Siskind LJ; Bruner E; Nowling TK. 2018. Neuraminidase activity mediates IL-6 production by activated lupus-prone mesangial cells. Am J Physiol Renal Physiol 314(4):F630-F642PubMed: 29357434 MGI: J:280619
Tian Y; Guo H; Miao X; Xu J; Yang R; Zhao L; Liu J; Yang L; Gao F; Zhang W; Liu Q; Sun S; Tian Y; Li H; Huang J; Gu C; Liu S; Feng X. 2020. Nestin protects podocyte from injury in lupus nephritis by mitophagy and oxidative stress. Cell Death Dis 11(5):319PubMed: 32371936 MGI: J:288797
Tsukahara T; Makino Y; Fujii T; Ogawa M; Saisho H; Hamano Y; Ueda S; Akikusa B; Danoff TM. 2002. Role of RANTES in the development of autoimmune tissue injuries in MRL-Fas lpr mice. Clin Immunol 103(1):89-97PubMed: 11987989 MGI: J:76389
Verhagen C; Rowshani T; Willekens B; van Haeringen NJ. 1995. Spontaneous development of corneal crystalline deposits in MRL/Mp mice. Invest Ophthalmol Vis Sci 36(2):454-61PubMed: 7843914 MGI: J:24024
Yamada A; Miyazaki T; Lu LM; Ono M; Ito MR; Terada M; Mori S; Hata K; Nozaki Y; Nakatsuru S; Nakamura Y; Onji M; Nose M. 2003. Genetic basis of tissue specificity of vasculitis in MRL/lpr mice. Arthritis Rheum 48(5):1445-51PubMed: 12746919 MGI: J:83832
Yang JQ; Chun T; Liu H; Hong S; Bui H; Van Kaer L; Wang CR; Singh RR. 2004. CD1d deficiency exacerbates inflammatory dermatitis in MRL-lpr/lpr mice. Eur J Immunol 34(6):1723-32PubMed: 15162443 MGI: J:90394
Zhang Y; Li J; Zhou N; Zhang Y; Wu M; Xu J; Shen C; An X; Shen G; Yang M; Zhang C; Tao J. 2017. The Unknown Aspect of BAFF: Inducing IL-35 Production by a CD5(+)CD1d(hi)FcgammaRIIb(hi) Regulatory B-Cell Subset in Lupus. J Invest Dermatol 137(12):2532-2543PubMed: 28844943 MGI: J:252974
Zhang Y; Schlossman SF; Edwards RA; Ou CN; Gu J; Wu MX. 2002. Impaired apoptosis, extended duration of immune responses, and a lupus-like autoimmune disease in IEX-1-transgenic mice. Proc Natl Acad Sci U S A 99(2):878-83PubMed: 11782530 MGI: J:73983

Additional - Fas^lpr related

Technical Support

CONTACT TECHNICAL SUPPORT

Genotyping Protocols
- Standard PCR:Fas
- Standard PCR:Fas MCA
- Genotyping resources and troubleshooting
Dietary Information
- LabDiet® 5K52 formulation (6% fat)
Breeding Considerations

This strain is a challenging breeder.

Due to the heightened healing which occurs in mice with the MRL genetic background, ear punch is not a good method for individual mouse identification in this strain. Mice may have only 2 litters before developing phenotype.
- Additional Breeding and Husbandry Support
Mating System
- Homozygote x Homozygote
Appearance
- albino
  Related Genotype: a/a Tyr^c/Tyr^c
Citation
When using the MRL-lpr mouse strain in a publication, please cite the originating article(s) and include JAX stock #000485 in your Materials and Methods section.

Animal Health Reports

Facility Barrier Level Descriptions

MP14 (Maximum)

RB03 (Maximum)

Pricing & Availability

Readily Available

Domestic
International

Live Mouse

Age

Genotype

Price

weeks

Cryorecovery - Pricing

Service/Product	Description	Price
	Homozygous for Fas<lpr>, 1 pair minimum

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The Jackson Laboratory has rigorous genetic quality control and mutant gene genotyping programs to ensure the genetic background of JAX® Mice strains as well as the genotypes of strains with identified molecular mutations. JAX® Mice strains are only made available to researchers after meeting our standards. However, the phenotype of each strain may not be fully characterized and/or captured in the strain data sheets. Therefore, we cannot guarantee a strain's phenotype will meet all expectations. To ensure that JAX® Mice will meet the needs of individual research projects or when requesting a strain that is new to your research, we suggest ordering and performing tests on a small number of mice to determine suitability for your particular project. We do not guarantee breeding performance and therefore suggest that investigators order more than one breeding pair to avoid delays in their research.

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Overview

Also Known As:lymphoproliferation, MRL-lpr

Genetic overview

Faslpr

Research Applications

Base Price

Details

Important Note

Detailed Description

Development

Control Suggestions

Additional Information

Selected References

Genetics

Faslpr

Allele Symbol: Faslpr

Disease/Phenotype

Disease Terms

Model with phenotypic similarity to human disease where etiologies involve orthologs. Human genes are associated with this disease. Orthologs of those genes appear in the mouse genotype(s).

Model with phenotypic similarity to human disease where etiologies are distinct. Human genes are associated with this disease. Orthologs of these genes do not appear in the mouse genotype(s).

Models with phenotypic similarity to human diseases where etiology is unknown or involving genes where ortholog is unknown.

Research Areas By Phenotype

This mouse can be used to support research in many areas including:

Genotype: Faslpr related

Mammalian Phenotype Terms by Genotype

Genotype: Faslpr/Faslprinvolves: C3H * MRL/Mp

cardiovascular system phenotype

hematopoietic system phenotype

immune system phenotype

growth/size/body region phenotype

hearing/vestibular/ear phenotype

Genotype: Faslpr/FaslprB6.MRL-Fas/J

cellular phenotype

immune system phenotype

liver/biliary system phenotype

nervous system phenotype

renal/urinary system phenotype

hematopoietic system phenotype

Genotype: Faslpr/FaslprMRL.Cg-Irf1 Fas

cellular phenotype

homeostasis/metabolism phenotype

immune system phenotype

integument phenotype

mortality/aging

renal/urinary system phenotype

Genotype: Faslpr/FaslprC3.MRL-Fas/J

cardiovascular system phenotype

cellular phenotype

mammalian phenotype

mortality/aging

renal/urinary system phenotype

respiratory system phenotype

hematopoietic system phenotype

immune system phenotype

Genotype: Faslpr/FaslprB6.MRL-Fas

cardiovascular system phenotype

cellular phenotype

mortality/aging

growth/size/body region phenotype

renal/urinary system phenotype

hematopoietic system phenotype

immune system phenotype

Genotype: Faslpr/FaslprAK.MRL-Fas

cardiovascular system phenotype

renal/urinary system phenotype

cellular phenotype

hematopoietic system phenotype

immune system phenotype

Genotype: Faslpr/FaslprC3.MRL-Fas

cellular phenotype

hematopoietic system phenotype

homeostasis/metabolism phenotype

immune system phenotype

mammalian phenotype

nervous system phenotype

reproductive system phenotype

vision/eye phenotype

digestive/alimentary phenotype

endocrine/exocrine gland phenotype

Genotype: Faslpr/Faslprinvolves: C57BL/6 * MRL/Mp

Fas^lpr

Fas^lpr

Allele Symbol: Fas^lpr

Genotype: Fas^lpr related

Genotype: Fas^lpr/Fas^lpr
involves: C3H * MRL/Mp

Genotype: Fas^lpr/Fas^lpr
B6.MRL-Fas/J

Genotype: Fas^lpr/Fas^lpr
MRL.Cg-Irf1 Fas

Genotype: Fas^lpr/Fas^lpr
C3.MRL-Fas/J

Genotype: Fas^lpr/Fas^lpr
B6.MRL-Fas

Genotype: Fas^lpr/Fas^lpr
AK.MRL-Fas

Genotype: Fas^lpr/Fas^lpr
C3.MRL-Fas

Genotype: Fas^lpr/Fas^lpr
involves: C57BL/6 * MRL/Mp

Genotype: Fas^lpr/Fas^lpr
involves: 129P2/OlaHsd * MRL

Genotype: Fas^lpr/Fas^lpr
MRL/Mp-Fas

Genotype: Fas^lpr/Fas^lpr
MRL/MpJ-Fas/J

Genotype: Fas^lpr/Fas^lpr
MRL-Fas

Genotype: Fas^lpr/Fas^lpr
MRL/MpJ-Fas

Genotype: Fas^lpr/Fas^lpr
involves: MRL/Mp

Additional - Fas^lpr related