Description

Strain Information

Former Names B6.MRL-Tnfrsf6lpr/J    (Changed: 26-JAN-05 ) Type Congenic; Mutant Strain; Spontaneous Mutation; Additional information on Genetically Engineered Mutant Mice. Mating System Homozygote x Homozygote         (Female x Male) Species laboratory mouse Background Strain C57BL/6J Donor Strain MRL/MpJ-Faslpr H2 Haplotype b Generation N11F91 (11-JAN-08)

Appearance
black
Related Genotype: a/a

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. Onset and severity of symptoms associated with the Fas^lpr allele 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 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). This mouse is a model for systemic lupus erythematosus-like autoimmune syndromes.

In an attempt to offer alleles on well-characterized or multiple genetic backgrounds, alleles are frequently moved to a genetic background different from that on which an allele was first characterized. This is the case for the strain above. It should be noted that the phenotype could vary from that originally described. We will modify the strain description if necessary as published results become available.

Control Information

Related Strains

Strains carrying   Fas^lpr allele

000480	C3.MRL-Faslpr/J
002455	MRL-Faslpr.129P2(B6)-B2mtm1Unc
003896	MRL/MpJ Faslpr-Foxq1sa-J/J
006825	MRL/MpJ-Faslpr/2J
000485	MRL/MpJ-Faslpr/J
004519	NOD.MRL(C3)-Faslpr/DoiJ
004922	NOD.MRL-Faslpr/Dvs

View Strains carrying   Fas^lpr     (7 strains)

Strains carrying other alleles of Fas

003233	B6.129P2-Fastm1Osa/J
007895	C57BL/6-Fastm1Cgn/J
001876	CBA/KlJms-Faslpr-cg/J
003234	MRL.129P2(B6)-Fastm1Osa/J
002983	MRL.CBAJms-Faslpr-cg/J

View Strains carrying other alleles of Fas     (5 strains)

Additional Web Information

Congenic Nomenclature
Genetic Quality Control Annual Report

Phenotype

Phenotype Information

View Related Disease (OMIM) Terms

Related Disease (OMIM) Terms

	Autoimmune Lymphoproliferative Syndrome; ALPS - Models with phenotypic similarity to human disease where etiologies involve orthologs.1
	Sjogren Syndrome - Models with phenotypic similarity to human disease where etiologies involve orthologs.1
	Sjogren Syndrome - 5
	Systemic Lupus Erythematosus; SLE - Models with phenotypic similarity to human disease where etiologies involve orthologs.1

1 Human genes are associated with this disease. Orthologs of those genes appear in the mouse genotype(s). 5 Conditionally targeted allele(s)

View Mammalian Phenotype Terms

Mammalian Phenotype Terms

      assigned by genotype

Fas^lpr/Fas^lpr

        B6.MRL-Fas^lpr/J

• immune system phenotype
• CNS inflammation (MGI Ref ID J:120427)
• brain inflammation (MGI Ref ID J:120427)
  • 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
• abnormal spleen cellularity (MGI Ref ID J:132217)
  • total number of CD19+ splenocytes is higher than wild-type
• abnormal splenic cell ratio (MGI Ref ID J:132217)
  • T1:follicular B cell ratio is higher than wild-type or Bcl2l11-deficient mice
• spleen hyperplasia (MGI Ref ID J:132217)
  • total number of splenocytes is increased relative to wild-type
• decreased B cell apoptosis (MGI Ref ID J:135830)
  • after bile duct ligation (BDL), Peyer's patch B cells do not display evidence of apoptosis
• enlarged lymph nodes (MGI Ref ID J:119584)
  • mice develop less severe lymphadenopathy at later ages than the double mutant Igh-6/Fas mice
• lymph node hyperplasia (MGI Ref ID J:132217)
  • total number of cells per lymph node is increased compared to wild-type
• increased autoantibody level (MGI Ref ID J:132217)
  • total anti-IgM antibody levels are increased compared to wild-type
• increased anti-nuclear antigen antibody level (MGI Ref ID J:132217)
  • anti-nuclear antibodies are increased compared to wild-type
• increased anti-double stranded DNA antibody level (MGI Ref ID J:132217)
  • anti-ssDNA IgM and IgG antibodies are increased compared to wild-type
• increased anti-histone antibody level (MGI Ref ID J:132217)
  • increased compared to wild-type
• increased anti-single stranded DNA antibody level (MGI Ref ID J:132217)
  • anti-ssDNA IgM and IgG antibodies are increased compared to wild-type
• increased follicular B cell number (MGI Ref ID J:132217)
  • higher in spleen relative to wild-type
• increased immature B cell number (MGI Ref ID J:132217)
  • plasmablast numbers in spleen are increased relative to wild-type
• increased transitional stage B cell number (MGI Ref ID J:132217)
  • higher numbers of T2 B cells in spleen relative to wild-type
• increased marginal zone B cell number (MGI Ref ID J:132217)
  • higher in spleen relative to wild-type, Fas^lpr homozygotes, and Bcl2l11-deficient mice
• increased susceptibility to bacterial infection (MGI Ref ID J:136745)
  • 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 viral infection (MGI Ref ID J:120427)
  • inflammation and tissue damage in the brain are slightly greater than in control, resistant mice at 45 and 180 days
• hematopoietic system phenotype
• abnormal spleen cellularity (MGI Ref ID J:132217)
  • total number of CD19+ splenocytes is higher than wild-type
• abnormal splenic cell ratio (MGI Ref ID J:132217)
  • T1:follicular B cell ratio is higher than wild-type or Bcl2l11-deficient mice
• spleen hyperplasia (MGI Ref ID J:132217)
  • total number of splenocytes is increased relative to wild-type
• decreased B cell apoptosis (MGI Ref ID J:135830)
  • after bile duct ligation (BDL), Peyer's patch B cells do not display evidence of apoptosis
• increased follicular B cell number (MGI Ref ID J:132217)
  • higher in spleen relative to wild-type
• increased immature B cell number (MGI Ref ID J:132217)
  • plasmablast numbers in spleen are increased relative to wild-type
• increased transitional stage B cell number (MGI Ref ID J:132217)
  • higher numbers of T2 B cells in spleen relative to wild-type
• increased marginal zone B cell number (MGI Ref ID J:132217)
  • higher in spleen relative to wild-type, Fas^lpr homozygotes, and Bcl2l11-deficient mice
• renal/urinary system phenotype
• abnormal kidney morphology (MGI Ref ID J:132217)
  • IgG deposits mainly localized to basement glomerular membrane are increased relative to wild-type
  • number of macrophages surrounding glomeruli is increased compared to wild-type which have no macrophage index
  • higher numbers of apoptotic cells are detected in glomeruli compared to wild-type
• liver/biliary system phenotype
• abnormal hepatocyte morphology (MGI Ref ID J:135830)
  • confluent foci of feathery hepatocyte degeneration due to bile acid cytotoxicity are significantly reduced compared to controls hours after BDL
• decreased hepatocyte apoptosis (MGI Ref ID J:135830)
  • hepatocyte cell death is reduced compared to controls after BDL
• abnormal liver physiology (MGI Ref ID J:135830)
  • after BDL, necroinflammatory foci and lymphocytic infiltration are obviously less than in controls
  • 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
  • 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
• focal hepatic necrosis (MGI Ref ID J:135830)
  • necroinflammatory foci after BDL are reduced in number compared to controls
• nervous system phenotype
• CNS inflammation (MGI Ref ID J:120427)
• brain inflammation (MGI Ref ID J:120427)
  • 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
• demyelination (MGI Ref ID J:120427)
  • 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)

Fas^lpr/Fas^lpr

        B6.MRL-Fas^lpr

• life span-post-weaning/aging
• premature death (MGI Ref ID J:6638)
  • median survival is 284 days, compared to 795 days for controls
  • 50% mortality is observed at 13.5 months with 90% mortality at 16 months, significantly reduced from wild-type
  • 64% survival at 24 weeks
• immune system phenotype
• abnormal lymph node morphology (MGI Ref ID J:7454)
  • larger lymph nodes often show extensive hemorrhage and necrosis
• enlarged lymph nodes (MGI Ref ID J:6638)
  • by 4 months of age, lymph nodes are increased 10- to 20-fold
  • nodes are 13 times normal size
  • generalized lymphadenopathy
• decreased interleukin-2 secretion (MGI Ref ID J:6638)
  • 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 spleen (MGI Ref ID J:135036)
• glomerulonephritis (MGI Ref ID J:7454)
  • 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 autoantibody level (MGI Ref ID J:7454)
  • increase in thymocytotoxic autoantibodies at 6 months is seen
  • mice have elevated levels of anti-chromatin antibodies compared to double mutants
• increased anti-nuclear antigen antibody level (MGI Ref ID J:6638)
  • anti-nuclear antibodies are present at 6 months of age
  • mice have significantly increased levels of anti-ssDNA antibodies
  • mice have elevated levels of anti-chromatin (anti-nucleosome) antibodies compared to double mutants
• increased anti-double stranded DNA antibody level (MGI Ref ID J:7454)
  • antibodies are increased relative to controls
• increased double-negative T cell number (MGI Ref ID J:135036)
• increased immunoglobulin level (MGI Ref ID J:7454)
  • IgG and IgM levels are increased in serum at 6 months
• renal/urinary system phenotype
• abnormal renal glomerulus morphology (MGI Ref ID J:7454)
  • nephritic changes consist of focal increase in mesangial substance and mild mesangial proliferation
• glomerulonephritis (MGI Ref ID J:7454)
  • 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
• hematopoietic system phenotype
• enlarged spleen (MGI Ref ID J:135036)
• increased double-negative T cell number (MGI Ref ID J:135036)

The following phenotype information may relate to a genetic background differing from this JAX^® Mice strain.

Fas^lpr/Fas^lpr

        MRL/Mp-Fas^lpr

• life span-post-weaning/aging
• premature death (MGI Ref ID J:13757)
  • mean age of death in females was 17 weeks of age
  • mean age of death in males was 22 weeks of age
  • life span of females is 120+/-4 days
  • life span of males is 154+/-32 days
  • 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
• immune system phenotype
• abnormal B cell morphology (MGI Ref ID J:108760)
  • frequency of C3d receptor bearing cells declines with age
• abnormal B cell receptor editing (MGI Ref ID J:131138)
  • Anti-dsDNA B cells escape receptor editing
• abnormal marginal zone B cell morphology (MGI Ref ID J:131138)
  • 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 (MGI Ref ID J:108760)
  • 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
  • the proliferating T cell population expresses cell surface markers that are normally expressed by B cells, in addition to normal T cell surface markers
  • mutant Lyt-2^- T cells express a cell surface marker that is also expressed on B cells
  • lymph node cells (T cell origin) are abnormal; cells are Ly-2^-/L3T4^-/surface Ig^-
• abnormal immune system organ morphology (MGI Ref ID J:28885)
• abnormal lymph node morphology (MGI Ref ID J:27634)
  • in mice with lymph node hyperplasia, larger nodes show extensive hemorrhage and cystic necrosis, which results in clinically observed terminal reduction in size
• abnormal lymph node cellularity (MGI Ref ID J:108760)
  • more than 90% of cells are positive for theta antigen
• lymph node hyperplasia (MGI Ref ID J:27634)
  • lymph nodes are up to 100 times normal size
• enlarged lymph nodes (MGI Ref ID J:108760)
  • 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
  • node architecture was blurred, with proliferation of lymphocytes with some admixture of plasma cells and histiocytes
  • no evidence of malignancy was present, despite enlargement
  • 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
• lymph node hyperplasia (MGI Ref ID J:27634)
  • lymph nodes are up to 100 times normal size
• abnormal marginal zone B cell morphology (MGI Ref ID J:131138)
  • mice have a larger marginal zone B cell population (10.8% of splenic lymphocytes) compared to BALB/c controls (1.9%)
• abnormal spleen cellularity (MGI Ref ID J:6257)
  • mice show 4- to 6-fold higher frequencies of immunoglobulin-secreting cells (IgSC) compared to normal controls
• abnormal thymus cortex morphology (MGI Ref ID J:28885)
  • atrophic cortex
• abnormal thymus medulla morphology (MGI Ref ID J:28885)
  • increase in thymus weight restricted to the medulla
• enlarged Peyer's patches (MGI Ref ID J:28885)
  • slight enlargement
• enlarged spleen (MGI Ref ID J:28885)
  • spleen is 7-fold larger than controls
• enlarged thymus (MGI Ref ID J:13757)
  • slighlty enlarged
• increased thymus weight (MGI Ref ID J:28885)
  • doubling of thymus weight
• thymus atrophy (MGI Ref ID J:27634)
  • thymic atrophy is observed; severity is most severe in the cortex but usually involves the medulla in most animals
  • initial lesion is loss of cortical thymocytes, with later degeneration (cystic) of thymocytes of medulla
  • in 5-10% of animals, there is medullary or stromal hyperplasia that maintains or increases the size of the thymus
• abnormal immune system physiology (MGI Ref ID J:28885)
• abnormal T cell physiology (MGI Ref ID J:8267)
  • cells do not generate CTL in response to stimulation with alloantigens
• abnormal T cell proliferation (MGI Ref ID J:8267)
  • cells do not proliferate in response to stimulation with alloantigens
• abnormal T-helper 2 physiology (MGI Ref ID J:6257)
  • activity of helper T cells is enhanced in older mice relative to younger animals or normal controls
• abnormal cytotoxic T cell physiology (MGI Ref ID J:7488)
  • 4-6 month old mice exhibit significantly depressed cytotoxic T cell response to alloantigens
• abnormal interleukin level (MGI Ref ID J:8267)
  • stimulation with concanavalin A does not induce cells to produce Il2
• decreased interleukin-2 secretion (MGI Ref ID J:6638)
  • 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
• glomerulonephritis (MGI Ref ID J:13757)
  • immune complex glomerulonephritis
  • glomerular lesions involve proliferation of both endothelial and mesangial cells and basement memebrane thickening
  • granular deposits of immunoglobulins present in the capillary walls
  • capsular cell proliferation, tubular damage, and casts were seen in severe lesions
  • mice show a largely subacute proliferative form of disease; lesions involve proliferation of endothelial and mesangial cells
• increased autoantibody level (MGI Ref ID J:28885)
  • thymocytoxic autoantibodies are detected with aging
• increased anti-erythrocyte antigen antibody level (MGI Ref ID J:27634)
  • levels reach 4 and 11% in males and females
• increased anti-nuclear antigen antibody level (MGI Ref ID J:28885)
  • antinuclear antibody titers are detectable at 8 weeks of age and increased rapidly
  • anti-Sm antibodies are detected in males and females but not in controls
  • anti-nuclear antigen antibody (ANA) activity in renal eluate Ig is much higher than activity in serum Ig for anti-ssDNA and anti-dsDNA
• increased anti-double stranded DNA antibody level (MGI Ref ID J:6257)
  • 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
  • significant levels of IgM and IgG antibodies that bind dsDNA antibodies are detected in mice 6-8 weeks of age
  • levels of these auto antibodies rise with age
• increased anti-single stranded DNA antibody level (MGI Ref ID J:27634)
  • detected at significant levels at 2 months, with very high levels detected at 4-5 months
• increased immunoglobulin level (MGI Ref ID J:28885)
  • hypergammaglobulinemia
  • mice show 4- to 6-fold higher frequencies of immunoglobulin-secreting cells in spleens compared to normal controls
• increased IgA level (MGI Ref ID J:28885)
  • 2-fold increase
• increased IgG level (MGI Ref ID J:27634)
  • at 2-3 months, concentration are up to 5 times control and 8 times control at 5 months
• increased IgG1 level (MGI Ref ID J:13757)
  • 10-fold increase
• increased IgG2a level (MGI Ref ID J:13757)
  • 10-fold increase
• increased IgG2b level (MGI Ref ID J:28885)
  • 2-fold increase
• increased IgM level (MGI Ref ID J:28885)
  • 2-fold increase
• increased susceptibility to autoimmune disorder (MGI Ref ID J:108760)
• salivary gland inflammation (MGI Ref ID J:21965)
  • 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⁺
  • 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
• thyroid inflammation (MGI Ref ID J:28171)
  • animals display thyroid gland infiltration (autoimmune thyroiditis)
• type III hypersensitivity reaction (MGI Ref ID J:28885)
  • perivascular infiltration of lymphocytes, plasma cells, and histiocytes in lung, kidney, salivary gland and liver
  • perivascular and peribronchial lymphoproliferation observed in lung reslting in patches of atelectasis and exudate containing patches
• vascular inflammation (MGI Ref ID J:28885)
  • arteritis is observed in a number of organs, and is associated with hemorrhage and infarcts in the lymph nodes
• renal/urinary system phenotype
• abnormal renal glomerulus morphology (MGI Ref ID J:27634)
  • between 2 and 5 months, granular IgG and C3 deposits increase in capillary wall and mesangium
• glomerulonephritis (MGI Ref ID J:13757)
  • immune complex glomerulonephritis
  • glomerular lesions involve proliferation of both endothelial and mesangial cells and basement memebrane thickening
  • granular deposits of immunoglobulins present in the capillary walls
  • capsular cell proliferation, tubular damage, and casts were seen in severe lesions
  • mice show a largely subacute proliferative form of disease; lesions involve proliferation of endothelial and mesangial cells
• proteinuria (MGI Ref ID J:28885)
  • incomplete penetrance, 50% of females tested have a 9-fold increase over controls
• skin/coat/nails phenotype
• skin lesions (MGI Ref ID J:28885)
  • lesions accompanied by hair loss and scab formation were common
  • erythemateous lesions of the ear often become necrotic
• homeostasis/metabolism phenotype
• abnormal circulating protein level (MGI Ref ID J:27634)
  • mice have high concentrations of circulating immune complex at 2-3 and 4-5 months
  • high levels of cyroglobulins are found in mice at 5 months
• hyperalbuminemia (MGI Ref ID J:28885)
• increased circulating total protein level (MGI Ref ID J:28885)
  • total serum protein levels are slightly increased
  • 2-fold increase in beta- and 5-fold increase in gamma-globulins
• abnormal interleukin level (MGI Ref ID J:8267)
  • stimulation with concanavalin A does not induce cells to produce Il2
• proteinuria (MGI Ref ID J:28885)
  • incomplete penetrance, 50% of females tested have a 9-fold increase over controls
• hematopoietic system phenotype
• abnormal B cell morphology (MGI Ref ID J:108760)
  • frequency of C3d receptor bearing cells declines with age
• abnormal B cell receptor editing (MGI Ref ID J:131138)
  • Anti-dsDNA B cells escape receptor editing
• abnormal marginal zone B cell morphology (MGI Ref ID J:131138)
  • 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 (MGI Ref ID J:108760)
  • 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
  • the proliferating T cell population expresses cell surface markers that are normally expressed by B cells, in addition to normal T cell surface markers
  • mutant Lyt-2^- T cells express a cell surface marker that is also expressed on B cells
  • lymph node cells (T cell origin) are abnormal; cells are Ly-2^-/L3T4^-/surface Ig^-
• abnormal T cell proliferation (MGI Ref ID J:8267)
  • cells do not proliferate in response to stimulation with alloantigens
• abnormal spleen cellularity (MGI Ref ID J:6257)
  • mice show 4- to 6-fold higher frequencies of immunoglobulin-secreting cells (IgSC) compared to normal controls
• abnormal thymus cortex morphology (MGI Ref ID J:28885)
  • atrophic cortex
• abnormal thymus medulla morphology (MGI Ref ID J:28885)
  • increase in thymus weight restricted to the medulla
• enlarged spleen (MGI Ref ID J:28885)
  • spleen is 7-fold larger than controls
• enlarged thymus (MGI Ref ID J:13757)
  • slighlty enlarged
• increased thymus weight (MGI Ref ID J:28885)
  • doubling of thymus weight
• thymus atrophy (MGI Ref ID J:27634)
  • thymic atrophy is observed; severity is most severe in the cortex but usually involves the medulla in most animals
  • initial lesion is loss of cortical thymocytes, with later degeneration (cystic) of thymocytes of medulla
  • in 5-10% of animals, there is medullary or stromal hyperplasia that maintains or increases the size of the thymus
• cardiovascular system phenotype
• abnormal cardiovascular system physiology (MGI Ref ID J:27634)
  • 15-30% of mice suffer old and/or acute myocardial infarction involving either ventricle and judged severe enough to contribute to death
• vascular inflammation (MGI Ref ID J:28885)
  • arteritis is observed in a number of organs, and is associated with hemorrhage and infarcts in the lymph nodes
• abnormal coronary artery morphology (MGI Ref ID J:27634)
• endocrine/exocrine gland phenotype
• *normal* endocrine/exocrine gland phenotype (MGI Ref ID J:18512)
  • 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
• abnormal gland morphology (MGI Ref ID J:18512)
  • dexamethasone treatment increases weight of lacrimal tissue compared to untreated mice; treatment results in a reduction in tear volume
• abnormal lacrimal gland morphology (MGI Ref ID J:18512)
  • adult lacrimal glands show infiltration by lymphocytes
  • treatment with steroids alleviates lymphocyte infiltration
• abnormal submandibular gland morphology (MGI Ref ID J:18512)
  • treatment with androgens increases gland weight in mutants
  • this treatment significantly decreases lymphocytic infiltration into submandibular glands
• abnormal thyroid gland morphology (MGI Ref ID J:28171)
  • inflamed tissue has massive infiltration organized into lymphoid follicle centers and extensive interstitially distributed lymphocytes
  • 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
• abnormal thyroid follicle morphology (MGI Ref ID J:28171)
  • marked decrease in follicle size is noted proceeding from center of lobe toward periphery
• salivary gland inflammation (MGI Ref ID J:21965)
  • 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⁺
  • 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
• thyroid inflammation (MGI Ref ID J:28171)
  • animals display thyroid gland infiltration (autoimmune thyroiditis)
• skeleton phenotype
• joint swelling (MGI Ref ID J:27634)
  • 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
• digestive/alimentary phenotype
• abnormal submandibular gland morphology (MGI Ref ID J:18512)
  • treatment with androgens increases gland weight in mutants
  • this treatment significantly decreases lymphocytic infiltration into submandibular glands
• salivary gland inflammation (MGI Ref ID J:21965)
  • 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⁺
  • 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
• vision/eye phenotype
• abnormal lacrimal gland morphology (MGI Ref ID J:18512)
  • adult lacrimal glands show infiltration by lymphocytes
  • treatment with steroids alleviates lymphocyte infiltration

Fas^lpr/Fas^lpr

        MRL/MpJ-Fas^lpr/J

• life span-post-weaning/aging
• premature death (MGI Ref ID J:7454)
  • 50% mortality is observed at 5 months with 90% mortality at 7.5 months, significantly reduced from wild-type
• immune system phenotype
• CNS inflammation (MGI Ref ID J:14151)
  • at 20 weeks, all mice show mononuclear infiltrates in the choroid plexus; at 10 weeks, all mice display monuclear infiltrates
• abnormal immunoglobulin level (MGI Ref ID J:122315)
  • 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 (MGI Ref ID J:122315)
  • production of anti-NP IgG is impaired in spleen cells
• increased immunoglobulin level (MGI Ref ID J:7454)
  • IgG and IgM levels are increased in serum at 6 months
  • mice display hypergammaglobulinemia; serum levels are comparable to Fas homozygotes
• abnormal lymph node morphology (MGI Ref ID J:7454)
  • larger lymph nodes often show extensive hemorrhage and necrosis
• enlarged lymph nodes (MGI Ref ID J:7454)
  • nodes are 62 times normal size
• conjunctivitis (MGI Ref ID J:123192)
• decreased immature B cell number (MGI Ref ID J:122315)
  • CD19+IgM+ immature B cells are reduced in the spleen
• decreased transitional stage B cell number (MGI Ref ID J:122315)
  • numbers of the T1 subset of B cells is reduced
• decreased mature B cell number (MGI Ref ID J:122315)
  • CD19+ IgD^high IgM^low B cells are severely reduced in the spleen
• decreased marginal zone B cell number (MGI Ref ID J:122315)
  • numbers of marginal zone (MZ) B cells is reduced
• decreased spleen germinal center number (MGI Ref ID J:122315)
  • staining intensity and number of germinal centers (GCs) is reduced 10 days post-challenge with NP-KLH antigen, compared to controls
• glomerulonephritis (MGI Ref ID J:7454)
  • severe immune complex glomerulonephritis develops by 6 months
  • mice show deposition of IgG or C3 in kidneys and inflammation, similar to Fas homozygotes
  • kidney lesions have lower scores than those in double mutants at 20 weeks
• increased autoantibody level (MGI Ref ID J:14151)
  • at 16 weeks, levels of anti-cardiolipin antibodies are significantly higher than in wild-type controls; levels are significantly higher at 8 weeks
• increased anti-nuclear antigen antibody level (MGI Ref ID J:111811)
  • 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)
  • at 16 weeks, anti-DNA titers are significantly higher than in wild-type controls
  • mice have significantly increased levels of anti-ssDNA antibodies
• increased anti-double stranded DNA antibody level (MGI Ref ID J:7454)
  • 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 neutrophil cell number (MGI Ref ID J:127199)
  • mild to moderated neutrophil accumulation is observed at 20 weeks
• increased plasma cell number (MGI Ref ID J:122315)
  • increased B220+IgM+ cells are observed in bone marrow; number of IgG-secreting cells are significantly increased compared to Fas^lpr homozygotes
• vasculitis (MGI Ref ID J:127199)
• hematopoietic system phenotype
• decreased immature B cell number (MGI Ref ID J:122315)
  • CD19+IgM+ immature B cells are reduced in the spleen
• decreased transitional stage B cell number (MGI Ref ID J:122315)
  • numbers of the T1 subset of B cells is reduced
• decreased mature B cell number (MGI Ref ID J:122315)
  • CD19+ IgD^high IgM^low B cells are severely reduced in the spleen
• decreased marginal zone B cell number (MGI Ref ID J:122315)
  • numbers of marginal zone (MZ) B cells is reduced
• decreased spleen germinal center number (MGI Ref ID J:122315)
  • staining intensity and number of germinal centers (GCs) is reduced 10 days post-challenge with NP-KLH antigen, compared to controls
• increased neutrophil cell number (MGI Ref ID J:127199)
  • mild to moderated neutrophil accumulation is observed at 20 weeks
• increased plasma cell number (MGI Ref ID J:122315)
  • increased B220+IgM+ cells are observed in bone marrow; number of IgG-secreting cells are significantly increased compared to Fas^lpr homozygotes
• renal/urinary system phenotype
• abnormal kidney physiology (MGI Ref ID J:127199)
  • progressive decline in renal function is observed, during progression to end-stage renal disease
• proteinuria (MGI Ref ID J:122315)
• albuminuria (MGI Ref ID J:122315)
  • mice have excessive urinary albumin compared to wild-type (>10-fold) at 3-4 months
• abnormal renal glomerulus morphology (MGI Ref ID J:7454)
  • 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
  • foot processes are only focally effaced
• abnormal mesangial cell (MGI Ref ID J:127199)
  • mild increase in mesangial cells and matrix is seen at 20 weeks of age
• cortical renal glomerulopathies (MGI Ref ID J:122315)
  • glomerulonephritic changes such as hypercellularity, lobularity, dilated capsules and crescent formation or enlarged glomeruli are observed in mice at 3-4 months
• glomerulonephritis (MGI Ref ID J:7454)
  • severe immune complex glomerulonephritis develops by 6 months
  • mice show deposition of IgG or C3 in kidneys and inflammation, similar to Fas homozygotes
  • kidney lesions have lower scores than those in double mutants at 20 weeks
• behavior/neurological phenotype
• abnormal spatial learning (MGI Ref ID J:14151)
  • 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
• impaired coordination (MGI Ref ID J:14151)
  • equilibrium is significantly impaired in mice at 18-20 weeks, as measured by performance in rotarod tests
• vision/eye phenotype
• *normal* vision/eye phenotype (MGI Ref ID J:123192)
• abnormal conjunctival epithelium (MGI Ref ID J:123192)
• conjunctivitis (MGI Ref ID J:123192)
• cardiovascular system phenotype
• abnormal cardiac muscle morphology (MGI Ref ID J:14151)
  • myocardium neighboring the heart valves shows mononuclear infiltration of the vessels, but valves are normal
• vasculitis (MGI Ref ID J:127199)
• hearing/vestibular/ear phenotype
• abnormal stria vascularis (MGI Ref ID J:3638)
  • slight degenerative changes in the stria vascularis of both the apical and basal turns
  • the basement membrane of the capillaries in the stria vascularis was thickened
  • widened intercellular space in the stria vascularis
  • the basal infolding of strial marginal cells
• abnormal strial intermediate cells (MGI Ref ID J:3638)
  • thinned intermediate cell layer
• decreased brainstem auditory evoked potential (MGI Ref ID J:3638)
  • 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
• muscle phenotype
• abnormal cardiac muscle morphology (MGI Ref ID J:14151)
  • myocardium neighboring the heart valves shows mononuclear infiltration of the vessels, but valves are normal
• nervous system phenotype
• CNS inflammation (MGI Ref ID J:14151)
  • at 20 weeks, all mice show mononuclear infiltrates in the choroid plexus; at 10 weeks, all mice display monuclear infiltrates
• homeostasis/metabolism phenotype
• abnormal enzyme/coenzyme activity (MGI Ref ID J:109815)
  • 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
  • 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
• proteinuria (MGI Ref ID J:122315)
• albuminuria (MGI Ref ID J:122315)
  • mice have excessive urinary albumin compared to wild-type (>10-fold) at 3-4 months
• pigmentation phenotype
• abnormal strial intermediate cells (MGI Ref ID J:3638)
  • thinned intermediate cell layer

Fas^lpr/Fas^lpr

        involves: C3H * MRL/Mp

• immune system phenotype
• autoimmune response (MGI Ref ID J:1060)
  • systemic autoimmune disease occurred at 2-3 months of age
  • characterized by elevated serum immune complexes, cryoglobulins, and antinuclear antibodies
• increased anti-nuclear antigen antibody level (MGI Ref ID J:34296)
  • beginning at 4 month of age
• increased susceptibility to systemic lupus erythematosus (MGI Ref ID J:34296)
  • beginning at 4 month of age
• increased spleen weight (MGI Ref ID J:34296)
  • at 2 months of age and on
• increased susceptibility to type III hypersensitivity reaction (MGI Ref ID J:34296)
  • beginning at 4 month of age
• hearing/vestibular/ear phenotype
• abnormal stria vascularis (MGI Ref ID J:1060)
  • 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
  • by 10 months of age, stria vascularis area was smaller
  • no degeneration of hair cells was seen at any age
  • edematous areas in the stria vascularis primarily in the basal turns due to enlarged extracellular spaces filled with fluid
  • 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
• abnormal stria vascularis vasculature (MGI Ref ID J:34296)
  • the stria capillaries often were larger than normal, and the endothelial cells were occasionally swollen or thickened due to hypertrophy and not hyperplasia
• decreased brainstem auditory evoked potential (MGI Ref ID J:1060)
  • the ABR thresholds of the 10-month-old mutant mice were significantly higher than those of wild-type C3H/HeJ controls
  • the 2- and 4-month-old mutant mice had normal auditory thresholds similar to control
  • after onset of systemic autoimmune disease at 3-4 months of age, threshold at 6 months were significantly elevated at 24 and 32 kHz
  • threshold continued to rise and by 8 months 16 kHz was elevated as well
  • threshold at the low frequencies (4 and 8 kHz) did not change with progression of systemic disease
• hematopoietic system phenotype
• increased spleen weight (MGI Ref ID J:34296)
  • at 2 months of age and on
• cardiovascular system phenotype
• abnormal stria vascularis vasculature (MGI Ref ID J:34296)
  • the stria capillaries often were larger than normal, and the endothelial cells were occasionally swollen or thickened due to hypertrophy and not hyperplasia

Fas^lpr/Fas^lpr

        MRL-Fas^lpr

• immune system phenotype
• abnormal T-helper 2 physiology (MGI Ref ID J:6257)
  • 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 (MGI Ref ID J:126261)
  • mean weight of axillary lymph nodes is 1.3 grams
• glomerulonephritis (MGI Ref ID J:126261)
  • lymphocyte infiltration, lobulation, and hyaline deposition noted in kidney
• increased anti-nuclear antigen antibody level (MGI Ref ID J:126261)
  • levels are elevated compared to wild-type mice
• increased anti-double stranded DNA antibody level (MGI Ref ID J:126261)
  • 30 fold higher than in mice without autoimmune disease
• increased immunoglobulin level (MGI Ref ID J:6257)
  • splenic cells in culture show four- to sixfold higher frequencies of spontaneous immunoglobulin release than controls
• increased IgG level (MGI Ref ID J:126261)
  • twice wild-type levels
• increased IgM level (MGI Ref ID J:126261)
  • about 1.7 fold higher than wild-type levels
• increased spleen weight (MGI Ref ID J:126261)
  • mean weight is 0.9 grams
• vasculitis (MGI Ref ID J:126261)
  • observed in kidneys with destruction of external elastic lamina common
• homeostasis/metabolism phenotype
• increased blood urea nitrogen level (MGI Ref ID J:126261)
  • mean levels are 52.4 mg/dl
• hematopoietic system phenotype
• increased spleen weight (MGI Ref ID J:126261)
  • mean weight is 0.9 grams
• cardiovascular system phenotype
• vasculitis (MGI Ref ID J:126261)
  • observed in kidneys with destruction of external elastic lamina common
• renal/urinary system phenotype
• glomerulonephritis (MGI Ref ID J:126261)
  • lymphocyte infiltration, lobulation, and hyaline deposition noted in kidney

Fas^lpr/Fas^lpr

        MRL.Cg-Irf1^tm1Mak Fas^lpr

• life span-post-weaning/aging
• premature death (MGI Ref ID J:114771)
  • mice typically die by 26 weeks of age from renal failure; 50% of mice are dead by 22 weeks
• renal/urinary system phenotype
• glomerulonephritis (MGI Ref ID J:114771)
  • at 26 weeks of age, mice show severe glomerulonephritis
  • mice show extensive glomerular deposition/staining of IgG and C3
• kidney failure (MGI Ref ID J:114771)
  • occurs around 26 weeks, leading to death
• proteinuria (MGI Ref ID J:114771)
  • by 24 weeks of age, 75% of mice have urine protein levels >200 mg/dl
• skin/coat/nails phenotype
• abnormal skin condition (MGI Ref ID J:114771)
  • mice show characteristic signs of skin disease at 24 weeks of age
• skin lesions (MGI Ref ID J:114771)
• epidermal necrosis (MGI Ref ID J:114771)
  • by 24 weeks, ear necrosis is observed in some mice
• immune system phenotype
• glomerulonephritis (MGI Ref ID J:114771)
  • at 26 weeks of age, mice show severe glomerulonephritis
  • mice show extensive glomerular deposition/staining of IgG and C3
• increased anti-double stranded DNA antibody level (MGI Ref ID J:114771)
  • at 26 weeks of age, levels are significantly higher relative to Fas^lpr, Irf1-null mice
• homeostasis/metabolism phenotype
• proteinuria (MGI Ref ID J:114771)
  • by 24 weeks of age, 75% of mice have urine protein levels >200 mg/dl

Fas^lpr/Fas^lpr

        C3.MRL-Fas^lpr/J

• life span-post-weaning/aging
• *normal* life span-post-weaning/aging (MGI Ref ID J:120650)
  • when placed under hyperoxic conditions for >5 days, mice do not show increased survival (resistance to hyperoxia) compared to wild-type mice
• premature death (MGI Ref ID J:7454)
  • 50% mortality is observed at 11.5 months with 90% mortality at 14 months, significantly reduced from wild-type
• hematopoietic system phenotype
• abnormal B cell activation (MGI Ref ID J:7454)
  • 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 (MGI Ref ID J:7454)
  • (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 (MGI Ref ID J:106288)
  • airway eosinophils are decreased with anti-Il5 teatment compared to contol IgG-teated animals at 96 hours
• immune system phenotype
• *normal* immune system phenotype (MGI Ref ID J:7454)
  • mice show normal spleen and lymph node cell cytotoxic T cell response to alloantigen
• abnormal B cell activation (MGI Ref ID J:7454)
  • 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 (MGI Ref ID J:7454)
  • (sIg^-, Ly-5(B220⁺) are present at 4 weeks of age in spleen and by 16-20 weeks, represent 80% of cells
• abnormal lymph node morphology (MGI Ref ID J:7454)
  • larger lymph nodes often show extensive hemorrhage and necrosis
• abnormal lymph node cellularity (MGI Ref ID J:7454)
  • 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^-)
• enlarged lymph nodes (MGI Ref ID J:7454)
  • nodes are 29 times normal size
• decreased eosinophil cell number (MGI Ref ID J:106288)
  • airway eosinophils are decreased with anti-Il5 teatment compared to contol IgG-teated animals at 96 hours
• decreased interleukin-2 secretion (MGI Ref ID J:7454)
  • after 6 weeks of age, spleen cells show significant decrease in ability to produce Il-2 induced by concanavalin A treatment
• glomerulonephritis (MGI Ref ID J:7454)
  • immune complex glomerulonephritis develops by 1 year of age but is much milder than in MRL homozygotes
• increased autoantibody level (MGI Ref ID J:7454)
  • marked increase in thymocytotoxic autoantibodies at 6 months is seen
• increased anti-nuclear antigen antibody level (MGI Ref ID J:7454)
  • mice have significantly increased levels of anti-ssDNA antibodies
• increased anti-double stranded DNA antibody level (MGI Ref ID J:7454)
  • antibodies are increased relative to controls
• increased immunoglobulin level (MGI Ref ID J:7454)
  • IgG and IgM levels are increased in serum at 6 months
• renal/urinary system phenotype
• abnormal renal glomerulus morphology (MGI Ref ID J:7454)
  • nephritic changes consist of focal increase in mesangial substance and mild mesangial proliferation
• glomerulonephritis (MGI Ref ID J:7454)
  • immune complex glomerulonephritis develops by 1 year of age but is much milder than in MRL homozygotes
• cellular phenotype
• increased apoptosis (MGI Ref ID J:106288)
  • a trend toward increased apoptosis in airways is observed in anti-Il5 treated mutants after IP-IN OVA challenge
• respiratory system phenotype
• abnormal airway responsiveness (MGI Ref ID J:106288)
  • 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

Fas^lpr/Fas^lpr

        AK.MRL-Fas^lpr

• immune system phenotype
• abnormal lymph node morphology (MGI Ref ID J:7454)
  • larger lymph nodes often show extensive hemorrhage and necrosis
• enlarged lymph nodes (MGI Ref ID J:7454)
  • nodes are 6 times normal size
• glomerulonephritis (MGI Ref ID J:7454)
  • immune complex glomerulonephritis develops by 1 year of age but is much milder than in MRL homozygotes
• increased autoantibody level (MGI Ref ID J:7454)
  • increase in thymocytotoxic autoantibodies at 6 months is seen
• increased anti-nuclear antigen antibody level (MGI Ref ID J:7454)
  • mice have significantly increased levels of anti-ssDNA antibodies
• increased anti-double stranded DNA antibody level (MGI Ref ID J:7454)
  • antibodies are increased relative to controls
• increased immunoglobulin level (MGI Ref ID J:7454)
  • IgG and IgM levels are modestly increased in serum at 6 months
• renal/urinary system phenotype
• abnormal renal glomerulus morphology (MGI Ref ID J:7454)
  • nephritic changes consist of focal increase in mesangial substance and mild mesangial proliferation
• glomerulonephritis (MGI Ref ID J:7454)
  • immune complex glomerulonephritis develops by 1 year of age but is much milder than in MRL homozygotes

Fas^lpr/Fas^lpr

        C3.MRL-Fas^lpr

• homeostasis/metabolism phenotype
• abnormal interleukin level (MGI Ref ID J:8267)
  • stimulation with concanavalin A does not induce cells to produce Il2
• immune system phenotype
• abnormal T cell morphology (MGI Ref ID J:8267)
  • lymph node cells (T cell origin) are abnormal; cells are Ly-2^-/L3T4^-/surface Ig^-
• abnormal T cell proliferation (MGI Ref ID J:8267)
  • cells do not proliferate in response to stimulation with alloantigens
• abnormal T cell physiology (MGI Ref ID J:8267)
  • cells do not generate CTL in response to stimulation with alloantigens
• abnormal T cell proliferation (MGI Ref ID J:8267)
  • cells do not proliferate in response to stimulation with alloantigens
• abnormal interleukin level (MGI Ref ID J:8267)
  • stimulation with concanavalin A does not induce cells to produce Il2
• lacrimal gland inflammation (MGI Ref ID J:1028)
  • 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 (MGI Ref ID J:1028)
• endocrine/exocrine gland phenotype
• *normal* endocrine/exocrine gland phenotype (MGI Ref ID J:1028)
  • submandibular gland inflammation is observed in most mice at 5 months, but differences compared to wild-type are not significant
  • no parotid gland inflammation is observed and only 1 animal showed sublingual gland inflammation at 5 months
  • 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
• salivary gland inflammation (MGI Ref ID J:1028)
• hematopoietic system phenotype
• abnormal T cell morphology (MGI Ref ID J:8267)
  • lymph node cells (T cell origin) are abnormal; cells are Ly-2^-/L3T4^-/surface Ig^-
• abnormal T cell proliferation (MGI Ref ID J:8267)
  • cells do not proliferate in response to stimulation with alloantigens
• vision/eye phenotype
• lacrimal gland inflammation (MGI Ref ID J:1028)
  • 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 (MGI Ref ID J:1028)
• cellular phenotype
• decreased apoptosis (MGI Ref ID J:114219)
  • vaginal cells treated with TNF or a Fas antibody do not undergo apoptosis but wild-type cells do
• nervous system phenotype
• decreased neuron apoptosis (MGI Ref ID J:124252)
  • 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 morphology (MGI Ref ID J:114219)
  • 2 days after gonadectomy, vaginae show no regression measured by a decrease in vaginal organ weight, indicating no vaginal cell death, in contrast to wild-type females that show >50% decrease in vaginal organ weight

Fas^lpr/Fas^lpr

        MRL/MpJ-Fas^lpr

• life span-post-weaning/aging
• premature death (MGI Ref ID J:137066)
  • 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
• hematopoietic system phenotype
• abnormal leukocyte morphology (MGI Ref ID J:126009)
  • 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 B cell number (MGI Ref ID J:137066)
• decreased CD4-positive T cell number (MGI Ref ID J:137066)
  • reduced compared to wild-type MRL animals
• decreased CD8-positive T cell number (MGI Ref ID J:137066)
  • reduced compared to wild-type MRL animals
• decreased activated T cell number (MGI Ref ID J:137066)
• increased double-negative T cell number (MGI Ref ID J:137066)
  • significantly increased relative to controls
• enlarged spleen (MGI Ref ID J:137066)
  • severe
• immune system phenotype
• abnormal leukocyte adhesion (MGI Ref ID J:126009)
  • significantly enhanced at 12 and 16 weeks
• abnormal leukocyte morphology (MGI Ref ID J:126009)
  • 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 B cell number (MGI Ref ID J:137066)
• decreased CD4-positive T cell number (MGI Ref ID J:137066)
  • reduced compared to wild-type MRL animals
• decreased CD8-positive T cell number (MGI Ref ID J:137066)
  • reduced compared to wild-type MRL animals
• decreased activated T cell number (MGI Ref ID J:137066)
• increased double-negative T cell number (MGI Ref ID J:137066)
  • significantly increased relative to controls
• abnormal leukocyte rolling (MGI Ref ID J:126009)
  • rolling is dramatically reduced, but not eliminated, in mutants compared to controls
  • in mice chronically treated with anti-E-selectin antibodies, rolling is completely eliminated
• autoimmune response (MGI Ref ID J:125114)
  • mice develop anti-nuclear antibodies (ie. anti-dsDNA, anti-ssDNA, etc)
• increased autoantibody level (MGI Ref ID J:137066)
  • IgG3 anti-IgG2a rheumatoid factor (RF) levels are much higher than wild-type controls
• increased anti-nuclear antigen antibody level (MGI Ref ID J:137066)
  • levels of anti-dsDNA and anti-chromatin autoantibodies are elevated compared to wild-type
• enlarged lymph nodes (MGI Ref ID J:137066)
  • severe
• enlarged spleen (MGI Ref ID J:137066)
  • severe
• glomerulonephritis (MGI Ref ID J:132514)
  • mice show deposition of IgG or C3 in kidneys and inflammation
• increased immunoglobulin level (MGI Ref ID J:125114)
  • mice develop hypergammaglobulinemia
• vascular inflammation (MGI Ref ID J:137066)
  • mice develop systemic necrotizing arteritis of small- and medium-sized arteries; frequently observed in kidneys
• cardiovascular system phenotype
• vascular inflammation (MGI Ref ID J:137066)
  • mice develop systemic necrotizing arteritis of small- and medium-sized arteries; frequently observed in kidneys
• renal/urinary system phenotype
• glomerulonephritis (MGI Ref ID J:132514)
  • mice show deposition of IgG or C3 in kidneys and inflammation

View Research Applications

Research Applications

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

Immunology and Inflammation Research
Autoimmunity (lupus erythematosus)

Fas^lpr related

Apoptosis Research
Death Receptors

Cancer Research
Genes Regulating Growth and Proliferation

Immunology and Inflammation Research
Autoimmunity (lupus erythematosus: rheumatoid arthritis)
Inflammation (rheumatoid arthritis)

Mouse/Human Gene Homologs
autoimmune lymphoproliferative syndrome

Genes & Alleles

Gene & Allele Information

Genotyping

Genotyping Information

Genotyping Protocols

Fas^lpr, SEP PCR, vers. 2

Helpful Links

Optimizing PCR Protocols

References

References

Selected Reference(s)

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):1198-215. [PubMed: 309911]  [MGI Ref ID J:27634]

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):10340-4. [PubMed: 7694292]  [MGI Ref ID J:15429]

Hewicker M; Kromschroder E; Trautwein G. 1990. Detection of circulating immune complexes in MRL mice with different forms of glomerulonephritis. Z Versuchstierkd 33(4):149-56. [PubMed: 2238887]  [MGI Ref ID 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):394-9. [PubMed: 1565490]  [MGI Ref ID 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):385-90. [PubMed: 7981049]  [MGI Ref ID J:19823]

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):674-81. [PubMed: 11441070]  [MGI Ref ID 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):2612-5. [PubMed: 6815273]  [MGI Ref ID 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):602-16. [PubMed: 2982991]  [MGI Ref ID J:7745]

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):2632-42. [PubMed: 8163351]  [MGI Ref ID 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):314-7. [PubMed: 1372394]  [MGI Ref ID J:1181]

Wigginton JM; Lee JK; Wiltrout TA; Alvord WG; Hixon JA; Subleski J; Back TC; Wiltrout RH. 2002. Synergistic engagement of an ineffective endogenous anti-tumor immune response and induction of IFN-gamma and Fas-ligand-dependent tumor eradication by combined administration of IL-18 and IL-2. J Immunol 169(8):4467-74. [PubMed: 12370382]  [MGI Ref ID J:109850]

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):235-40. [PubMed: 2489281]  [MGI Ref ID J:27853]

Additional References

Alexander CE; Kaye PM; Engwerda CR. 2001. CD95 is required for the early control of parasite burden in the liver of Leishmania donovani-infected mice. Eur J Immunol 31(4):1199-210. [PubMed: 11298345]  [MGI Ref ID J:68808]

Bowen DG; Warren A; Davis T; Hoffmann MW; McCaughan GW; De St Groth BF; Bertolino P. 2002. Cytokine-dependent bystander hepatitis due to intrahepatic murine CD8 T-cell activation by bone marrow-derived cells. Gastroenterology 123(4):1252-64. [PubMed: 12360486]  [MGI Ref ID J:79335]

Do Y; Rafi-Janajreh AQ; McKallip RJ; Nagarkatti PS; Nagarkatti M. 2003. Combined deficiency in CD44 and Fas leads to exacerbation of lymphoproliferative and autoimmune disease. Int Immunol 15(11):1327-40. [PubMed: 14565931]  [MGI Ref ID J:86310]

Fuller MJ; Khanolkar A; Tebo AE; Zajac AJ. 2004. Maintenance, loss, and resurgence of T cell responses during acute, protracted, and chronic viral infections. J Immunol 172(7):4204-14. [PubMed: 15034033]  [MGI Ref ID J:88714]

Jung KC; Park WS; Kim HJ; Choi EY; Kook MC; Lee HW; Bae Y. 2004. TCR-independent and caspase-independent apoptosis of murine thymocytes by CD24 cross-linking. J Immunol 172(2):795-802. [PubMed: 14707049]  [MGI Ref ID J:87358]

Kelley VE; Roths JB. 1985. Interaction of mutant lpr gene with background strain influences renal disease. Clin Immunol Immunopathol 37(2):220-9. [PubMed: 4042431]  [MGI Ref ID J:109439]

Kong PL; Morel L; Croker BP; Craft J. 2004. The centromeric region of chromosome 7 from MRL mice (Lmb3) is an epistatic modifier of Fas for autoimmune disease expression. J Immunol 172(5):2785-94. [PubMed: 14978078]  [MGI Ref ID J:88238]

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):578-84. [PubMed: 11590194]  [MGI Ref ID 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):380-7. [PubMed: 15004557]  [MGI Ref ID J:89208]

Mitchell DA; Pickering MC; Warren J; Fossati-Jimack L; Cortes-Hernandez J; Cook HT; Botto M; Walport MJ. 2002. C1q deficiency and autoimmunity: the effects of genetic background on disease expression. J Immunol 168(5):2538-43. [PubMed: 11859149]  [MGI Ref ID J:74721]

Nguyen QD; Uy HS; Merchant A; Medina CA; Baltatzis S; Zhao T; Zhao ZS; Cantor H; Foster CS. 2001. Effect of Fas and Fas ligand deficiency in resistance of C57BL/6 mice to HSV-1 keratitis and chorioretinitis. Invest Ophthalmol Vis Sci 42(11):2505-9. [PubMed: 11581190]  [MGI Ref ID J:72055]

Seagal J; Edry E; Naftali H; Melamed D. 2004. Generation and selection of an IgG-driven autoimmune repertoire during B-lymphopoiesis in Igmicro-deficient/lpr mice. Int Immunol 16(7):905-13. [PubMed: 15148286]  [MGI Ref ID J:90752]

Seagal J; Melamed D. 2004. Contribution of alphabeta and gammadelta T cells to the generation of primary immunoglobulin G-driven autoimmune response in immunoglobulin- mu-deficient/lpr mice. Immunology 112(2):265-73. [PubMed: 15147570]  [MGI Ref ID J:90503]

Ugolini G; Raoul C; Ferri A; Haenggeli C; Yamamoto Y; Salaun D; Henderson CE; Kato AC; Pettmann B; Hueber AO. 2003. Fas/tumor necrosis factor receptor death signaling is required for axotomy-induced death of motoneurons in vivo. J Neurosci 23(24):8526-31. [PubMed: 13679421]  [MGI Ref ID J:85525]

Wu X; Jiang N; Deppong C; Singh J; Dolecki G; Mao D; Morel L; Molina HD. 2002. A role for the Cr2 gene in modifying autoantibody production in systemic lupus erythematosus. J Immunol 169(3):1587-92. [PubMed: 12133988]  [MGI Ref ID J:78006]

Xiao S; Zhang X; Mann KK; Jodo S; Li L; Jarjour WN; Marshak-Rothstein A; Sherr DH; Ju ST. 2004. Changes in sensitivity of peripheral lymphocytes of autoimmune gld mice to FasL-mediated apoptosis reveal a mechanism for the preferential deletion of CD4-CD8-B220+ T cells. Int Immunol 16(5):759-66. [PubMed: 15096479]  [MGI Ref ID J:89570]

Yajima K; Nakamura A; Sugahara A; Takai T. 2003. FcgammaRIIB deficiency with Fas mutation is sufficient for the development of systemic autoimmune disease. Eur J Immunol 33(4):1020-9. [PubMed: 12672068]  [MGI Ref ID J:82862]

Yin Z; Bahtiyar G; Zhang N; Liu L; Zhu P; Robert ME; McNiff J; Madaio MP; Craft J. 2002. IL-10 regulates murine lupus. J Immunol 169(4):2148-55. [PubMed: 12165544]  [MGI Ref ID J:78239]

Fas^lpr related

Adachi K; Tsutsui H; Kashiwamura S; Seki E; Nakano H; Takeuchi O; Takeda K; Okumura K; Van Kaer L; Okamura H; Akira S; Nakanishi K. 2001. Plasmodium berghei infection in mice induces liver injury by an IL-12- and toll-like receptor/myeloid differentiation factor 88-dependent mechanism. J Immunol 167(10):5928-34. [PubMed: 11698470]  [MGI Ref ID J:118004]

Adachi M; Watanabe-Fukunaga R; Nagata S. 1993. Aberrant transcription caused by the insertion of an early transposable element in an intron of the Fas antigen gene of lpr mice. Proc Natl Acad Sci U S A 90(5):1756-60. [PubMed: 7680478]  [MGI Ref ID J:4342]

Aicher WK; Fujihashi K; Yamamoto M; Kiyono H; Pitts AM; McGhee JR. 1992. Effects of the lpr/lpr mutation on T and B cell populations in the lamina propria of the small intestine, a mucosal effector site. Int Immunol 4(9):959-68. [PubMed: 1390438]  [MGI Ref ID J:3154]

Akashi T; Nagafuchi S; Anzai K; Kitamura D; Wang J; Taniuchi I; Niho Y; Watanabe T. 1998. Proliferation of CD3+ B220- single-positive normal T cells was suppressed in B-cell-deficient lpr mice. Immunology 93(2):238-48. [PubMed: 9616374]  [MGI Ref ID J:45808]

Alarcon-Riquelme ME; Fernandez C. 1995. CDR3 regions in the preimmune VH B cell repertoire of lpr mice. Clin Exp Immunol 101(1):73-7. [PubMed: 7621595]  [MGI Ref ID J:26829]

Alarcon-Riquelme ME; Fernandez C. 1995. Expression of the B cell repertoire in lpr mice; abnormal expansion of a few VHJ558 germ-line genes. Clin Exp Immunol 99(2):262-8. [PubMed: 7851020]  [MGI Ref ID J:22861]

Alenzi FQ; Marley SB; Lewis JL; Chandrashekran A; Warrens AN; Goldman JM; Gordon MY. 2002. A role for the Fas/Fas ligand apoptotic pathway in regulating myeloid progenitor cell kinetics. Exp Hematol 30(12):1428-35. [PubMed: 12482505]  [MGI Ref ID J:118008]

Alexander JJ; Jacob A; Bao L; Macdonald RL; Quigg RJ. 2005. Complement-dependent apoptosis and inflammatory gene changes in murine lupus cerebritis. J Immunol 175(12):8312-9. [PubMed: 16339572]  [MGI Ref ID J:122254]

Alexander JJ; Jacob A; Vezina P; Sekine H; Gilkeson GS; Quigg RJ. 2007. Absence of functional alternative complement pathway alleviates lupus cerebritis. Eur J Immunol 37(6):1691-701. [PubMed: 17523212]  [MGI Ref ID J:123511]

Alexander JJ; Zwingmann C; Jacob A; Quigg R. 2007. Alteration in kidney glucose and amino acids are implicated in renal pathology in MRL/lpr mice. Biochim Biophys Acta 1772(10):1143-9. [PubMed: 17942282]  [MGI Ref ID J:130687]

Alexander JJ; Zwingmann C; Quigg R. 2005. MRL/lpr mice have alterations in brain metabolism as shown with [1H-13C] NMR spectroscopy. Neurochem Int 47(1-2):143-51. [PubMed: 15893408]  [MGI Ref ID J:129820]

Ali M; Weinreich M; Balcaitis S; Cooper CJ; Fink PJ. 2003. Differential regulation of peripheral CD4+ T cell tolerance induced by deletion and TCR revision. J Immunol 171(11):6290-6. [PubMed: 14634147]  [MGI Ref ID J:132828]

Allison J; Thomas HE; Catterall T; Kay TW; Strasser A. 2005. Transgenic expression of dominant-negative Fas-associated death domain protein in beta cells protects against Fas ligand-induced apoptosis and reduces spontaneous diabetes in nonobese diabetic mice. J Immunol 175(1):293-301. [PubMed: 15972661]  [MGI Ref ID J:100606]

Alsharifi M; Lobigs M; Simon MM; Kersten A; Muller K; Koskinen A; Lee E; Mullbacher A. 2006. NK cell-mediated immunopathology during an acute viral infection of the CNS. Eur J Immunol 36(4):887-96. [PubMed: 16541469]  [MGI Ref ID J:114787]

Altman A. 1994. Abnormal antigen receptor-initiated signal transduction in lpr T lymphocytes. Semin Immunol 6(1):9-17. [PubMed: 7513195]  [MGI Ref ID J:19053]

Amital H; Heilweil M; Ulmansky R; Szafer F; Bar-Tana R; Morel L; Foster MH; Mostoslavsky G; Eilat D; Pizov G; Naparstek Y. 2005. Treatment with a laminin-derived peptide suppresses lupus nephritis. J Immunol 175(8):5516-23. [PubMed: 16210660]  [MGI Ref ID J:119103]

Anderson CC; Mukherjee R; Sinclair NR; Jevnikar AM. 1997. Hypogammaglobulinaemia occurs in Fas-deficient MRL-lpr mice following deletion of MHC class II molecules. Clin Exp Immunol 109(3):473-9. [PubMed: 9328125]  [MGI Ref ID J:42959]

Apte RS; Richter J; Herndon J; Ferguson TA. 2006. Macrophages inhibit neovascularization in a murine model of age-related macular degeneration. PLoS Med 3(8):e310. [PubMed: 16903779]  [MGI Ref ID J:134144]

Arens R; Baars PA; Jak M; Tesselaar K; van der Valk M; van Oers MH; van Lier RA. 2005. Cutting edge: CD95 maintains effector T cell homeostasis in chronic immune activation. J Immunol 174(10):5915-20. [PubMed: 15879081]  [MGI Ref ID J:98994]

Ashany D; Savir A; Bhardwaj N; Elkon KB. 1999. Dendritic cells are resistant to apoptosis through the Fas (CD95/APO-1) pathway. J Immunol 163(10):5303-11. [PubMed: 10553053]  [MGI Ref ID J:118433]

Balasa B; Van Gunst K; Jung N; Balakrishna D; Santamaria P; Hanafusa T; Itoh N; Sarvetnick N. 2000. Islet-specific expression of IL-10 promotes diabetes in nonobese diabetic mice independent of Fas, perforin, TNF receptor-1, and TNF receptor-2 molecules. J Immunol 165(5):2841-9. [PubMed: 1094631