Mouse Genome Informatics
tg
    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