Mouse Genome Informatics
hm1
    Faslpr/Faslpr
AK.MRL-Faslpr
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
• IgG and IgM levels are modestly increased in serum at 6 months
• larger lymph nodes often show extensive hemorrhage and necrosis
• nodes are 6 times normal size
• increase in thymocytotoxic autoantibodies at 6 months is seen
• mice have significantly increased levels of anti-ssDNA antibodies
• antibodies are increased relative to controls
• Background Sensitivity: immune complex glomerulonephritis develops by 1 year of age but is much milder than in MRL homozygotes

renal/urinary system
• nephritic changes consist of focal increase in mesangial substance and mild mesangial proliferation
• Background Sensitivity: immune complex glomerulonephritis develops by 1 year of age but is much milder than in MRL homozygotes
• mild mesangial proliferation
• focal increase in mesangial substance

hematopoietic system
• IgG and IgM levels are modestly increased in serum at 6 months


Mouse Genome Informatics
hm2
    Faslpr/Faslpr
B6.Cg-Apoetm1Unc Faslpr
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cardiovascular system
N
• at 5 months, mice show no atherosclerotic lesions in the aorta when on a normal chow diet or after 5 weeks of a high-fat diet (J:121671)


Mouse Genome Informatics
hm3
    Faslpr/Faslpr
B6.MRL-Faslpr
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• median survival is 284 days, compared to 795 days for controls (J:6638)
• 50% mortality is observed at 13.5 months with 90% mortality at 16 months, significantly reduced from wild-type (J:7454)
• 64% survival at 24 weeks (J:135036)

immune system
• IgG and IgM levels are increased in serum at 6 months
• larger lymph nodes often show extensive hemorrhage and necrosis
• by 4 months of age, lymph nodes are increased 10- to 20-fold (J:6638)
• nodes are 13 times normal size (J:7454)
• generalized lymphadenopathy (J:135036)
• defect in Il2 activity begins during early life and worsens with age; spleen cells show no stimulated Il2 production upon stimulation with concanavalin A
• increase in thymocytotoxic autoantibodies at 6 months is seen (J:7454)
• mice have elevated levels of anti-chromatin antibodies compared to double mutants (J:135036)
• anti-nuclear antibodies are present at 6 months of age (J:6638)
• mice have significantly increased levels of anti-ssDNA antibodies (J:7454)
• mice have elevated levels of anti-chromatin (anti-nucleosome) antibodies compared to double mutants (J:135036)
• antibodies are increased relative to controls
• Background Sensitivity: immune complex glomerulonephritis develops by 1 year of age but is much milder than in MRL homozygotes (J:7454)
• interstitial lymphoid infiltration is observed at 6 months; glomerular IgG deposits that are exclusively mesangial are observed (J:135036)

renal/urinary system
• nephritic changes consist of focal increase in mesangial substance and mild mesangial proliferation
• Background Sensitivity: immune complex glomerulonephritis develops by 1 year of age but is much milder than in MRL homozygotes (J:7454)
• interstitial lymphoid infiltration is observed at 6 months; glomerular IgG deposits that are exclusively mesangial are observed (J:135036)
• mild mesangial proliferation
• focal increase in mesangial substance

hematopoietic system
• IgG and IgM levels are increased in serum at 6 months


Mouse Genome Informatics
hm4
    Faslpr/Faslpr
B6.MRL-Faslpr/J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
• after bile duct ligation (BDL), Peyer's patch B cells do not display evidence of apoptosis
• plasmablast numbers in spleen are increased relative to wild-type
• higher numbers of T2 B cells in spleen relative to wild-type
• higher in spleen relative to wild-type
• higher in spleen relative to wild-type, Faslpr homozygotes, and Bcl2l11-deficient mice
• T1:follicular B cell ratio is higher than wild-type or Bcl2l11-deficient mice
• total number of CD19+ splenocytes is higher than wild-type
• total number of splenocytes is increased relative to wild-type
• continuous treatment with recombinant murine IL12 results in sustained recruitment of NK cells to the liver
• mice develop less severe lymphadenopathy at later ages than the double mutant Igh-6/Fas mice
• total number of cells per lymph node is increased compared to wild-type
• total anti-IgM antibody levels are increased compared to wild-type
• anti-nuclear antibodies are increased compared to wild-type
• anti-ssDNA IgM and IgG antibodies are increased compared to wild-type
• increased compared to wild-type
• anti-ssDNA IgM and IgG antibodies are increased compared to wild-type
• 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
• 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 Faslgld mice
• inflammation and tissue damage in the brain are slightly greater than in control, resistant mice at 45 and 180 days

hematopoietic system
• after bile duct ligation (BDL), Peyer's patch B cells do not display evidence of apoptosis
• plasmablast numbers in spleen are increased relative to wild-type
• higher numbers of T2 B cells in spleen relative to wild-type
• higher in spleen relative to wild-type
• higher in spleen relative to wild-type, Faslpr homozygotes, and Bcl2l11-deficient mice
• T1:follicular B cell ratio is higher than wild-type or Bcl2l11-deficient mice
• total number of CD19+ splenocytes is higher than wild-type
• total number of splenocytes is increased relative to wild-type
• continuous treatment with recombinant murine IL12 results in sustained recruitment of NK cells to the liver

renal/urinary system
• higher numbers of apoptotic cells are detected in glomeruli compared to wild-type
• number of macrophages surrounding glomeruli is increased compared to wild-type which have no macrophage index
• IgG deposits mainly localized to glomerular basement membrane are increased relative to wild-type

liver/biliary system
• confluent foci of feathery hepatocyte degeneration due to bile acid cytotoxicity are significantly reduced compared to controls hours after BDL
• necroinflammatory foci after BDL are reduced in number compared to 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 (J:120559)
• 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 (J:120559)
• after BDL, necroinflammatory foci and lymphocytic infiltration are obviously less than in controls (J:135830)
• hepatocyte cell death is reduced compared to controls after BDL

nervous system
• 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
• 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)

cellular
• after bile duct ligation (BDL), Peyer's patch B cells do not display evidence of apoptosis
• higher numbers of apoptotic cells are detected in glomeruli compared to wild-type
• hepatocyte cell death is reduced compared to controls after BDL


Mouse Genome Informatics
hm5
    Faslpr/Faslpr
C3.MRL-Faslpr
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
homeostasis/metabolism
• stimulation with concanavalin A does not induce cells to produce Il2

immune system
• 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
• lymph node cells (T cell origin) are abnormal; cells are Ly-2-/L3T4-/surface Ig-
• cells do not generate CTL in response to stimulation with alloantigens
• cells do not proliferate in response to stimulation with alloantigens
• stimulation with concanavalin A does not induce cells to produce Il2

endocrine/exocrine glands
N
• submandibular gland inflammation is observed in most mice at 5 months, but differences compared to wild-type are not significant (J:1028)
• no parotid gland inflammation is observed and only 1 animal showed sublingual gland inflammation at 5 months (J:1028)
• 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 (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

hematopoietic system
• lymph node cells (T cell origin) are abnormal; cells are Ly-2-/L3T4-/surface Ig-
• cells do not generate CTL in response to stimulation with alloantigens
• cells do not proliferate in response to stimulation with alloantigens

vision/eye
• 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 system

cellular
• 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
• 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

nervous system
• 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
• 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 (J:114219)

Mouse Models of Human Disease
OMIM IDRef(s)
Sjogren Syndrome 270150 J:1028


Mouse Genome Informatics
hm6
    Faslpr/Faslpr
C3.MRL-Faslpr/J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
N
• when placed under hyperoxic conditions for >5 days, mice do not show increased survival (resistance to hyperoxia) compared to wild-type mice (J:120650)
• 50% mortality is observed at 11.5 months with 90% mortality at 14 months, significantly reduced from wild-type

hematopoietic system
• airway eosinophils are decreased with anti-Il5 teatment compared to contol IgG-teated animals at 96 hours
• 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
• (sIg-, Ly-5(B220+) are present at 4 weeks of age in spleen and by 16-20 weeks, represent 80% of cells
• IgG and IgM levels are increased in serum at 6 months

immune system
N
• mice show normal spleen and lymph node cell cytotoxic T cell response to alloantigen (J:7454)
• airway eosinophils are decreased with anti-Il5 teatment compared to contol IgG-teated animals at 96 hours
• 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
• (sIg-, Ly-5(B220+) are present at 4 weeks of age in spleen and by 16-20 weeks, represent 80% of cells
• IgG and IgM levels are increased in serum at 6 months
• larger lymph nodes often show extensive hemorrhage and necrosis
• nodes are 29 times normal size
• 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-)
• after 6 weeks of age, spleen cells show significant decrease in ability to produce Il-2 induced by concanavalin A treatment
• marked increase in thymocytotoxic autoantibodies at 6 months is seen
• mice have significantly increased levels of anti-ssDNA antibodies
• antibodies are increased relative to controls
• Background Sensitivity: immune complex glomerulonephritis develops by 1 year of age but is much milder than in MRL homozygotes

renal/urinary system
• nephritic changes consist of focal increase in mesangial substance and mild mesangial proliferation
• Background Sensitivity: immune complex glomerulonephritis develops by 1 year of age but is much milder than in MRL homozygotes
• mild mesangial proliferation
• focal increase in mesangial substance

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

respiratory system
• 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


Mouse Genome Informatics
hm7
    Faslpr/Faslpr
involves: 129P2/OlaHsd * MRL
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• about 10% of mice are moribund by 16 weeks of age

immune system
• develop massive lymphadenopathy due to alpha beta DN T cell accumulation
• develop massive lymphadenopathy due to alpha beta DN T cell accumulation
• periglomerular infiltration

homeostasis/metabolism
• significantly elevated
• compared to age-matched B10.A mice

renal/urinary system
• compared to age-matched B10.A mice
• periglomerular infiltration
• glomerular hypercellularity

hematopoietic system
• develop massive lymphadenopathy due to alpha beta DN T cell accumulation


Mouse Genome Informatics
hm8
    Faslpr/Faslpr
involves: C3H * MRL/Mp
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
• at 2 months of age and on
• systemic autoimmune disease occurred at 2-3 months of age
• characterized by elevated serum immune complexes, cryoglobulins, and antinuclear antibodies
• beginning at 4 month of age

hearing/vestibular/ear
• degeneration of the stria vascularis was seen starting at 2 month and progressed throughout the lifespan (J:1060)
• early edema of the stria occurred in the apex and progressed basalward (J:1060)
• by 10 months of age, stria vascularis area was smaller (J:1060)
• no degeneration of hair cells was seen at any age (J:1060)
• edematous areas in the stria vascularis primarily in the basal turns due to enlarged extracellular spaces filled with fluid (J:34296)
• 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 (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
• the ABR thresholds of the 10-month-old mutant mice were significantly higher than those of wild-type C3H/HeJ controls (J:1060)
• the 2- and 4-month-old mutant mice had normal auditory thresholds similar to control (J:34296)
• after onset of systemic autoimmune disease at 3-4 months of age, threshold at 6 months were significantly elevated at 24 and 32 kHz (J:34296)
• threshold continued to rise and by 8 months 16 kHz was elevated as well (J:34296)
• threshold at the low frequencies (4 and 8 kHz) did not change with progression of systemic disease (J:34296)

hematopoietic system
• at 2 months of age and on

cardiovascular system
• the stria capillaries often were larger than normal, and the endothelial cells were occasionally swollen or thickened due to hypertrophy and not hyperplasia


Mouse Genome Informatics
hm9
    Faslpr/Faslpr
involves: C57BL/6 * MRL/Mp
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
• at day 175 and 275 compared with wild-type mice
• at day 175 and 275 compared with wild-type mice
• at day 175 and 275 compared with wild-type mice
• at day 175 and 275 compared with wild-type mice
• at day 175 and 275 compared with wild-type mice
• at day 175 and 275 compared with wild-type mice
• at day 175 and 275 compared with wild-type mice
• at day 175 and 275 compared with wild-type mice

hematopoietic system
• at day 175 and 275 compared with wild-type mice
• at day 175 and 275 compared with wild-type mice
• at day 175 and 275 compared with wild-type mice
• at day 175 and 275 compared with wild-type mice
• at day 175 and 275 compared with wild-type mice
• at day 175 and 275 compared with wild-type mice
• at day 175 and 275 compared with wild-type mice


Mouse Genome Informatics
hm10
    Faslpr/Faslpr
involves: MRL/Mp
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• mice exhibit increased Pseudomonas aerugiosa exotoxin-induced mortality compared with similarly treated wild-type mice

immune system
• macrophages exhibit 60% less cholesterol-induced apoptosis compared with similarly treated wild-type cells
• mice exhibit increased Pseudomonas aerugiosa exotoxin-induced mortality compared with similarly treated wild-type mice

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

hematopoietic system
• macrophages exhibit 60% less cholesterol-induced apoptosis compared with similarly treated wild-type cells


Mouse Genome Informatics
hm11
    Faslpr/Faslpr
MRL-Faslpr
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
• observed in kidneys with destruction of external elastic lamina common
• mean weight is 0.9 grams
• splenic cells in culture show four- to sixfold higher frequencies of spontaneous immunoglobulin release than controls
• twice wild-type levels
• about 1.7 fold higher than wild-type levels
• 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
• mean weight of axillary lymph nodes is 1.3 grams
• levels are elevated compared to wild-type mice
• 30 fold higher than in mice without autoimmune disease
• lymphocyte infiltration, lobulation, and hyaline deposition noted in kidney

homeostasis/metabolism
• mean levels are 52.4 mg/dl

hematopoietic system
• mean weight is 0.9 grams
• splenic cells in culture show four- to sixfold higher frequencies of spontaneous immunoglobulin release than controls
• twice wild-type levels
• about 1.7 fold higher than wild-type levels
• 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

cardiovascular system
• observed in kidneys with destruction of external elastic lamina common

renal/urinary system
• lymphocyte infiltration, lobulation, and hyaline deposition noted in kidney


Mouse Genome Informatics
hm12
    Faslpr/Faslpr
MRL.Cg-Irf1tm1Mak Faslpr
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• mice typically die by 26 weeks of age from renal failure; 50% of mice are dead by 22 weeks

renal/urinary system
• by 24 weeks of age, 75% of mice have urine protein levels >200 mg/dl
• at 26 weeks of age, mice show severe glomerulonephritis
• mice show extensive glomerular deposition/staining of IgG and C3
• occurs around 26 weeks, leading to death

immune system
• at 26 weeks of age, levels are significantly higher relative to Faslpr, Irf1-null mice
• at 26 weeks of age, mice show severe glomerulonephritis
• mice show extensive glomerular deposition/staining of IgG and C3

homeostasis/metabolism
• by 24 weeks of age, 75% of mice have urine protein levels >200 mg/dl

integument
• by 24 weeks, ear necrosis is observed in some mice
• mice show characteristic signs of skin disease at 24 weeks of age


Mouse Genome Informatics
hm13
    Faslpr/Faslpr
MRL.Cg-Tnfrsf9tm1Byk Faslpr
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• by 5 months, 40% mortality is observed

integument
• by 5 months, skin lesions develop around tip of nose and around the ears


Mouse Genome Informatics
hm14
    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)
• 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 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
• 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
• 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
• 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
• 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
• 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
• 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 Genome Informatics
hm15
    Faslpr/Faslpr
MRL/Mp-Faslpr atms
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
growth/size
• body weight is increased by 3 weeks of age in homozygotes that may or may not be heterozygous for atms

hematopoietic system

immune system
• develop lymphadenopathy

tumorigenesis
• develop subcutaneous tumors

integument
• ruffled hair due to superficial prominent lymphadenopathy

endocrine/exocrine glands


Mouse Genome Informatics
hm16
    Faslpr/Faslpr
MRL/MpJ-Faslpr
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• animals start to die at 4.5 months, with >50% mortality observed at 7 months (J:125114)
• 50% mortality by 20 weeks; <40% survival beyond 40 weeks (J:137066)

hematopoietic system
• 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
• significantly enhanced at 12 and 16 weeks
• 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
• reduced compared to wild-type MRL animals
• reduced compared to wild-type MRL animals
• significantly increased relative to controls
• severe
• mice develop hypergammaglobulinemia

immune system
• mice develop systemic necrotizing arteritis of small- and medium-sized arteries; frequently observed in kidneys
• 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
• significantly enhanced at 12 and 16 weeks
• 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
• reduced compared to wild-type MRL animals
• reduced compared to wild-type MRL animals
• significantly increased relative to controls
• severe
• mice develop hypergammaglobulinemia
• mice develop anti-nuclear antibodies (ie. anti-dsDNA, anti-ssDNA, etc)
• IgG3 anti-IgG2a rheumatoid factor (RF) levels are much higher than wild-type controls
• levels of anti-dsDNA and anti-chromatin autoantibodies are elevated compared to wild-type
• mice show deposition of IgG or C3 in kidneys and inflammation (J:125114)

cardiovascular system
• mice develop systemic necrotizing arteritis of small- and medium-sized arteries; frequently observed in kidneys

renal/urinary system
• mice show deposition of IgG or C3 in kidneys and inflammation (J:125114)

cellular
• 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
• significantly enhanced at 12 and 16 weeks


Mouse Genome Informatics
hm17
    Faslpr/Faslpr
MRL/MpJ-Faslpr/J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• 50% mortality is observed at 5 months with 90% mortality at 7.5 months, significantly reduced from wild-type

immune system
• mild to moderated neutrophil accumulation is observed at 20 weeks
• CD19+IgM+ immature B cells are reduced in the spleen
• numbers of the T1 subset of B cells is reduced
• CD19+ IgDhigh IgMlow B cells are severely reduced in the spleen
• numbers of marginal zone (MZ) B cells is reduced
• increased B220+IgM+ cells are observed in bone marrow; number of IgG-secreting cells are significantly increased compared to Faslpr homozygotes
• staining intensity and number of germinal centers (GCs) is reduced 10 days post-challenge with NP-KLH antigen, compared to controls
• 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
• production of anti-NP IgG is impaired in spleen cells
• IgG and IgM levels are increased in serum at 6 months (J:7454)
• mice display hypergammaglobulinemia; serum levels are comparable to Fas homozygotes (J:122315)
• mice exhibit increased serum IgG levels and IgG deposits in the kidney unlike wild-type mice
• larger lymph nodes often show extensive hemorrhage and necrosis
• nodes are 62 times normal size (J:7454)
• 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
• at 16 weeks, levels of anti-cardiolipin antibodies are significantly higher than in wild-type controls; levels are significantly higher at 8 weeks (J:14151)
• mice exhibit increased serum levels of kappa-chain rheumatoid factor compared to in wild-type mice (J:92084)
• mice have significantly increased levels of anti-ssDNA antibodies (J:7454)
• at 16 weeks, anti-DNA titers are significantly higher than in wild-type controls (J:14151)
• DNA auto-antibodies are increased compared to in wild-type mice at 12 weeks (J:92084)
• by 5-6 months of age, Fas-deficient mice have antinuclear antibody (ANA) levels comparable to >50% of C4b-deficient females (on Ighb haplotype homozygous background) (J:111811)
• antibodies are increased relative to controls and other mutant strains with Faslpr mutations (J:7454)
• mice produce high titers of IgG1 and IgG2a anti-dsDNA antibodies, comparable to Fas homozygotes (J:122315)
• at 20 weeks, all mice show mononuclear infiltrates in the choroid plexus; at 10 weeks, all mice display monuclear infiltrates
• Background Sensitivity: severe immune complex glomerulonephritis develops by 6 months (J:7454)
• mice show deposition of IgG or C3 in kidneys and inflammation, similar to Fas homozygotes (J:122315)
• kidney lesions have lower scores than those in double mutants at 20 weeks (J:127199)

hematopoietic system
• mild to moderated neutrophil accumulation is observed at 20 weeks
• CD19+IgM+ immature B cells are reduced in the spleen
• numbers of the T1 subset of B cells is reduced
• CD19+ IgDhigh IgMlow B cells are severely reduced in the spleen
• numbers of marginal zone (MZ) B cells is reduced
• increased B220+IgM+ cells are observed in bone marrow; number of IgG-secreting cells are significantly increased compared to Faslpr homozygotes
• staining intensity and number of germinal centers (GCs) is reduced 10 days post-challenge with NP-KLH antigen, compared to controls
• 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
• production of anti-NP IgG is impaired in spleen cells
• IgG and IgM levels are increased in serum at 6 months (J:7454)
• mice display hypergammaglobulinemia; serum levels are comparable to Fas homozygotes (J:122315)
• mice exhibit increased serum IgG levels and IgG deposits in the kidney unlike wild-type mice

renal/urinary system
• mice have excessive urinary albumin compared to wild-type (>10-fold) at 3-4 months
• foot processes are only focally effaced
• dilated capsules are observed in mice at 3-4 months
• abnormalities due to severe glomerulonephritis (J:7454)
• at 20 weeks, lesions show some neutrophil infiltration and hypercellularity (J:127199)
• tuft necrosis, capsular proliferation and fibrosis are less common and less severe than observed in double mutants (J:127199)
• mild increase in mesangial cells is seen at 20 weeks of age
• mild increase in mesangial matrix is seen at 20 weeks of age
• glomerulonephritic changes such as hypercellularity, lobularity, dilated capsules and crescent formation or enlarged glomeruli are observed in mice at 3-4 months
• Background Sensitivity: severe immune complex glomerulonephritis develops by 6 months (J:7454)
• mice show deposition of IgG or C3 in kidneys and inflammation, similar to Fas homozygotes (J:122315)
• kidney lesions have lower scores than those in double mutants at 20 weeks (J:127199)
• crescent formation is observed in mice at 3-4 months
• enlarged glomeruli are observed in mice at 3-4 months
• progressive decline in renal function is observed, during progression to end-stage renal disease

behavior/neurological
• 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
• equilibrium is significantly impaired in mice at 18-20 weeks, as measured by performance in rotarod tests

vision/eye

cardiovascular system
• myocardium neighboring the heart valves shows mononuclear infiltration of the vessels, but valves are normal

hearing/vestibular/ear
• 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
• thinned intermediate cell layer
• 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

nervous system
• at 20 weeks, all mice show mononuclear infiltrates in the choroid plexus; at 10 weeks, all mice display monuclear infiltrates

homeostasis/metabolism
• mice have excessive urinary albumin compared to wild-type (>10-fold) at 3-4 months
• 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

pigmentation
• thinned intermediate cell layer

digestive/alimentary system

endocrine/exocrine glands

Mouse Models of Human Disease
OMIM IDRef(s)
Sjogren Syndrome 270150 J:123192


Mouse Genome Informatics
hm18
    Faslpr/Faslpr
NOD.MRL(B6)-Faslpr
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
• during the 24 week period, no animals show diabetes or insulitis (mice are considered diabetic after a blood glucose measure of >300 mg/dl)

Mouse Models of Human Disease
OMIM IDRef(s)
NOT Diabetes Mellitus, Insulin-Dependent; IDDM 222100 J:64051


Mouse Genome Informatics
hm19
    Faslpr/Faslpr
NOD.MRL-Faslpr
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
• when mice are injected with islet specific CD8+ T cell clones, Faslpr mice are resistant to diabetogenic effect of injected T cells; 0/5 of Fas mutants are diabetic within 20 day observation period, while control NOD littermates become diabetic within 6 days


Mouse Genome Informatics
ht20
    Faslpr/Fastm1.1Cgn
involves: C57BL/6 * MRL
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
hematopoietic system

immune system
• develop the typical Faslpr homozygous phenotype


Mouse Genome Informatics
cn21
    Cd19tm1(cre)Cgn/Cd19+
Faslpr/Fastm1Cgn
Tg(Cd4-cre)1Cwi/0

involves: 129P2/OlaHsd * C57BL/6 * DBA/2 * MRL
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
• similar to mice with recombination only in T cells
• similar to mice with recombination only in T cells
• similar to mice with recombination only in T cells

hematopoietic system
• similar to mice with recombination only in T cells
• similar to mice with recombination only in T cells


Mouse Genome Informatics
cn22
    Cd19tm1(cre)Cgn/Cd19+
Faslpr/Fastm1Cgn

involves: 129P2/OlaHsd * C57BL/6 * MRL
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
• 5-fold enlargement
• 17-fold enlargement in the lymph nodes
• weight of the enlarged lymph nodes is still 200- to 300-fold less than in Fastm1.1Cgn Faslpr trans-heterozygous mice

hematopoietic system
• 5-fold enlargement


Mouse Genome Informatics
cn23
    Faslpr/Fastm1Cgn
Tg(Cd4-cre)1Cwi/0

involves: C57BL/6 * DBA/2 * MRL
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
• 4 of 5 mice had 2 fold enlargement
• 12-fold enlargement in the lymph nodes
• weight of the enlarged lymph nodes is still 200- to 300-fold less than in Fastm1.1Cgn Faslpr trans-heterozygous mice

hematopoietic system
• 4 of 5 mice had 2 fold enlargement


Mouse Genome Informatics
cx24
    Apoetm1Unc/Apoetm1Unc
Faslpr/Faslpr

B6.Cg-Apoetm1Unc Faslpr
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
hematopoietic system
N
• at 5 months, there are no significant differences in most leukocyte subsets (NK-cells, monocytes/macrophages, and neutrophils) compared to controls (J:121671)
• numbers of circulating cells are significantly reduced
• numbers of circulating cells are significantly reduced comparted to Apoe-wt, Fas-homozygous mice at 5 months
• significantly enlarged compared to Apoe-null, Fas-heterozygous mice or Apoe-wt, Fas-homozygous mice at 5 months
• serum levels of IgG are significantly higher than in Apoe-null and Apoe-null, Fas-heterozygous mice at 6 weeks and at 5 months

immune system
• numbers of circulating cells are significantly reduced
• numbers of circulating cells are significantly reduced comparted to Apoe-wt, Fas-homozygous mice at 5 months
• significantly enlarged compared to Apoe-null, Fas-heterozygous mice or Apoe-wt, Fas-homozygous mice at 5 months
• serum levels of IgG are significantly higher than in Apoe-null and Apoe-null, Fas-heterozygous mice at 6 weeks and at 5 months
• serum antibodies against oxidized phospholipid (OxPL) are decreased compared to Apoe-wt, Fas-homozygous and Apoe-null, Fas-wt controls
• levels of IgG anti-cardiolipin antibodies are increased at 5 months relative to controls
• levels of IgG anti-POVPC and anti-PGPC autoantibodies are significantly higher than in controls at 5 months; IgM anti-POVPC levels are increased also
• serum levels of IgG anti-dsDNA antibodies are significantly higher than in Apoe-null, Fas-wt controls and Apoe-null, Fas-heterozygous mice at 6 weeks and at 5 months
• renal damage is observed, with IgG and C3 deposits present in the mesangium and peripheral capillary loops

renal/urinary system
• at 5 months, renal sections show an increase in apoptotic cells
• increased apoptotic cells are seen in renal tubules at 5 months
• proteinuria is increased compared to Fas-homozygous controls; proteinuria is not evident at 1 month of age
• renal damage is observed, with IgG and C3 deposits present in the mesangium and peripheral capillary loops
• proliferation of glomerular cells and lobule formation are observed
• glomerular tuft areas are enlarged compared to controls

cardiovascular system
• IgG deposition in thickened aortic intimas is seen at 5 months, but is not observed in controls; neglible complement C3 deposition is observed in double homozygotes
• increased lesion area at aortic valves in mice on a normal chow diet compared to Apoe-null, Fas-wt controls
• increase in apoptotic cells in vessel walls of heart (in vascular lesions) is observed at 5 months relative to controls

limbs/digits/tail
• femoral BMD in females is lower than in Apoe-null, Fas-wt controls at 5 months and at 9 months

skeleton
• femoral BMD in females is lower than in Apoe-null, Fas-wt controls at 5 months and at 9 months
• at 5 months, vertebrae BMD trends to lower values than controls; at 9 months, BMD is significantly lower
• all limbs of female mutants have lower bone mineral densities (BMD) than male mutants at 5 months of age; ostopenia is similar to Apoe-wt, Fas-null mice at 5 months
• femoral BMD is lower in females than controls at 5 months and 9 months; vertebrae BMD shows a similar trend at 5 months and is lower at 9 months
• at 9 months, a progressive decrease in trabecular bones (BV/TV, connectivity density, trabecular number, trabecular thickness) is observed in females compared to female Apoe-null, Fas-wt controls

homeostasis/metabolism
• total serum cholesterol and unesterified cholesterol levels are lower than Apoe-null, Fas-wt controls
• proteinuria is increased compared to Fas-homozygous controls; proteinuria is not evident at 1 month of age

cellular
• at 5 months, renal sections show an increase in apoptotic cells
• increased apoptotic cells are seen in renal tubules at 5 months

endocrine/exocrine glands


Mouse Genome Informatics
cx25
    Bcl2l11tm1.1Ast/Bcl2l11tm1.1Ast
Faslpr/Faslpr

B6.Cg-Bcl2l11tm1.1Ast Faslpr
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
• increased in spleen relative to Faslpr homozygotes
• lower in spleen and lymph node compared to wild-type or single mutants
• mice show reduced amount of naż×e T cells compared to wild-type or Bcl2l11-deficient mice
• no difference in number of regulatory T cells is observed
• T cell subpopulations in the spleen and lymph nodes including single-positive, central memory and effector memory T cells are increased compared to single-deficient mice
• increased memory T cell numbers in spleen and lymph nodes relative to single mutant animals
• number of CD45+ cells is increased 4.6-fold vs wild-type, 3.2-fold vs Faslpr homozygotes, and 2.8-fold vs Bcl2l11-deficient mice
• plasmablast numbers in spleen are increased 30-fold relative to wild-type, 2-fold relative to Bcl2l11-deficient and 4-fold relative to Faslpr homozygous mice
• number of T1 and T2 B cells is increased relative to wild-type, Faslpr homozygotes, and Bcl2l11-deficient mice
• higher in spleen relative to wild-type, Faslpr homozygotes, and Bcl2l11-deficient mice
• higher in spleen relative to wild-type, Faslpr homozygotes, and Bcl2l11-deficient mice
• increased numbers in spleen and lymph nodes are observed
• increased effector memory T cell numbers in spleen and lymph nodes relative to single mutant animals
• enlargement of spleen is accompanied by alteration of spleen architecture, characterized by decreased red pulp amount
• severely enlarged by 16 weeks
• enlargement of spleen is accompanied by alteration of spleen architecture, characterized by increased white pulp amount
• T1:follicular B cell ratio is disturbed; ratio is higher significantly higher than wild-type, Bcl2l11-deficient mice or Faslpr homozygotes
• increased B cell number; CD19+ B cells are increased by 4.3-fold over wild-type, 1.8-fold over Bcl2l11-null mice and by 3.6-fold over Faslpr mice
• CD19+ B cells are increased 2.2-fold over wild-type and Bcl2l11-deficient mice
• no difference from B cell number in Faslpr mice
• severely enlarged by 16 weeks
• on a normally resistant background, mice develop extreme lymphadenopathy and SLE
• total anti-IgM and total anti-IgG antibody levels are increased compared to wild-type, Faslpr homozygotes, and Bcl2l11-deficient mice; anti-nuclear, anti-cytoplasmic and anti-glomerular antibodies are increased relative to wild-type, Faslpr homozygotes, and Bcl2l11-deficient mice
• anti-nuclear antibodies are increased compared to wild-type, Faslpr homozygotes, and Bcl2l11-deficient mice
• anti-dsDNA IgM and IgG antibodies are increased compared to wild-type and Bcl2l11-deficient mice; anti-dsDNA IgM antibody levels are increased over levels in Faslpr homozygotes
• increased compared to wild-type, Faslpr homozygotes, and Bcl2l11-deficient mice
• anti-ssDNA IgM and IgG antibodies are increased compared to wild-type and Bcl2l11-deficient mice; anti-ssDNA IgM antibody levels are increased over levels in Faslpr homozygotes

hematopoietic system
• increased in spleen relative to Faslpr homozygotes
• lower in spleen and lymph node compared to wild-type or single mutants
• mice show reduced amount of naż×e T cells compared to wild-type or Bcl2l11-deficient mice
• no difference in number of regulatory T cells is observed
• T cell subpopulations in the spleen and lymph nodes including single-positive, central memory and effector memory T cells are increased compared to single-deficient mice
• increased memory T cell numbers in spleen and lymph nodes relative to single mutant animals
• number of CD45+ cells is increased 4.6-fold vs wild-type, 3.2-fold vs Faslpr homozygotes, and 2.8-fold vs Bcl2l11-deficient mice
• plasmablast numbers in spleen are increased 30-fold relative to wild-type, 2-fold relative to Bcl2l11-deficient and 4-fold relative to Faslpr homozygous mice
• number of T1 and T2 B cells is increased relative to wild-type, Faslpr homozygotes, and Bcl2l11-deficient mice
• higher in spleen relative to wild-type, Faslpr homozygotes, and Bcl2l11-deficient mice
• higher in spleen relative to wild-type, Faslpr homozygotes, and Bcl2l11-deficient mice
• increased numbers in spleen and lymph nodes are observed
• increased effector memory T cell numbers in spleen and lymph nodes relative to single mutant animals
• enlargement of spleen is accompanied by alteration of spleen architecture, characterized by decreased red pulp amount
• severely enlarged by 16 weeks
• enlargement of spleen is accompanied by alteration of spleen architecture, characterized by increased white pulp amount
• T1:follicular B cell ratio is disturbed; ratio is higher significantly higher than wild-type, Bcl2l11-deficient mice or Faslpr homozygotes
• increased B cell number; CD19+ B cells are increased by 4.3-fold over wild-type, 1.8-fold over Bcl2l11-null mice and by 3.6-fold over Faslpr mice

renal/urinary system
• higher numbers of apoptotic cells are detected in glomeruli compared to wild-type and single mutant mice
• glomerular proliferation is increased
• significant increase in renal B cells (CD19+) compared to wild-type, Faslpr homozygotes, and Bcl2l11-deficient mice
• number of macrophages surrounding glomeruli is increased compared to wild-type and Faslpr homozygotes; macrophage index is 2.5-fold higher than in Fas homozygotes
• IgG deposits mainly localized to basement glomerular membrane are increased relative to wild-type, Faslpr homozygotes, and Bcl2l11-deficient mice
• glomerular basement membrane thickening
• mesangial expansion, basement membrane thickening, increased interstitial infiltration, and loss of open capillary loops are characteristic hallmarks of renal damage observed
• kidney damage pathological scores are increased over wild-type, Faslpr homozygotes, and Bcl2l11-deficient glomeruli
• glomerular proliferation is increased
• loss of open capillary loops
• mesangial expansion
• glomerular size is increased relative to wild-type, Faslpr homozygotes, and Bcl2l11-deficient mice

cellular
• higher numbers of apoptotic cells are detected in glomeruli compared to wild-type and single mutant mice
• glomerular proliferation is increased

cardiovascular system
• loss of open capillary loops


Mouse Genome Informatics
cx26
    Faslpr/Faslpr
Havcr1tm1Kuch/Havcr1tm1Kuch

B6.Cg-Havcr1tm1Kuch Faslpr
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
• massive accumulation of B cells
• increase in the number of B220+CD3+ T cells in the peripheral lymphoid compartments compared to mice homozygous for Faslpr alone
• massive increase in the accumulation of CD3+B220- CD4+ T cells
• increase in the frequency of IFNG+ cells
• massive increase in the accumulation of CD3+B220- CD8+ T cells
• increase in the frequency of IFNG+ cells
• most T cells have an activated/memory like phenotype
• massive increase in CD3+B220-CD4-CD8- and CD3+B220+CD4-CD8- T cells
• more severe in mice over 10 months of age compared to mice homozygous for Faslpr alone
• unlike IgG levels, IgM levels are decreased compared to mice homozygous for Faslpr alone
• compared to mice homozygous for Faslpr alone
• compared to mice homozygous for Faslpr alone
• compared to mice homozygous for Faslpr alone
• compared to mice homozygous for Faslpr alone
• more severe in mice over 10 months of age compared to mice homozygous for Faslpr alone
• more severe autoimmune response compared to mice homozygous for Faslpr alone
• serum levels of some autoantibodies to lupus associated autoantigens are increased at 14 weeks of age in double mutant mice but not in mice homozygous for Faslpr alone
• autoantibodies can be detected as early as 10 weeks of age
• compared to mice homozygous for Faslpr alone

hematopoietic system
• massive accumulation of B cells
• increase in the number of B220+CD3+ T cells in the peripheral lymphoid compartments compared to mice homozygous for Faslpr alone
• massive increase in the accumulation of CD3+B220- CD4+ T cells
• increase in the frequency of IFNG+ cells
• massive increase in the accumulation of CD3+B220- CD8+ T cells
• increase in the frequency of IFNG+ cells
• most T cells have an activated/memory like phenotype
• massive increase in CD3+B220-CD4-CD8- and CD3+B220+CD4-CD8- T cells
• more severe in mice over 10 months of age compared to mice homozygous for Faslpr alone
• unlike IgG levels, IgM levels are decreased compared to mice homozygous for Faslpr alone
• compared to mice homozygous for Faslpr alone
• compared to mice homozygous for Faslpr alone
• compared to mice homozygous for Faslpr alone
• compared to mice homozygous for Faslpr alone


Mouse Genome Informatics
cx27
    Faslpr/Faslpr
Il2ratm1Dw/Il2ratm1Dw
Tg(CD2-Ccdc86)1Hfuj/?

B6.Cg-Il2ratm1Dw Faslpr Tg(CD2-Ccdc86)1Hfuj
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
• absence of the Fas receptor prevents the transgene from rescuing the splenomegaly associated with Il2ratm1Dw homozygotes

hematopoietic system
• absence of the Fas receptor prevents the transgene from rescuing the splenomegaly associated with Il2ratm1Dw homozygotes


Mouse Genome Informatics
cx28
    Faslpr/Faslpr
Tlr9tm1Aki/Tlr9tm1Aki

B6.Cg-Tlr9tm1Aki Faslpr
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• 66% survival at 24 weeks

hematopoietic system
• dramatically increased compared to wild-type; increased relative to Tlr9 and Fas mutants
• spleens are 5-fold heavier than in MRL/MpJ-Faslpr mice
• total levels are higher than wild-type or Faslpr mice
• lower than in Faslpr mice

immune system
• dramatically increased compared to wild-type; increased relative to Tlr9 and Fas mutants
• spleens are 5-fold heavier than in MRL/MpJ-Faslpr mice
• total levels are higher than wild-type or Faslpr mice
• lower than in Faslpr mice
• generalized lymphadenopathy
• axillary and inguinal lymph node weights are greater than in Faslpr mice (by >5-fold)
• autoantibodies such as anti-ssDNA, anti-dsDNA, anti-cardiolipin, and anti-IgG are detected, and levels are not different from Fas mutants
• interstitial lymphoid infiltration is observed at 13 weeks; glomerular IgG deposits that are exclusively mesangial are more severe than in Fas single mutants
• mesangial proliferation is greater than in Fas single mutants

homeostasis/metabolism
• increased more from 13 to 24 weeks than in Fas single mutants but not significantly so

renal/urinary system
• increased more from 13 to 24 weeks than in Fas single mutants but not significantly so
• interstitial lymphoid infiltration is observed at 13 weeks; glomerular IgG deposits that are exclusively mesangial are more severe than in Fas single mutants
• mesangial proliferation is greater than in Fas single mutants


Mouse Genome Informatics
cx29
    Dsg4hage/Dsg4hage
Faslpr/Faslpr
X/Yaa

EOD-Dsg4hage
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• the mean life span of these male mice is 99 days, which is significantly longer than the 88 day mean lifespan that males from this strain normally live (J:140028)

growth/size
• mice are generally smaller than controls (J:140028)

immune system
• the characteristic B220+Thy1+ T cells population found in the spleen of mice carrying the Faslps allele is reduced by more than 5-fold in these mice (J:140028)
• increased mast cell numbers are found in the superficial layer of the epidermis, with about a 3-fold increase over controls (J:140028)

hematopoietic system
• the characteristic B220+Thy1+ T cells population found in the spleen of mice carrying the Faslps allele is reduced by more than 5-fold in these mice (J:140028)
• increased mast cell numbers are found in the superficial layer of the epidermis, with about a 3-fold increase over controls (J:140028)

integument
• pups have scanty growth of short hair on the head and back (J:140028)
• the number of hair follicles in a given patch of skin appears to be higher than controls but counting is difficult because of the unusual orientation of the follicles (J:140028)
• axes of hair shafts are randomly oriented, with some being horizontal to the skin layer (J:140028)
• mice fail to grow vibrissae hairs (J:140028)
• mice have thick skin with hyperplasia of the epidermis that is prone to injury (J:140028)

Mouse Models of Human Disease
OMIM IDRef(s)
Hypotrichosis 6; HYPT6 607903 J:140028


Mouse Genome Informatics
cx30
    Faslpr/Faslpr
Fasltm2.1Bksa/Fasltm2.1Bksa

involves: 129 * C57BL/6 * MRL/Mp
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
vision/eye
N
• TNFalpha-treated mice do not exhibit a decrease in retinal nerve fibers like in similarly treated wild-type mice (J:171440)
• after 1 week, TNFalpha-treated mice fail to exhibit a decrease in retinal ganglion cells unlike in similarly treated wild-type mice

nervous system
• after 1 week, TNFalpha-treated mice fail to exhibit a decrease in retinal ganglion cells unlike in similarly treated wild-type mice


Mouse Genome Informatics
cx31
    Faslpr/Faslpr
Tnfrsf1atm1Gkl/Tnfrsf1atm1Gkl

involves: 129/Sv * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
• liver inflammation is seen by 3-4 weeks of age and persists throughout adulthood
• no change in the severity of liver inflammation is seen compared to Tnfrsf1atm1Gkl in homozygotes

liver/biliary system
• liver inflammation is seen by 3-4 weeks of age and persists throughout adulthood
• no change in the severity of liver inflammation is seen compared to Tnfrsf1atm1Gkl in homozygotes


Mouse Genome Informatics
cx32
    Faslpr/Fas+
Raf1tm1Bacc/Raf1tm1Bacc

involves: 129/SvHsd * 129P2/OlaHsd * C57BL/6 * MRL
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
N
• introduction of a Faslpr allele onto the Raf1-null background rescues the lethality shown by the homozygous Raf1-null embryos (J:135681)

hematopoietic system
N
• introduction of a Faslpr allele onto the Raf1-null background rescues the anemia observed in homozygous Raf1-null embryos (J:135681)
• differentiation of erythroblasts is delayed, restoring differentiation to level of Raf1 heterozygotes; differentiation is slower than observed in Raf1-null cells


Mouse Genome Informatics
cx33
    Faslpr/Faslpr
Raf1tm1Bacc/Raf1tm1Bacc

involves: 129/SvHsd * 129P2/OlaHsd * C57BL/6 * MRL
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
hematopoietic system
• differentiation of erythroblasts is blocked even at 60 hours after induction of differentiation, as measured by cell proliferation, volume decrease, and hemoglobin accumulation

cellular
• number of apoptotic erthroblasts is increased under 10U/ml of erythropoietin


Mouse Genome Informatics
cx34
    Faslpr/Fas+
Raf1tm1Bacc/Raf1+

involves: 129/SvHsd * 129P2/OlaHsd * C57BL/6 * MRL
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
hematopoietic system
N
• differentiation of erythroblasts from double heterozygotes is indistinguishable from wild-type cells (J:135681)


Mouse Genome Informatics
cx35
    Faslpr/Faslpr
Tcratm1Mjo/Tcratm1Mjo

involves: 129P2/OlaHsd * 129S2/SvPas * MRL
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• relative to mutant mice wild-type for Tcra

immune system
• lower titers of immunoglobulins, other than IgE, compared to mutant mice wild-type for Tcra
• lower titers autoantibodies compared to mutant mice wild-type for Tcra

integument
• development of skin lesions is delayed (develop by 7 to 8 months of age) compared to mutant mice wild-type by Tcra

renal/urinary system
• substantial reduction in renal disease compared to mutant mice wild-type for Tcra

hematopoietic system
• lower titers of immunoglobulins, other than IgE, compared to mutant mice wild-type for Tcra


Mouse Genome Informatics
cx36
    Cd40lgtm1Flv/Cd40lgtm1Flv
Faslpr/Faslpr

involves: 129P2/OlaHsd * 129S2/SvPas * MRL
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• relative to mutant mice wild-type for Cd40lg (J:38492)

immune system
• lower titers of immunoglobulins compared to mutant mice wild-type for Cd40lg (J:38492)
• lower titers of IgG1, IgG2a dna IgG2b compared to mice homozygous for Faslpr and Cd40lgtm1Flv (J:38492)
• lower titers autoantibodies compared to mutant mice wild-type for Cd40lg (J:38492)

integument
• develop severe hair loss by 24 weeks of age (J:38492)
• develop scabs and purpuric lesions of the dorsal neck and ears by 24 weeks of age (J:38492)

renal/urinary system
• substantial reduction in renal disease compared to mutant mice wild-type for Cd40lg (J:38492)

hematopoietic system
• lower titers of immunoglobulins compared to mutant mice wild-type for Cd40lg (J:38492)
• lower titers of IgG1, IgG2a dna IgG2b compared to mice homozygous for Faslpr and Cd40lgtm1Flv (J:38492)


Mouse Genome Informatics
cx37
    Cd40lgtm1Flv/Y
Faslpr/Faslpr

involves: 129P2/OlaHsd * 129S2/SvPas * MRL
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• relative to mutant mice wild-type for Cd40lg (J:38492)

immune system
• lower titers of immunoglobulins compared to mutant mice wild-type for Cd40lg (J:38492)
• lower titers of IgG1, IgG2a dna IgG2b compared to mice homozygous for Faslpr and Cd40lgtm1Flv (J:38492)
• lower titers autoantibodies compared to mutant mice wild-type for Cd40lg (J:38492)

integument
• develop severe hair loss by 24 weeks of age (J:38492)
• develop scabs and purpuric lesions of the dorsal neck and ears by 24 weeks of age (J:38492)

renal/urinary system
• substantial reduction in renal disease compared to mutant mice wild-type for Cd40lg (J:38492)

hematopoietic system
• lower titers of immunoglobulins compared to mutant mice wild-type for Cd40lg (J:38492)
• lower titers of IgG1, IgG2a dna IgG2b compared to mice homozygous for Faslpr and Cd40lgtm1Flv (J:38492)


Mouse Genome Informatics
cx38
    Cd40lgtm1Flv/Y
Faslpr/Faslpr
Tcratm1Mjo/Tcratm1Mjo

involves: 129P2/OlaHsd * 129S2/SvPas * MRL
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
• lower titers autoantibodies compared to mutant mice wild-type for Cd40lg (J:38492)
• decrease in the anti-snRNP and anti-Ig titers relative to mutant mice compared to mutant mice wild-type for Cd40lg (J:38492)
• relative to mutant mice wild-type for Tcra (J:38492)

integument
N
• do not develop the skin lesions seen in mutant mice wild-type for Tcra and/or Cd40lg (J:38492)

renal/urinary system
• renal disease is decreased compared to mutant mice wild-type Cd40lg but more diseased than mutant mice wild-type for Tcra (J:38492)


Mouse Genome Informatics
cx39
    Cd40lgtm1Flv/Cd40lgtm1Flv
Faslpr/Faslpr
Tcratm1Mjo/Tcratm1Mjo

involves: 129P2/OlaHsd * 129S2/SvPas * MRL
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
• lower titers autoantibodies compared to mutant mice wild-type for Cd40lg (J:38492)
• decrease in the anti-snRNP and anti-Ig titers relative to mutant mice compared to mutant mice wild-type for Cd40lg (J:38492)
• relative to mutant mice wild-type for Tcra (J:38492)

integument
N
• do not develop the skin lesions seen in mutant mice wild-type for Tcra and/or Cd40lg (J:38492)

renal/urinary system
• renal disease is decreased compared to mutant mice wild-type Cd40lg but more diseased than mutant mice wild-type for Tcra (J:38492)


Mouse Genome Informatics
cx40
    Faslpr/Faslpr
Pou2af1tm1Pmt/Pou2af1tm1Pmt

involves: 129P2/OlaHsd * C57BL/6 * MRL
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
N
• at 7 months, all double mutants are still alive compared to extensive mortality observed in Fas single mutants by this age (J:125114)

immune system
• number of splenic IgG-secreting cells is dramatically lower than in Fas single mutants
• number of bone marrow IgG-secreting cells is dramatically lower than in Fas single mutants
• in bone marrow, numbers of CD19+IgM- and CD19+IgD- B cells is increased
• accumulation of B220+CD3+ cells in spleens and lymph nodes is markedly reduced compared to Fas single mutants
• serum immunoglobulin levels are significantly reduced compared to Fas single mutants and are similar to Pou2af1-null mice
• serum level of IgA is reduced but not to same extent as IgG
• IgM production is decreased
• mice do not develop autoantibodies (anti-dsDNA or any IgG antinuclear autoantibodies)

hematopoietic system
N
• splenic immature and mature B cell numbers are not reduced (a slight increase is observed) (J:125114)
• number of splenic IgG-secreting cells is dramatically lower than in Fas single mutants
• number of bone marrow IgG-secreting cells is dramatically lower than in Fas single mutants
• in bone marrow, numbers of CD19+IgM- and CD19+IgD- B cells is increased
• accumulation of B220+CD3+ cells in spleens and lymph nodes is markedly reduced compared to Fas single mutants
• serum immunoglobulin levels are significantly reduced compared to Fas single mutants and are similar to Pou2af1-null mice
• serum level of IgA is reduced but not to same extent as IgG
• IgM production is decreased

renal/urinary system
• no IgG or C3 deposition is observed, but crescent formation and enlargement of glomeruli is observed
• no inflammation is observed
• crescent formation is observed
• enlargement of glomeruli is observed


Mouse Genome Informatics
cx41
    Faslpr/Faslpr
Il4tm1Cgn/Il4tm1Cgn

involves: 129P2/OlaHsd * C57BL/6J * MRL/Mp
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
• lympadenopathy (based on spleen weight and cellularity) is reduced compared to mice homozygous for Faslpr and wild-type for Il4
• relative to wild-type controls but decreased relative to mice homozygous for Faslpr and wild-type for Il4
• relative to wild-type controls but decreased relative to mice homozygous for Faslpr and wild-type for Il4
• at 7-8 months of age relative to mice homozygous for Faslpr and wild-type for Il4
• at 3 and 7-8 months of age relative to mice homozygous for Faslpr and wild-type for Il4
• at 3 and 7-8 months of age relative to mice homozygous for Faslpr and wild-type for Il4
• at 7-8 months of age relative to mice homozygous for Faslpr and wild-type for Il4
• lympadenopathy (based on lymph node weight and cellularity) is reduced compared to mice homozygous for Faslpr and wild-type for Il4
• while mice develop the typical autoimmune lesions end organ disease is decreased compared to mice homozygous for Faslpr and wild-type for Ifng
• incidence of end organ disease is increased compared to wild-type controls
• decrease in the percentage of FANA positive sera compared to controls at 3 months of age
• however, no significant differences in anti-dsDNA or anti-snRNP autoantibody levels are detected

homeostasis/metabolism
• levels are lower compared to mice homozygous for Faslpr and wild-type for Il4

hematopoietic system
• lympadenopathy (based on spleen weight and cellularity) is reduced compared to mice homozygous for Faslpr and wild-type for Il4
• relative to wild-type controls but decreased relative to mice homozygous for Faslpr and wild-type for Il4
• relative to wild-type controls but decreased relative to mice homozygous for Faslpr and wild-type for Il4
• at 7-8 months of age relative to mice homozygous for Faslpr and wild-type for Il4
• at 3 and 7-8 months of age relative to mice homozygous for Faslpr and wild-type for Il4
• at 3 and 7-8 months of age relative to mice homozygous for Faslpr and wild-type for Il4
• at 7-8 months of age relative to mice homozygous for Faslpr and wild-type for Il4


Mouse Genome Informatics
cx42
    Faslpr/Faslpr
Tcratm1Mjo/Tcratm1Mjo

involves: 129P2/OlaHsd * MRL
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
N
• unlike in mutant mice wild-type for Tcra, massive lymphadenopathy is not seen at 16 weeks of age (J:26250)
• 6 fold increase in TCRB+ cells compared to mutant mice wild-type for Fas
• within the TCRB+ cell population the proportion of DN B220+ cells is increased compared mutant mice wild-type for Fas
• 15 fold expansion at 16 weeks of age compared to mutant mice wild-type for Fas
• the majority of these cells express B220 and DN as a result of preferential expansion (300 fold) of this population of cells
• increase in the proportion of T cells in the peripheral lymph nodes expressing the gamma delta variable regions typical of intestinal intraepithelial T cell compared to mutant mice wild-type for Fas
• periglomerular infiltration and perivasculitis

renal/urinary system
• compared to age-matched B10.A mice
• periglomerular infiltration and perivasculitis
• develop glomerular, interstitial and sometimes perivascular lesions
• lesion development is reduced compared mutant mice wild-type for Tcra
• focal glomerular hypercellularity

homeostasis/metabolism
• significantly elevated
• compared to age-matched B10.A mice

hematopoietic system
• 6 fold increase in TCRB+ cells compared to mutant mice wild-type for Fas
• within the TCRB+ cell population the proportion of DN B220+ cells is increased compared mutant mice wild-type for Fas
• 15 fold expansion at 16 weeks of age compared to mutant mice wild-type for Fas
• the majority of these cells express B220 and DN as a result of preferential expansion (300 fold) of this population of cells
• increase in the proportion of T cells in the peripheral lymph nodes expressing the gamma delta variable regions typical of intestinal intraepithelial T cell compared to mutant mice wild-type for Fas


Mouse Genome Informatics
cx43
    Faslpr/Faslpr
Tlr7tm1Flv/Y

involves: 129S1/Sv * C57BL/6 * MRL/Mp
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
• decrease in accumulation of double-negative T cells in the spleen compared to Faslpr homozygotes (J:113557)
• general B cell activation is inhibited compared to Faslpr homozygotes, as indicated by decreased CD44 expression in splenic B cells (J:113557)
• decrease in proportion of CD4+ T cells expressing CD44, both in the lymph node and spleen compared to Faslpr homozygotes (J:113557)
• spleen weight is decreased compared to Faslpr homozygotes (J:113557)
• serum IgG2a levels are decreased compared to Faslpr homozygotes (J:113557)
• serum IgG3 levels are decreased compared to Faslpr homozygotes (J:113557)
• lymph node weight is decreased compared to Faslpr homozygotes (J:113557)
• plasmacytoid DCs exhibit a more immature phenotype compared to Faslpr homozygotes, with decreased expression of MHC class II (J:113557)
• renal disease is significantly decreased compared to Faslpr homozygotes, with mice showing decreased glomerular protein deposition and preserved glomerular structure (J:113557)
• although skin disease is evident in mutants, it occurs with a very low frequency and very little is seen at 16 weeks of age (J:113557)
• mutants exhibit impaired generation of antibodies to RNA complexes and generation of high-titer Smith antibodies is blocked (J:113557)
• DNA autoantibodies are seen in mutants (J:113557)

hematopoietic system
• decrease in accumulation of double-negative T cells in the spleen compared to Faslpr homozygotes (J:113557)
• general B cell activation is inhibited compared to Faslpr homozygotes, as indicated by decreased CD44 expression in splenic B cells (J:113557)
• decrease in proportion of CD4+ T cells expressing CD44, both in the lymph node and spleen compared to Faslpr homozygotes (J:113557)
• spleen weight is decreased compared to Faslpr homozygotes (J:113557)
• serum IgG2a levels are decreased compared to Faslpr homozygotes (J:113557)
• serum IgG3 levels are decreased compared to Faslpr homozygotes (J:113557)


Mouse Genome Informatics
cx44
    Faslpr/Faslpr
Ighmtm1Cgn/Ighmtm1Cgn

involves: 129S2/SvPas * C57BL/6 * MRL/Mp
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
• number of Ig-positive B cells in spleen are 10- to 20-fold lower than in wild-type or Faslpr mice
• cell outgrowth in lymphadenopathy is dominated by Tcrb/B220+ cells
• a transitional block in early B cell development in evident in bone marrow; pre-B cells are decreased in number
• at 8-10 weeks of age, mice develop significant lymphadenopathy
• mice fail to respond to T cell-dependent (OVA) or T cell-independent (dextra) antigenic stimulation and do not produce serum specific antibodies to these antigens
• levels of IgG2a and IgA are elevated compared to wild-type mice; significant levels (up to 10-fold) of serum antibodies have the gamma light chain isotype compared to control
• levels are much lower than in controls, comparable to Igh-6 single nulls
• mice have high titers of chromatin antibodies compared to controls and titer increased with age; anti-cardiolipin antibodies are increased in serum in 40% of double mutants

hematopoietic system
• number of Ig-positive B cells in spleen are 10- to 20-fold lower than in wild-type or Faslpr mice
• cell outgrowth in lymphadenopathy is dominated by Tcrb/B220+ cells
• a transitional block in early B cell development in evident in bone marrow; pre-B cells are decreased in number
• levels of IgG2a and IgA are elevated compared to wild-type mice; significant levels (up to 10-fold) of serum antibodies have the gamma light chain isotype compared to control
• levels are much lower than in controls, comparable to Igh-6 single nulls

homeostasis/metabolism
• mice show significant proteinuria

renal/urinary system
• mice show significant proteinuria


Mouse Genome Informatics
cx45
    Dntttm1Gfn/Dntttm1Gfn
Faslpr/Faslpr

involves: 129S2/SvPas * C57BL/6 * MRL/MpJ
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
• significantly lower sera anti-DNA and rheumatoid factor activity than control


Mouse Genome Informatics
cx46
    C4btm1Crr/C4btm1Crr
Faslpr/Faslpr

involves: 129S4/SvJae * C57BL/6 * MRL
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
• spleen mass is significantly increased relative to C3 /Faslpr or single Faslpr mutants at 17 weeks of age
• lymph node mass is increased relative to C3-null, Faslpr or single Faslpr mutants at 13 and 17 weeks of age
• frequency of antibody-secreting cells (ASCs) or antibody-forming cells (AFCs) is significantly increased in spleen and bone marrow compared to C3-deficient Fas mutants
• titers of serum ANA are significantly increased at 10, 13, and 17 weeks
• anti-dsDNA titers are elevated significantly at 17 weeks

hematopoietic system
• spleen mass is significantly increased relative to C3 /Faslpr or single Faslpr mutants at 17 weeks of age

renal/urinary system
• increased IgG deposition relative to C3/Fas mutants is observed in kidney sections
• more severe glomerular abnormalities are observed relative to C3/Fas mutants


Mouse Genome Informatics
cx47
    C3tm1Crr/C3tm1Crr
Faslpr/Faslpr

involves: 129S4/SvJae * C57BL/6 * MRL
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
N
• mutant and Faslpr spleens and lymph nodes do not significantly differ in weight at 10 or 13 weeks; at 17 weeks, LN mass is elevated but not significantly (J:127292)
• lack of autoantibodies (ANA, anti-dsDNA) is observed (J:127292)

renal/urinary system
• pathology score is minimally increased relative to B6.MRL-Faslpr mutants, but no IgG deposition is observed in kidneys


Mouse Genome Informatics
cx48
    C3tm1Crr/C3tm1Crr
C4btm1Crr/C4btm1Crr
Faslpr/Faslpr

involves: 129S4/SvJae * C57BL/6 * MRL
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
• spleen mass is significantly increased relative to C3-null, Faslpr or single Faslpr mutants at 17 weeks of age
• lymph node mass is increased relative to C3-null, Faslpr or single Faslpr mutants at 10 and 13 weeks of age
• frequency of antibody-secreting cells (ASCs) or antibody-forming cells (AFCs) is significantly increased in spleen, bone marrow, and lymph nodes compared to C3-deficient Fas mutants or single Faslpr mutants
• titers of serum ANA are significantly increased at 10 and 17 weeks, compared to single-deficient mice
• anti-dsDNA titers are elevated significantly relative to C4, Fas double mutants

hematopoietic system
• spleen mass is significantly increased relative to C3-null, Faslpr or single Faslpr mutants at 17 weeks of age

renal/urinary system
• increased IgG deposition relative to C3/Fas mutants is observed in kidney sections; deposition is similar to C4/Fas mutants
• more severe glomerular abnormalities are observed relative to C3/Fas mutants, and pathology is similar to that of C4/Fas double mutants


Mouse Genome Informatics
cx49
    Faslpr/Faslpr
Itfg2Gt(OST215121)Lex/Itfg2Gt(OST215121)Lex

involves: 129S5/SvEvBrd * C57BL/6J * MRL/Mp
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
• decreased circulating B cells for the first 13 weeks of age compared with Faslpr homozygotes
• increased faster in the blood and to a higher proportion than in Faslpr homozygotes
• worse than in Faslpr homozygotes
• from 19 weeks compared with Faslpr homozygotes
• from 19 weeks compared with Faslpr homozygotes
• worse than in Faslpr homozygotes
• more severe autoimmune disease development with inflammatory cell infiltration of the kidney and hypertrophy in the lymphoid organs compared with Faslpr homozygotes
• compared with Faslpr homozygotes
• compared with Faslpr homozygotes

homeostasis/metabolism
• compared with Faslpr homozygotes

renal/urinary system
• compared with Faslpr homozygotes

hematopoietic system
• decreased circulating B cells for the first 13 weeks of age compared with Faslpr homozygotes
• increased faster in the blood and to a higher proportion than in Faslpr homozygotes
• worse than in Faslpr homozygotes
• from 19 weeks compared with Faslpr homozygotes
• from 19 weeks compared with Faslpr homozygotes


Mouse Genome Informatics
cx50
    Faslpr/Faslpr
Spp1tm1Rit/Spp1tm1Rit

involves: 129S7/SvEvBrd * C57BL/6 * MRL/Mp
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
• at day 175 compared with wild-type mice with further increase at day 275 compared with Faslpr homozygotes
• at day 275 compared with wild-type mice
• however, at day 175 IgA levels are normal unlike in Faslpr homozygotes
• at day 275 compared with wild-type mice
• however, at day 175 IgG1 levels are normal unlike in Faslpr homozygotes