Phenotypes Associated with This Genotype

Genotype
MGI:5800315

• Allelic Composition: Irak3^tm1Flv/Irak3^tm1Flv
• Genetic Background: NOD.129S1(B6)-Irak3^tm1Flv

• ♀: phenotype observed in females
• ♂: phenotype observed in males
• N: normal phenotype

homeostasis/metabolism

impaired glucose tolerance ( J:229884 )

♀ • blood glucose levels of nondiabetic females at a prediabetic stage are higher at both 15 min and 30 min after glucose injection indicating impaired glucose tolerance

immune system

insulitis ( J:229884 )

♀ • although there are more islets with severe insulitis in wild-type mice, the total number of infiltrated islets is much higher in mutant females

abnormal T cell differentiation ( J:229884 )

♀ • in vitro, mutant dendritic cells promote more CD4+ and CD8+ T cells to differentiate into IFN-gamma and TNF-alpha producing Th1 and Tc2 cells, respectively

increased effector memory T-helper cell number ( J:229884 )

♀ • splenic T cells from 3 month old females show a higher proportion of effector/memory cells (CD44^hiCD62L^lo) compared with wild-type mice

abnormal T cell activation ( J:229884 )

♀ • females exhibit enhanced T-cell activation

♀ • splenic T cells from 3 month old females show a higher proportion of effector/memory cells (CD44^hiCD62L^lo) compared with wild-type mice

♀ • females exhibit more IFN-gamma-producing CD4+ T cells and more TNF-alpha-producing CD8+ T cells in splenocytes

♀ • the frequency of proinflammatory cytokine-producing CD4+ T cells is higher in the pancreatic lymph nodes of mutant mice compared with wild-type mice

♀ • however, the frequency of proinflammatory cytokine-producing CD8+ T cells from pancreatic lymph nodes and the number of regulatory T cells is similar to wild-type mice

abnormal professional antigen presenting cell physiology ( J:229884 )

♀ • antigen-presenting cells exhibit a more activated phenotype

♀ • higher number of CD11b+ macrophages and CD11c+ dendritic cells from 3 month old females express the activation/costimulatory marker CD80, CD86, and MHC class II molecules, and females show higher numbers of IFN-gamma-producing CD11b+ macrophages and CD11c+ dendritic cells, and a higher frequency of IL-6-producing and IL-12-producing CD11c+ cells, indicating that antigen-presenting cells are more activated and produce more type I T-helper cell-driven cytokines

abnormal dendritic cell physiology ( J:229884 )

♀ • a higher percentage of dendritic cells from mutant females express activation and costimulatory molecules compared to wild-type mice both without stimulation and in response to stimulation with different TLR agonists (LPS, CpG, or Pam3CKS4)

♀ • dendritic cells secrete higher levels of IL-1beta, IL-6, IL-12(p40) and IFN-gamma both in the absence of TLR ligation and following TLR ligation

♀ • in vitro, in the presence of anti-CD3 mAbs , mutant dendritic cells enhance the activation of both CD4+ and CD8+ T cells

increased susceptibility to autoimmune diabetes ( J:229884 )

♀ • females develop diabetes as early as 6-7 weeks of age, with a higher total incidence compared with onset at 11 and 14 week in heterozygotes and wild-type mice, respectively

♀ • males shows no difference in the development of diabetes compared to wild-type mice, although they show a trend toward early onset

♀ • adoptive transfer of mutant splenocytes into wild-type mice mice results in accelerated development of diabetes in recipient mice compared to transfer of wild-type splenocytes

increased anti-insulin autoantibody level ( J:229884 )

♀ • females show increased anti-insulin IgG autoantibody levels in the serum

endocrine/exocrine glands

insulitis ( J:229884 )

♀ • although there are more islets with severe insulitis in wild-type mice, the total number of infiltrated islets is much higher in mutant females

hematopoietic system

abnormal T cell differentiation ( J:229884 )

♀ • in vitro, mutant dendritic cells promote more CD4+ and CD8+ T cells to differentiate into IFN-gamma and TNF-alpha producing Th1 and Tc2 cells, respectively

increased effector memory T-helper cell number ( J:229884 )

♀ • splenic T cells from 3 month old females show a higher proportion of effector/memory cells (CD44^hiCD62L^lo) compared with wild-type mice

abnormal T cell activation ( J:229884 )

♀ • females exhibit enhanced T-cell activation

♀ • splenic T cells from 3 month old females show a higher proportion of effector/memory cells (CD44^hiCD62L^lo) compared with wild-type mice

♀ • females exhibit more IFN-gamma-producing CD4+ T cells and more TNF-alpha-producing CD8+ T cells in splenocytes

♀ • the frequency of proinflammatory cytokine-producing CD4+ T cells is higher in the pancreatic lymph nodes of mutant mice compared with wild-type mice

♀ • however, the frequency of proinflammatory cytokine-producing CD8+ T cells from pancreatic lymph nodes and the number of regulatory T cells is similar to wild-type mice

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
type 1 diabetes mellitus		DOID:9744	OMIM:222100	J:229884