Mouse Genome Informatics
cx1
    Cd40tm1Kik/Cd40tm1Kik
Tg(Tnfsf13b)1Fma/?

B6.Cg-Cd40tm1Kik Tg(Tnfsf13b)1Fma
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
• the number of splenic marginal zone B cells is increased by about 3-fold
• B cells have a vigorous response to T cell independent antigens producing much higher levels of antigen-specific IgG1, IgG2a, IgG2b, IgG3, and IgA class antibodies than controls
• B cells exhibit reduced class switching in response to T cell-dependent antigens
• mice are defective in germinal center formation upon after immunization
• anti-dsDNA antibodies of the IgM class, IgA class, and all IgG subclasses are found in circulation
• titers of these auto-antibodies increase with age
• kidneys of 10-month old mice have necrotic lesions
• immunohistology of kidneys with severe lesions reveal numerous glomerular deposits of IgG

renal/urinary system
• all 8-month old mice have proteinuria in their urine at 100-300 mg/dl concentration
• kidneys of 10-month old mice have necrotic lesions
• immunohistology of kidneys with severe lesions reveal numerous glomerular deposits of IgG

homeostasis/metabolism
• all 8-month old mice have proteinuria in their urine at 100-300 mg/dl concentration

hematopoietic system
• the number of splenic marginal zone B cells is increased by about 3-fold
• B cells have a vigorous response to T cell independent antigens producing much higher levels of antigen-specific IgG1, IgG2a, IgG2b, IgG3, and IgA class antibodies than controls
• B cells exhibit reduced class switching in response to T cell-dependent antigens
• mice are defective in germinal center formation upon after immunization


Mouse Genome Informatics
cx2
    Chuktm2Mka/Chuktm2Mka
Tg(Tnfsf13b)1Fma/?

B6.Cg-Chuktm2Mka Tg(Tnfsf13b)1Fma
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
• marginal zone B cell numbers are reduced compared to controls
• numbers of T2 B cells are slightly enlarged in the spleen
• B cells have a strong response to T cell independent antigens producing higher levels of antigen-specific IgM, IgG2a, IgG2b class antibodies than wild-type controls
• however, there is no significant elevation of antigen-specific IgG1, IgG3, and IgA antibodies as is observed in transgenic mice on a wild-type background
• levels of antibodies produced are also lower than those in transgenic mice on a wild-type background
• marginal zones could not be localized in these mice
• anti-dsDNA antibodies of the IgM class are found in circulation
• titers of these auto-antibodies increase slightly with age
• no significantly elevated anti-dsDNA antibodies are found within the other immunoglobulin classes which differs from transgenic mice not homozygote for the Chuktm2Mka allele

homeostasis/metabolism
• about half of 8-month old mice have proteinuria in their urine at 30 mg/dl concentration

renal/urinary system
• about half of 8-month old mice have proteinuria in their urine at 30 mg/dl concentration

hematopoietic system
• marginal zone B cell numbers are reduced compared to controls
• numbers of T2 B cells are slightly enlarged in the spleen
• B cells have a strong response to T cell independent antigens producing higher levels of antigen-specific IgM, IgG2a, IgG2b class antibodies than wild-type controls
• however, there is no significant elevation of antigen-specific IgG1, IgG3, and IgA antibodies as is observed in transgenic mice on a wild-type background
• levels of antibodies produced are also lower than those in transgenic mice on a wild-type background
• marginal zones could not be localized in these mice


Mouse Genome Informatics
cx3
    Nfkb1tm1Bal/Nfkb1tm1Bal
Tg(Tnfsf13b)1Fma/?

B6.Cg-Nfkb1tm1Bal Tg(Tnfsf13b)1Fma
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
hematopoietic system
• marginal zone B cells are almost completely absent in the spleen
• numbers of T1 B cells in the spleen are increased almost 3-fold while T2 numbers are almost about doubled
• B cells have a strong response to T cell independent antigens producing higher levels of antigen-specific IgM class antibodies than wild-type controls
• the Nfkb1 null background significantly reduced the IgG2a and IgG2b responses and virtually abrogated the IgG3 and IgA responses compared to transgenic mice on a wild-type background
• class switch recombination mediated by T cell independent antigens or by BAFF incubation is defective in these mice

immune system
N
• there are no elevated levels of anti-dsDNA antibodies detected in circulation compared to transgenic mice on a wild-type background that have high levels of auto-antbodies (J:113556)
• marginal zone B cells are almost completely absent in the spleen
• numbers of T1 B cells in the spleen are increased almost 3-fold while T2 numbers are almost about doubled
• B cells have a strong response to T cell independent antigens producing higher levels of antigen-specific IgM class antibodies than wild-type controls
• the Nfkb1 null background significantly reduced the IgG2a and IgG2b responses and virtually abrogated the IgG3 and IgA responses compared to transgenic mice on a wild-type background
• class switch recombination mediated by T cell independent antigens or by BAFF incubation is defective in these mice


Mouse Genome Informatics
cx4
    Nfkb2tm2Brv/Nfkb2tm2Brv
Tg(Tnfsf13b)1Fma/?

B6.Cg-Nfkb2tm2Brv Tg(Tnfsf13b)1Fma
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
N
• there are no elevated levels of anti-dsDNA antibodies detected in circulation compared to transgenic mice on a wild-type background that have high levels of auto-antbodies (J:113556)
• marginal zone B cells are almost completely absent in the spleen
• B cells have a strong response to T cell independent antigens producing higher levels of antigen-specific IgM, IgG2a, IgG2b class antibodies than wild-type controls
• however, there is no significant elevation of antigen-specific IgG1, IgG3, and IgA antibodies as is observed in transgenic mice on a wild-type background
• levels of antibodies produced are also lower than those in transgenic mice on a wild-type background
• marginal zones are absent in these mice

homeostasis/metabolism
• about half of 8-month old mice have proteinuria in their urine at 30 mg/dl concentration

renal/urinary system
• about half of 8-month old mice have proteinuria in their urine at 30 mg/dl concentration

hematopoietic system
• marginal zone B cells are almost completely absent in the spleen
• B cells have a strong response to T cell independent antigens producing higher levels of antigen-specific IgM, IgG2a, IgG2b class antibodies than wild-type controls
• however, there is no significant elevation of antigen-specific IgG1, IgG3, and IgA antibodies as is observed in transgenic mice on a wild-type background
• levels of antibodies produced are also lower than those in transgenic mice on a wild-type background
• marginal zones are absent in these mice


Mouse Genome Informatics
cx5
    Tg(Tnfsf13b)1Fma/?
Tnfrsf13btm1Rjb/Tnfrsf13btm1Rjb

B6.Cg-Tnfrsf13btm1Rjb Tg(Tnfsf13b)1Fma
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
hematopoietic system
• class switch recombination mediated by T cell independent antigens is defective in these mice

immune system
• class switch recombination mediated by T cell independent antigens is defective in these mice


Mouse Genome Informatics
cx6
    Tg(Tnfsf13b)1Fma/?
Tnfrsf13ctm1Mass/Tnfrsf13ctm1Mass

B6.Cg-Tnfrsf13ctm1Mass Tg(Tnfsf13b)1Fma
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
hematopoietic system
• class switch recombination mediated by BAFF incubation is defective in these mice

immune system
• class switch recombination mediated by BAFF incubation is defective in these mice


Mouse Genome Informatics
cx7
    Tg(Tnfsf13b)1Fma/0
Tnfsf14tm1Kpf/Tnfsf14tm1Kpf

involves: 129P2/OlaHsd * C57BL/6 * DBA/2J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
hematopoietic system
• a marked increase in some B cell subsets compared to wild-type is detected in 12 week old mice
• there is an increased frequency of B220neg/lo, IgA+ plasma cells in lamina propria preparations
• numerous germinal centers are observed in B cell follicles of mutants
• splenic marginal zone is increased in size
• augmented IgA staining is found in lamina propria of mutants

immune system
• a marked increase in some B cell subsets compared to wild-type is detected in 12 week old mice
• there is an increased frequency of B220neg/lo, IgA+ plasma cells in lamina propria preparations
• numerous germinal centers are observed in B cell follicles of mutants
• splenic marginal zone is increased in size
• augmented IgA staining is found in lamina propria of mutants

renal/urinary system
• deposition of IgA in nearly all glomeruli is detected, similar to Tnfsf14-sufficient transgenic mice
• in 8-month old mice, some thickening of mesangial and basement membranes


Mouse Genome Informatics
cx8
    Ighatm1(Myc)Janz/Igha+
Tg(Tnfsf13b)1Fma/0

involves: 129S1/Sv * C57BL/6 * DBA/2J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• median lifespan of mice with leukemia is 10 months

hematopoietic system
• males develop lymphocytosis at 3 months of age
• males exhibit an increase in blood B-cell number, with an expansion of the CD5+CD3-B220low IgMlow B-cell population in blood and spleens
• B-cell increase results from a monoclonal expansion of mature B cell-like cells
• splenomegaly is obvious in males after 4 months of age
• 8 month old spleens of males exhibit enlarged white pulp with loss of normal splenic architecture resulting from a diffuse infiltration of mature lymphocytes

immune system
• males develop lymphocytosis at 3 months of age
• males exhibit an increase in blood B-cell number, with an expansion of the CD5+CD3-B220low IgMlow B-cell population in blood and spleens
• B-cell increase results from a monoclonal expansion of mature B cell-like cells
• splenomegaly is obvious in males after 4 months of age
• 8 month old spleens of males exhibit enlarged white pulp with loss of normal splenic architecture resulting from a diffuse infiltration of mature lymphocytes

tumorigenesis
• mutants, mainly males, develop a CD5+ B-cell lymphoproliferative disease by 8 months of age that resembles human chronic lymphocytic leukemia
• male mice exhibit increased splenic 18F-labeled 2-fluoro-2-deoxy-D-glucose (FDG) uptake suggesting elevated leukemic cell metabolism

Mouse Models of Human Disease
OMIM IDRef(s)
Leukemia, Chronic Lymphocytic; CLL 151400 J:166158


Mouse Genome Informatics
cx9
    Ighatm1Grh/Ighatm1Grh
Tg(Tnfsf13b)1Fma/Tg(Tnfsf13b)1Fma

involves: 129S7/SvEvBrd * C57BL/6 * DBA/2
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
N
• double mutant do not exhibit the impaired kidney function seen in single Tg(Tnfsf13b)1Fma homozygotes and have reduced levels of serum IgA and IgA deposits in the kidney, and reduced hematuria, urinary protein and albumin levels indicating that IgA is important for renal disease development in Tg(Tnfsf13b)1Fma homozygotes (J:178227)


Mouse Genome Informatics
cx10
    Nba2NZB/Nba2NZB
Tg(Tnfsf13b)1Fma/0

involves: C57BL/6 * DBA/2J * NZB
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
• increased total splenic B cell numbers
• increased total serum IgG antibodies
• increased total serum IgM antibodies
• increased serum IgG and IgM antibodies
• increased incidence of glomerulonephritis by 3 months of age
• increased serum IgG anti-dsDNA Abs shows positive correlation to glomerulonephritis severity
• increased glomerulonephritis incidence at 3 months of age

renal/urinary system
• increased glomerulonephritis incidence at 3 months of age

hematopoietic system
• increased total splenic B cell numbers
• increased total serum IgG antibodies
• increased total serum IgM antibodies


Mouse Genome Informatics
cx11
    Sle1NZW/Sle1NZW
Tg(Tnfsf13b)1Fma/0

involves: C57BL/6 * DBA/2J * NZW
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
• increased total splenic B cell numbers
• increased total serum IgG antibodies
• increased total serum IgM antibodies
• increased serum IgG and IgM antibodies
• increased incidence of glomerulonephritis by 3 months of age
• increased glomerulonephritis incidence at 3 months of age

renal/urinary system
• increased glomerulonephritis incidence at 3 months of age

hematopoietic system
• increased total splenic B cell numbers
• increased total serum IgG antibodies
• increased total serum IgM antibodies


Mouse Genome Informatics
tg12
    Tg(Tnfsf13b)1Fma/Tg(Tnfsf13b)1Fma
involves: C57BL/6 * DBA/2
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging

immune system
• mutants exhibit an increased percentage of B cells in mucosal lymphoid tissues, including the gut lamina propria and the mesenteric lymph nodes, and in the spleen
• both specific pathogen free and germ-free mutants exhibit B cell hyperplasia in the spleen
• both specific pathogen free and germ-free mutants exhibit expanded percentages of transitional 2 B cells
• both specific pathogen free and germ-free mutants exhibit expanded percentages of splenic marginal zone B cells
• serum IgA level in germ-free mutants is decreased about 100-fold compared to specific-pathogen free mutants but is similar to those for germ-free wild-type mutants
• germ-free mutants do not exhibit increased IgA in plasma cells in the gut and deposition of IgA in the glomeruli as is seen in conventionally housed specific pathogen free mutants
• while IgM and IgA levels are elevated in mutants, serum IgG levels and antinuclear IgG antibodies are not elevated in mutants
• by 8 months of age, most mutants exhibit IgA mesangial deposition in the glomeruli, however little C4 deposition is seen
• IgA serum levels are elevated by 8 weeks of age in males and remain at this elevated level until 6 to 8 months of age, at which point, IgA levels begin to drop
• in most females, serum IgA levels do not rise
• serum IgA in mutants is aberrantly glycosylated, with reduced amounts of terminal galactose and sialic acid, is polymeric and is not associated with the secretory component
• germ-free mutants colonized with a limited commensal microbiota called altered Schaedler flora (ASF) at 6 weeks of age exhibit an increase in serum IgA levels that continue to increase until about 3.5 weeks and then stabilize compared to wild-type mice colonized with ASF
• conventionally housed specific pathogen free mutants colonized with ASF exhibit widespread dissemination of IgA+ plasma cells in the periphery while germ-free mutants housed in a barrier facility do not show IgA+ plasma cells in the periphery after colonization, indicating that the hyper-IgA syndrome is influenced by ongoing-commensual-dependent signaling in the intestine
• mutants with mild proteinuria at 6-8 months of age, exhibit mesangial deposits of IgM in the glomeruli
• IgM serum levels are elevated by 8 weeks of age
• mutants develop severe and fatal nephritis by 17 months of age
• males develop nephritis faster than females and this gender bias is thought to result from sexual dimorphism in expression in the kidneys of the alpha1-antitrypsin driven transgene

homeostasis/metabolism
• by 6 months of age, mutants exhibit modest albuminuria that gets worse with age

hematopoietic system
• mutants exhibit an increased percentage of B cells in mucosal lymphoid tissues, including the gut lamina propria and the mesenteric lymph nodes, and in the spleen
• both specific pathogen free and germ-free mutants exhibit B cell hyperplasia in the spleen
• both specific pathogen free and germ-free mutants exhibit expanded percentages of transitional 2 B cells
• both specific pathogen free and germ-free mutants exhibit expanded percentages of splenic marginal zone B cells
• serum IgA level in germ-free mutants is decreased about 100-fold compared to specific-pathogen free mutants but is similar to those for germ-free wild-type mutants
• germ-free mutants do not exhibit increased IgA in plasma cells in the gut and deposition of IgA in the glomeruli as is seen in conventionally housed specific pathogen free mutants
• while IgM and IgA levels are elevated in mutants, serum IgG levels and antinuclear IgG antibodies are not elevated in mutants
• by 8 months of age, most mutants exhibit IgA mesangial deposition in the glomeruli, however little C4 deposition is seen
• IgA serum levels are elevated by 8 weeks of age in males and remain at this elevated level until 6 to 8 months of age, at which point, IgA levels begin to drop
• in most females, serum IgA levels do not rise
• serum IgA in mutants is aberrantly glycosylated, with reduced amounts of terminal galactose and sialic acid, is polymeric and is not associated with the secretory component
• germ-free mutants colonized with a limited commensal microbiota called altered Schaedler flora (ASF) at 6 weeks of age exhibit an increase in serum IgA levels that continue to increase until about 3.5 weeks and then stabilize compared to wild-type mice colonized with ASF
• conventionally housed specific pathogen free mutants colonized with ASF exhibit widespread dissemination of IgA+ plasma cells in the periphery while germ-free mutants housed in a barrier facility do not show IgA+ plasma cells in the periphery after colonization, indicating that the hyper-IgA syndrome is influenced by ongoing-commensual-dependent signaling in the intestine
• mutants with mild proteinuria at 6-8 months of age, exhibit mesangial deposits of IgM in the glomeruli
• IgM serum levels are elevated by 8 weeks of age

renal/urinary system
• by 6 months of age, mutants exhibit modest albuminuria that gets worse with age
• kidneys show expanded glomeruli and glomerular capillary thickening but no sclerosis
• with age, mutants display severe, global, and diffuse deposition of hyaline material in the glomeruli
• kidneys show rare mild mesangial cell proliferation but no glomerular sclerosis, tubular atrophy, or interstitial perivascular infiltration
• kidneys exhibit segmental multifocal expansion of the mesangial matrix with hyaline materials
• mild focal tubular atrophy
• mutants exhibit impaired kidney function by 14-15 months of age that is preceded by an elevation in IgA at 8-10 months of age
• mutants develop severe and fatal nephritis by 17 months of age
• males develop nephritis faster than females and this gender bias is thought to result from sexual dimorphism in expression in the kidneys of the alpha1-antitrypsin driven transgene

Mouse Models of Human Disease
OMIM IDRef(s)
Iga Nephropathy, Susceptibility to, 1; IGAN1 161950 J:178227


Mouse Genome Informatics
tg13
    Tg(Tnfsf13b)1Fma/0
B6.Cg-Tg(Tnfsf13b)1Fma
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
hematopoietic system
• a marked increase in some B cell subsets compared to wild-type is detected in 12 week old mice
• presence of B-1a (CD5+) B cells are detected compared to controls
• a 3-fold increase in B-1b (CD5-) B cells
• there is an increased frequency of B220neg/lo, IgA+ plasma cells in lamina propria preparations (mutants 45.5% vs wild-type 14.4%)
• IgM dull subset of B cells is larger in transgenic mice compared to control
• B220hi/IgMhi B cell subset is greatly increased in transgenic mice
• large IgMhi B cell subset is phenotypically different from the small IgMhi B cell subset in controls, resembling marginal zone B cells
• numerous germinal centers are observed in B cell follicles of young transgenic mice compared to wild-type and aged transgenic mice
• splenic marginal zone is increased in size, particularly notable in aged mice
• mice exhibit elevated levels in both steady state and in response to antigen stimulation; at 12 weeks of age, IgA levels are increased 1500-fold over wild-type (22.7 mg/ml IgA vs 0.015 mg/ml in wild-type - hyper-IgA)
• augmented IgA staining is found in lamina propria of transgenic mice

immune system
• 60% of mice over 12 months of age have severely inflamed salivary glands with large leukocytic infiltrates
• a marked increase in some B cell subsets compared to wild-type is detected in 12 week old mice
• there is an increased frequency of B220neg/lo, IgA+ plasma cells in lamina propria preparations (mutants 45.5% vs wild-type 14.4%)
• IgM dull subset of B cells is larger in transgenic mice compared to control
• B220hi/IgMhi B cell subset is greatly increased in transgenic mice
• large IgMhi B cell subset is phenotypically different from the small IgMhi B cell subset in controls, resembling marginal zone B cells
• presence of B-1a (CD5+) B cells are detected compared to controls
• a 3-fold increase in B-1b (CD5-) B cells
• numerous germinal centers are observed in B cell follicles of young transgenic mice compared to wild-type and aged transgenic mice
• splenic marginal zone is increased in size, particularly notable in aged mice
• mice exhibit elevated levels in both steady state and in response to antigen stimulation; at 12 weeks of age, IgA levels are increased 1500-fold over wild-type (22.7 mg/ml IgA vs 0.015 mg/ml in wild-type - hyper-IgA)
• augmented IgA staining is found in lamina propria of transgenic mice
• most mice over 13 months of age show signs of severe nephritis

renal/urinary system
• proteinuria is detected only in a subset of 8-month old mice
• most mice over 13 months of age show signs of severe nephritis
• IgA immune complexes are detected in majority of young and aged mice
• IgA deposits are found in nearly all glomeruli, while deposits of each IgG, and IgM are also detected, while very little Ig deposition is found in wild-type kidneys
• significant IgA deposits are found specifically in kidney glomerular mesangium
• in 8-month old mice, glomeruli are slightly enlarged and hypercellular

homeostasis/metabolism
• proteinuria is detected only in a subset of 8-month old mice

digestive/alimentary system
• many mice over 13 months of age have enlarged salivary glands
• mice aged 12-15.5 months of age produce significantly less saliva compared to age-matched controls; this difference is not observed in mice aged 8-10 months
• 60% of mice over 12 months of age have severely inflamed salivary glands with large leukocytic infiltrates

endocrine/exocrine glands
• many mice over 13 months of age have enlarged salivary glands
• mice aged 12-15.5 months of age produce significantly less saliva compared to age-matched controls; this difference is not observed in mice aged 8-10 months
• 60% of mice over 12 months of age have severely inflamed salivary glands with large leukocytic infiltrates

tumorigenesis
• some mice (3 cases) have large submaxillary tumors which contain hyperplastic lymphoid tissue composed of activated B cells and numerous germinal centers; these abnormal aggregates of B lymphoid cells are found in lymphocytic infiltrates of some tumor-free mice

Mouse Models of Human Disease
OMIM IDRef(s)
Sjogren Syndrome 270150 J:73711


Mouse Genome Informatics
tg14
    Tg(Tnfsf13b)1Fma/0
involves: C57BL/6 * DBA/2J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
hematopoietic system
N
• total numbers of T and B cells in bone marrow of transgenic mice is similar to control (J:58798)
• alterations in T cell numbers are present in transgenic mice
• absolute numbers of CD4 circulating T cells are reduced 50% compared to control; similar observations are made for CD8 T cell subset
• total number of T cells in spleen and MLN of transgenics is increased 2-fold
• transgenic mice have higher numbers of circulating lymphocytes than nontransgenic littermates, with numbers as high as 13000 lymphocytes/ul blood
• numbers of peripheral blood B cells are increased compared to controls; expansion of B cell compartment is observed, with global B cell activation
• total B cell number is 7-fold higher than in controls in spleen and mesenteric lymph nodes (MLN)
• mature B cell number in spleen and mesenteric lymph nodes (MLN) is increased compared to controls
• proportion of marginal zone B cells is increased compared to controls, while fraction of newly formed B cells is slightly decreased
• large numbers of plasma cells are present in spleen and mesenteric lymph nodes
• B cell/T cell ratios are increased in transgenics
• mice have enlarged spleens compared to control
• enlarged B cell follicles
• dendritic cells in T cell zone and marginal zone are reduced, compared to controls
• spleens contain large and numerous germinal centers in absence of immunization compared to control
• reduced periarteriolar lymphocyte sheath (or T cell area)
• all B cells in peripheral blood have increased MHC II and Bcl2 expression compared to controls, indicating some level of activation
• mice have hyperglobulinemia
• IgG levels are elevated (50 mg/ml vs ~5-8 mg/ml in controls)
• IgM levels are increased, but not as much as IgG levels
• 40-56% of CD4 or CD8 T cells are activated, with a CD44hi, L-selectinlo phenotype, compared to only 8-12% in control littermates

immune system
• alterations in T cell numbers are present in transgenic mice
• absolute numbers of CD4 circulating T cells are reduced 50% compared to control; similar observations are made for CD8 T cell subset
• total number of T cells in spleen and MLN of transgenics is increased 2-fold
• transgenic mice have higher numbers of circulating lymphocytes than nontransgenic littermates, with numbers as high as 13000 lymphocytes/ul blood
• numbers of peripheral blood B cells are increased compared to controls; expansion of B cell compartment is observed, with global B cell activation
• total B cell number is 7-fold higher than in controls in spleen and mesenteric lymph nodes (MLN)
• mature B cell number in spleen and mesenteric lymph nodes (MLN) is increased compared to controls
• proportion of marginal zone B cells is increased compared to controls, while fraction of newly formed B cells is slightly decreased
• large numbers of plasma cells are present in spleen and mesenteric lymph nodes
• B cell/T cell ratios are increased in transgenics
• mice have enlarged spleens compared to control
• enlarged B cell follicles
• dendritic cells in T cell zone and marginal zone are reduced, compared to controls
• spleens contain large and numerous germinal centers in absence of immunization compared to control
• reduced periarteriolar lymphocyte sheath (or T cell area)
• all B cells in peripheral blood have increased MHC II and Bcl2 expression compared to controls, indicating some level of activation
• mice have hyperglobulinemia
• IgG levels are elevated (50 mg/ml vs ~5-8 mg/ml in controls)
• IgM levels are increased, but not as much as IgG levels
• 40-56% of CD4 or CD8 T cells are activated, with a CD44hi, L-selectinlo phenotype, compared to only 8-12% in control littermates
• Peyer's patches are enlarged
• mice have increased levels of anti-IgG autoantibodies compared to controls; levels of rheumatoid factors (RF) and circulating immune complexes (CIC) are elevated

homeostasis/metabolism
• all transgenics display proteinuria

renal/urinary system
• all transgenics display proteinuria
• immunoglobulin deposition in kidneys is detected


Mouse Genome Informatics
tg15
    Tg(Tnfsf13b)1Fma/0
involves: C57BL/6J * DBA/2J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
hematopoietic system
• expression of CD21/CD35 on B-1 cells from mutants is increased compared to wild-type

immune system
• expression of CD21/CD35 on B-1 cells from mutants is increased compared to wild-type


Mouse Genome Informatics
tg16
    Tg(Tnfsf13b)1Fma/?
B6.Cg-Tg(Tnfsf13b)1Fma
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
• splenic B cell numbers are about twice that of controls
• numbers of T1 B cells in the spleen are increased almost 3-fold while T2 numbers are almost about doubled
• B cells have a vigorous response to T cell independent antigens producing much higher levels of IgG1, IgG2a, IgG2b, IgG3, and IgA class immunoglobulins than controls
• the size of the marginal zone is increased
• the number of splenic marginal zone B cells is increased by about 3-fold
• marginal zone B cells (MZB) mediate autoimmune disease in these transgenic mice as demonstrated by auto-antibody production when MZB are transferred into transgenic mice on a B-cell deficient background
• MZB from transgenic mice have higher integrin adhesion activity
• anti-dsDNA antibodies of the IgM class, IgA class, and all IgG subclasses are found in circulation
• titers of these auto-antibodies increase with
• splenectomy at three weeks of age significantly reduces IgG auto-antibodies and partially reduces auto-antibodies in the other subclasses
• kidneys of 10-month old mice have necrotic lesions
• immunohistology of kidneys with severe lesions reveal numerous glomerular deposits of IgG

renal/urinary system
• all 8-month old mice have proteinuria in their urine with most having 100-300 mg/dl
• kidneys of 10-month old mice have necrotic lesions
• immunohistology of kidneys with severe lesions reveal numerous glomerular deposits of IgG

homeostasis/metabolism
• all 8-month old mice have proteinuria in their urine with most having 100-300 mg/dl

hematopoietic system
• splenic B cell numbers are about twice that of controls
• numbers of T1 B cells in the spleen are increased almost 3-fold while T2 numbers are almost about doubled
• B cells have a vigorous response to T cell independent antigens producing much higher levels of IgG1, IgG2a, IgG2b, IgG3, and IgA class immunoglobulins than controls
• the size of the marginal zone is increased
• the number of splenic marginal zone B cells is increased by about 3-fold
• marginal zone B cells (MZB) mediate autoimmune disease in these transgenic mice as demonstrated by auto-antibody production when MZB are transferred into transgenic mice on a B-cell deficient background
• MZB from transgenic mice have higher integrin adhesion activity