Mouse Genome Informatics
hm
    Faslpr/Faslpr
MRL/Mp-Faslpr
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
       
mortality/aging
• mean age of death in females was 17 weeks of age (J:13757)
• mean age of death in males was 22 weeks of age (J:13757)
• 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 (J:27634)
• life span of females is 120+/-4 days (J:28885)
• life span of males is 154+/-32 days (J:28885)

immune system
• frequency of C3d receptor bearing cells declines with age
• Anti-dsDNA B cells escape receptor editing
• the proliferating T cell population expresses cell surface markers that are normally expressed by B cells, in addition to normal T cell surface markers (J:6902)
• mutant Lyt-2- T cells express a cell surface marker that is also expressed on B cells (J:7094)
• lymph node cells (T cell origin) are abnormal; cells are Ly-2-/L3T4-/surface Ig- (J:8267)
• 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 (J:108760)
• mice have a larger marginal zone B cell population (10.8% of splenic lymphocytes) compared to BALB/c controls (1.9%)
• spleen is 7-fold larger than controls
• atrophic cortex (J:13757)
• increase in thymus weight restricted to the medulla
• slighlty enlarged
• doubling of thymus weight
• 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
• slight enlargement
• in mice with lymph node hyperplasia, larger nodes show extensive hemorrhage and cystic necrosis, which results in clinically observed terminal reduction in size
• mice show 4- to 6-fold higher frequencies of immunoglobulin-secreting cells (IgSC) compared to normal controls
• 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 (J:13757)
• node architecture was blurred, with proliferation of lymphocytes with some admixture of plasma cells and histiocytes (J:13757)
• no evidence of malignancy was present, despite enlargement (J:13757)
• 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 (J:27634)
• lymph nodes are up to 100 times normal size
• arteritis is observed in a number of organs, and is associated with hemorrhage and infarcts in the lymph nodes
• lymphocytic infiltration and lymphocytic foci are observed in mice 3.4-3.7 months of age (J:18512)
• 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 (J:18512)
• autoimmune sialodenitis with parenchymal destruction is observed in 4-6 month old mice in submandibular salivary glands of female mice (J:21965)
• most infiltrating cells are CD4+ and Vbeta8+ with a minority being CD4+ and Vbeta6+ (J:21965)
• animals display thyroid gland infiltration (autoimmune thyroiditis)
• mice show 4- to 6-fold higher frequencies of immunoglobulin-secreting cells in spleens compared to normal controls (J:6257)
• hypergammaglobulinemia (J:13757)
• 2-fold increase
• at 2-3 months, concentration are up to 5 times control and 8 times control at 5 months
• 10-fold increase (J:28885)
• 10-fold increase (J:28885)
• 2-fold increase
• 2-fold increase
• cells do not generate CTL in response to stimulation with alloantigens
• cells do not proliferate in response to stimulation with alloantigens
• activity of helper T cells is enhanced in older mice relative to younger animals or normal controls
• 4-6 month old mice exhibit significantly depressed cytotoxic T cell response to alloantigens
• stimulation with concanavalin A does not induce cells to produce Il2
• 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
• 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 (J:6638)
• mice have severe deficiency in Il-2 production (J:7488)
• thymocytoxic autoantibodies are detected with aging
• levels reach 4 and 11% in males and females
• anti-Sm antibodies are detected in males and females but not in controls (J:27634)
• anti-nuclear antigen antibody (ANA) activity in renal eluate Ig is much higher than activity in serum Ig for anti-ssDNA and anti-dsDNA (J:27634)
• antinuclear antibody titers are detectable at 8 weeks of age and increased rapidly (J:28885)
• 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. (J:6257)
• high levels detected at 4-5 months (J:27634)
• significant levels of IgM and IgG antibodies that bind dsDNA antibodies are detected in mice 6-8 weeks of age (J:131138)
• levels of these auto antibodies rise with age (J:131138)
• detected at significant levels at 2 months, with very high levels detected at 4-5 months
• immune complex glomerulonephritis (J:13757)
• mice show a largely subacute proliferative form of disease; lesions involve proliferation of endothelial and mesangial cells (J:27634)
• glomerular lesions involve proliferation of both endothelial and mesangial cells and basement membrane thickening (J:28885)
• granular deposits of immunoglobulins present in the capillary walls (J:28885)
• capsular cell proliferation, tubular damage, and casts were seen in severe lesions (J:28885)

renal/urinary system
• glomerular lesions involve proliferation of endothelial and mesangial cells
• incomplete penetrance, 50% of females tested have a 9-fold increase over controls
• glomerular basement membrane thickening
• between 2 and 5 months, granular IgG and C3 deposits increase in capillary wall and mesangium
• granular deposits of immunoglobulins present in the capillary walls
• proliferation of endothelial cells
• immune complex glomerulonephritis (J:13757)
• mice show a largely subacute proliferative form of disease; lesions involve proliferation of endothelial and mesangial cells (J:27634)
• glomerular lesions involve proliferation of both endothelial and mesangial cells and basement membrane thickening (J:28885)
• granular deposits of immunoglobulins present in the capillary walls (J:28885)
• capsular cell proliferation, tubular damage, and casts were seen in severe lesions (J:28885)
• proliferation of mesangial cells
• capsular cell proliferation is seen in severe glomerular lesions
• casts were seen in severe glomerular lesions

homeostasis/metabolism
• 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
• total serum protein levels are slightly increased
• 2-fold increase in beta- and 5-fold increase in gamma-globulins
• stimulation with concanavalin A does not induce cells to produce Il2
• incomplete penetrance, 50% of females tested have a 9-fold increase over controls

hematopoietic system
• frequency of C3d receptor bearing cells declines with age
• Anti-dsDNA B cells escape receptor editing
• mice have a larger marginal zone B cell population (10.8% of splenic lymphocytes) compared to BALB/c controls (1.9%)
• the proliferating T cell population expresses cell surface markers that are normally expressed by B cells, in addition to normal T cell surface markers (J:6902)
• mutant Lyt-2- T cells express a cell surface marker that is also expressed on B cells (J:7094)
• lymph node cells (T cell origin) are abnormal; cells are Ly-2-/L3T4-/surface Ig- (J:8267)
• 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 (J:108760)
• spleen is 7-fold larger than controls
• atrophic cortex (J:13757)
• increase in thymus weight restricted to the medulla
• slighlty enlarged
• doubling of thymus weight
• 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
• mice show 4- to 6-fold higher frequencies of immunoglobulin-secreting cells in spleens compared to normal controls (J:6257)
• hypergammaglobulinemia (J:13757)
• 2-fold increase
• at 2-3 months, concentration are up to 5 times control and 8 times control at 5 months
• 10-fold increase (J:28885)
• 10-fold increase (J:28885)
• 2-fold increase
• 2-fold increase
• cells do not generate CTL in response to stimulation with alloantigens
• cells do not proliferate in response to stimulation with alloantigens
• activity of helper T cells is enhanced in older mice relative to younger animals or normal controls
• 4-6 month old mice exhibit significantly depressed cytotoxic T cell response to alloantigens

cardiovascular system
• granular deposits of immunoglobulins present in the capillary walls
• proliferation of endothelial cells
• 15-30% of mice suffer old and/or acute myocardial infarction involving either ventricle and judged severe enough to contribute to death
• arteritis is observed in a number of organs, and is associated with hemorrhage and infarcts in the lymph nodes

endocrine/exocrine glands
N
• 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 (J:18512)
• lymphocytic infiltration and lymphocytic foci are observed in mice 3.4-3.7 months of age (J:18512)
• 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 (J:18512)
• autoimmune sialodenitis with parenchymal destruction is observed in 4-6 month old mice in submandibular salivary glands of female mice (J:21965)
• most infiltrating cells are CD4+ and Vbeta8+ with a minority being CD4+ and Vbeta6+ (J:21965)
• dexamethasone treatment increases weight of lacrimal tissue compared to untreated mice; treatment results in a reduction in tear volume
• treatment with androgens increases gland weight in mutants
• this treatment significantly decreases lymphocytic infiltration into submandibular glands
• adult lacrimal glands show infiltration by lymphocytes
• treatment with steroids alleviates lymphocyte infiltration
• 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
• marked decrease in follicle size is noted proceeding from center of lobe toward periphery
• animals display thyroid gland infiltration (autoimmune thyroiditis)

skeleton
• 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 system
• treatment with androgens increases gland weight in mutants
• this treatment significantly decreases lymphocytic infiltration into submandibular glands
• lymphocytic infiltration and lymphocytic foci are observed in mice 3.4-3.7 months of age (J:18512)
• 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 (J:18512)
• autoimmune sialodenitis with parenchymal destruction is observed in 4-6 month old mice in submandibular salivary glands of female mice (J:21965)
• most infiltrating cells are CD4+ and Vbeta8+ with a minority being CD4+ and Vbeta6+ (J:21965)

vision/eye
• adult lacrimal glands show infiltration by lymphocytes
• treatment with steroids alleviates lymphocyte infiltration

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

cellular
• glomerular lesions involve proliferation of endothelial and mesangial cells

Mouse Models of Human Disease
OMIM IDRef(s)
Autoimmune Lymphoproliferative Syndrome; ALPS 601859 J:28885
Sjogren Syndrome 270150 J:1028 , J:18512 , J:21965
Systemic Lupus Erythematosus; SLE 152700 J:27634 , J:28885 , J:108760 , J:131138