Phenotypes associated with this allele

• Allele Symbol: Tlr9^tm1Aki
• Allele Name: targeted mutation 1, Shizuo Akira
• Allele ID: MGI:2660562
• Summary: 9 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Tlr9^tm1Aki/Tlr9^tm1Aki	B6.129P2-Tlr9^tm1Aki	MGI:3696117
hm2	Tlr9^tm1Aki/Tlr9^tm1Aki	involves: 129P2/OlaHsd	MGI:4950288
hm3	Tlr9^tm1Aki/Tlr9^tm1Aki	involves: 129P2/OlaHsd * BALB/c * C57BL/6	MGI:3033909
hm4	Tlr9^tm1Aki/Tlr9^tm1Aki	involves: 129P2/OlaHsd * C57BL/6	MGI:2660568
cx5	Fas^lpr/Fas^lpr Tlr9^tm1Aki/Tlr9^tm1Aki	B6.Cg-Tlr9^tm1Aki Fas^lpr	MGI:3799744
cx6	Smcr8^em1Btlr/Smcr8^em1Btlr Tlr3^tm1Flv/Tlr3^tm1Flv Tlr7^tm1Aki/Tlr7^tm1Aki Tlr9^tm1Aki/Tlr9^tm1Aki	involves: 129P2/OlaHsd * 129S1/Sv * C57BL/6J	MGI:6272653
cx7	Tlr9^tm1Aki/Tlr9^tm1Aki Tg(IghelMD4)4Ccg/0 Tg(KLK4mHEL)6Ccg/0	involves: 129P2/OlaHsd * C57BL/6	MGI:3694807
cx8	Tlr9^tm1Aki/Tlr9^tm1Aki Unc93b1^tm1.1Kmiy/Unc93b1^tm1.1Kmiy	involves: 129P2/OlaHsd * C57BL/6	MGI:5140971
cx9	Fas^lpr/Fas^lpr Tlr9^tm1Aki/Tlr9^tm1Aki	MRL.Cg-Tlr9^tm1Aki Fas^lpr	MGI:5478500

Genotype
MGI:3696117

hm1

• Allelic Composition: Tlr9^tm1Aki/Tlr9^tm1Aki
• Genetic Background: B6.129P2-Tlr9^tm1Aki

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

immune system

abnormal immune system physiology ( J:121070 )

• response to LPS and CpG is completely abrogated

impaired natural killer cell mediated cytotoxicity ( J:125611 )

• no NK cell activation is observed following infection with L. infantum

decreased interferon-alpha secretion ( J:125611 )

• following infection with Leishmania baziliensis

• however, secretion could be restored by treatment with GU-rich ssRNA, a TLR7 ligand

decreased interferon-beta secretion ( J:125611 )

• following infection with Leishmania baziliensis

• however, secretion could be restored by treatment with GU-rich ssRNA, a TLR7 ligand

decreased interleukin-12b secretion ( J:118954 , J:125611 )

• following infection with attenuated yellow fever vaccine 17D (YF-17D), dendritic cells produce less IL-12p40 relative to wild-type mice (J:118954)

• unlike in wild-type mice, IL-12p40 production from dendritic cells following infection with Leishmania infantum is indetectable (J:125611)

decreased tumor necrosis factor secretion ( J:121070 )

• following treatment with PbA(Plasmodium bergbei ANKA)-parasitized erythrocytes or LPS-stimulation, TNF secretion is reduced

decreased susceptibility to experimental autoimmune encephalomyelitis ( J:105435 )

• myelin oligodendrocyte glycoprotein injection results in delayed onset of disease, 17.9 days after injection rather than 15.9 days as in controls

• fewer infiltrating foci in the spinal cord

abnormal response to infection ( J:121070 )

• following treatment with PbA (Plasmodium bergbei ANKA)-parasitized erythrocytes, mice have a partially decreased immune response in terms of TNF secretion and response to CpG

decreased susceptibility to parasitic infection ( J:116763 )

• resistant to cerebral malaria

• reduced accumulation of hemozoin

• less upregulation of TNF-alpha in Plasmodium infection

hematopoietic system

impaired natural killer cell mediated cytotoxicity ( J:125611 )

• no NK cell activation is observed following infection with L. infantum

Genotype
MGI:4950288

hm2

• Allelic Composition: Tlr9^tm1Aki/Tlr9^tm1Aki
• Genetic Background: involves: 129P2/OlaHsd

immune system

abnormal leukocyte migration ( J:171379 )

• CpG-treated mice exhibit reduced Ly6C^hi monocyte emigration from the bone marrow compared with similarly treated wild-type mice

cellular

abnormal leukocyte migration ( J:171379 )

• CpG-treated mice exhibit reduced Ly6C^hi monocyte emigration from the bone marrow compared with similarly treated wild-type mice

hematopoietic system

abnormal leukocyte migration ( J:171379 )

• CpG-treated mice exhibit reduced Ly6C^hi monocyte emigration from the bone marrow compared with similarly treated wild-type mice

Genotype
MGI:3033909

hm3

• Allelic Composition: Tlr9^tm1Aki/Tlr9^tm1Aki
• Genetic Background: involves: 129P2/OlaHsd * BALB/c * C57BL/6

immune system

abnormal dendritic cell physiology ( J:88244 )

• failed to produce IFN-gamma in response to HSV-1 in vitro, but ability to control HSV-1 replication in vivo comparable to wild-type mice

Genotype
MGI:2660568

hm4

• Allelic Composition: Tlr9^tm1Aki/Tlr9^tm1Aki
• Genetic Background: involves: 129P2/OlaHsd * C57BL/6

immune system

immune system phenotype ( J:66049 )

N • normal lymphocyte composition, as assessed by flow cytometry

abnormal B cell physiology ( J:66049 )

• impaired MHC class II expression in response to CpG DNA

abnormal T-helper 1 physiology ( J:66049 )

• no observed CpG-DNA-induced Th1-like response in vivo

abnormal macrophage physiology ( J:66049 , J:117688 )

• impaired ability to produce IL6, IL12 and TNF-alpha in response to CpG DNA (J:66049)

• production of IL6, IL12, and TNF-alpha in response to LPS, PGN, lipoprotein from Escherichia coli, zymosan, and heat-killed Staphylococcus aureus was comparable to wild-type controls (J:66049)

• response to CpG is considerably decreased compared to wild-type (J:117688)

abnormal dendritic cell physiology ( J:66049 )

• impaired production of IL12 in response to CpG DNA, but not LPS

• impaired expression of CD40, CD80, CD86, and MHC II in response to CpG DNA, but not LPS

decreased inflammatory response ( J:66049 )

• resistant to CpG-DNA-induced shock syndrome compared to wild-type mice

• unlike wild-type controls, no increase in serum IL6, IL12, or TNF-alpha in response to CpG-DNA in vivo

hematopoietic system

abnormal B cell physiology ( J:66049 )

• impaired MHC class II expression in response to CpG DNA

abnormal T-helper 1 physiology ( J:66049 )

• no observed CpG-DNA-induced Th1-like response in vivo

abnormal macrophage physiology ( J:66049 , J:117688 )

• impaired ability to produce IL6, IL12 and TNF-alpha in response to CpG DNA (J:66049)

• production of IL6, IL12, and TNF-alpha in response to LPS, PGN, lipoprotein from Escherichia coli, zymosan, and heat-killed Staphylococcus aureus was comparable to wild-type controls (J:66049)

• response to CpG is considerably decreased compared to wild-type (J:117688)

Genotype
MGI:3799744

cx5

• Allelic Composition: Fas^lpr/Fas^lpr; Tlr9^tm1Aki/Tlr9^tm1Aki
• Genetic Background: B6.Cg-Tlr9^tm1Aki Fas^lpr

mortality/aging

premature death ( J:135036 )

• 66% survival at 24 weeks

hematopoietic system

enlarged spleen ( J:135036 )

• spleens are 5-fold heavier than in MRL/MpJ-Fas^lpr mice

increased double-negative T cell number ( J:135036 )

• dramatically increased compared to wild-type; increased relative to Tlr9 and Fas mutants

increased IgG level ( J:135036 )

• total levels are higher than wild-type or Fas^lpr mice

decreased IgM level ( J:135036 )

• lower than in Fas^lpr mice

immune system

enlarged spleen ( J:135036 )

• spleens are 5-fold heavier than in MRL/MpJ-Fas^lpr mice

increased double-negative T cell number ( J:135036 )

• dramatically increased compared to wild-type; increased relative to Tlr9 and Fas mutants

increased IgG level ( J:135036 )

• total levels are higher than wild-type or Fas^lpr mice

decreased IgM level ( J:135036 )

• lower than in Fas^lpr mice

enlarged lymph nodes ( J:135036 )

• generalized lymphadenopathy

• axillary and inguinal lymph node weights are greater than in Fas^lpr mice (by >5-fold)

autoimmune response ( J:135036 )

• autoantibodies such as anti-ssDNA, anti-dsDNA, anti-cardiolipin, and anti-IgG are detected, and levels are not different from Fas mutants

glomerulonephritis ( J:135036 )

• interstitial lymphoid infiltration is observed at 13 weeks

• mesangial proliferation is greater than in Fas single mutants

homeostasis/metabolism

increased urine protein level ( J:135036 )

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

renal/urinary system

increased urine protein level ( J:135036 )

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

glomerulonephritis ( J:135036 )

• interstitial lymphoid infiltration is observed at 13 weeks

• mesangial proliferation is greater than in Fas single mutants

renal glomerular immunoglobulin deposits ( J:135036 )

• glomerular IgG deposits that are exclusively mesangial are more severe than in Fas single mutants

growth/size/body

enlarged spleen ( J:135036 )

• spleens are 5-fold heavier than in MRL/MpJ-Fas^lpr mice

Genotype
MGI:6272653

cx6

• Allelic Composition: Smcr8^em1Btlr/Smcr8^em1Btlr; Tlr3^tm1Flv/Tlr3^tm1Flv; Tlr7^tm1Aki/Tlr7^tm1Aki; Tlr9^tm1Aki/Tlr9^tm1Aki
• Genetic Background: involves: 129P2/OlaHsd * 129S1/Sv * C57BL/6J

immune system

immune system phenotype ( J:268243 )

N • unlike in Smcr8^em1Btlr homozygotes, spleen and lymph nodes are restored to normal as well as is the hyperactivation of T cells and increased circulating IL12p40 levels

Genotype
MGI:3694807

cx7

• Allelic Composition: Tlr9^tm1Aki/Tlr9^tm1Aki; Tg(IghelMD4)4Ccg/0; Tg(KLK4mHEL)6Ccg/0
• Genetic Background: involves: 129P2/OlaHsd * C57BL/6

hematopoietic system

decreased mature B cell number ( J:115059 )

• a 37% reduction in number of recirculating mature autoreactive B cells is observed compared to wild-type

increased B-1 B cell number ( J:115059 )

• more B1 cells are detected among peritoneal lymphocytes in double transgenic mutants compared to Tg(IghelMD4)4Ccg single transgenic mutants

immune system

decreased mature B cell number ( J:115059 )

• a 37% reduction in number of recirculating mature autoreactive B cells is observed compared to wild-type

increased B-1 B cell number ( J:115059 )

• more B1 cells are detected among peritoneal lymphocytes in double transgenic mutants compared to Tg(IghelMD4)4Ccg single transgenic mutants

Genotype
MGI:5140971

cx8

• Allelic Composition: Tlr9^tm1Aki/Tlr9^tm1Aki; Unc93b1^tm1.1Kmiy/Unc93b1^tm1.1Kmiy
• Genetic Background: involves: 129P2/OlaHsd * C57BL/6

mortality/aging

premature death ( J:174308 )

• as in Unc93b1^tm1.1Kmiy homozygotes

hematopoietic system

thrombocytopenia ( J:174308 )

• as in Unc93b1^tm1.1Kmiy homozygotes

Genotype
MGI:5478500

cx9

• Allelic Composition: Fas^lpr/Fas^lpr; Tlr9^tm1Aki/Tlr9^tm1Aki
• Genetic Background: MRL.Cg-Tlr9^tm1Aki Fas^lpr

mortality/aging

premature death ( J:113557 )

• mutants show accelerated mortality relative to Fas^lpr homozygotes, with a median survival of 16.4 weeks compared to 25.1 weeks for Fas^lpr homozygotes

immune system

enlarged spleen ( J:113557 )

• splenomegaly is increased more than in Fas^lpr homozygotes

increased double-negative T cell number ( J:113557 )

• 3-fold increase in the number of CD4- CD8- double-negative T cells in the spleen compared to Fas^lpr homozygotes

increased CD4-positive, alpha-beta T cell number ( J:113557 )

• increase in number of CD4+ helper T cells compared to Fas^lpr homozygotes

abnormal B cell activation ( J:113557 )

• B cells have increased expression of activation markers CD44 and CD69 compared to Fas^lpr homozygotes, indicating increased B cell activation

increased IgG level ( J:113557 )

• increase in concentration of every IgG isotype compared to Fas^lpr homozygotes, with most prominent increases in IgG2a and IgG3

increased IgG2a level ( J:113557 )

• compared to Fas^lpr homozygotes

increased IgG3 level ( J:113557 )

• compared to Fas^lpr homozygotes

increased circulating interferon-alpha level ( J:113557 )

• mice exhibit increased serum IFN-alpha concentration compared to Fas^lpr homozygotes

enlarged lymph nodes ( J:113557 )

• lymphadenopathy is increased more than in Fas^lpr homozygotes

abnormal plasmacytoid dendritic cell physiology ( J:113557 )

• splenic plasmacytoid dendritic cells (pDC) are more activated than those in single Fas^lpr homozygotes based on increased expression of MHC class II

• plasmacytoid DCs have an increased expression of the activation markers CD80 and CD86 compared to Fas^lpr homozygotes

increased susceptibility to systemic lupus erythematosus ( J:113557 )

• mutants exhibit an increase in the incidence and severity of autoimmune skin disease compared to single Fas^lpr homozygous littermates

• mutants develop exacerbated kidney disease (lupus nephritis) compared to single Fas^lpr homozygotes

decreased autoantibody level ( J:113557 )

• mutants show impaired ability to generate antibodies to DNA antigens compared to single Fas^lpr homozygotes, however they do generate antibodies reacting with cytoplasmic antigens that may include RNA

increased autoantibody level ( J:113557 )

• mice exhibit an elevated baseline level of anti-Smith-ribonucleoprotein autoantibodies compared to single Fas^lpr homozygotes

kidney inflammation ( J:113557 )

• mutants develop exacerbated kidney disease (lupus nephritis) compared to Fas^lpr homozygotes

• a trend towards increased severity of interstitial infiltrates compared to Fas^lpr homozygotes

glomerulonephritis ( J:113557 )

• increase in glomerular size, cellularity, and protein deposition in kidneys leading to glomerulonephritis

renal/urinary system

kidney inflammation ( J:113557 )

• mutants develop exacerbated kidney disease (lupus nephritis) compared to Fas^lpr homozygotes

• a trend towards increased severity of interstitial infiltrates compared to Fas^lpr homozygotes

glomerulonephritis ( J:113557 )

• increase in glomerular size, cellularity, and protein deposition in kidneys leading to glomerulonephritis

abnormal renal glomerulus morphology ( J:113557 )

• glomerular size and cellularity are increased compared to Fas^lpr homozygotes

hematopoietic system

enlarged spleen ( J:113557 )

• splenomegaly is increased more than in Fas^lpr homozygotes

increased double-negative T cell number ( J:113557 )

• 3-fold increase in the number of CD4- CD8- double-negative T cells in the spleen compared to Fas^lpr homozygotes

increased CD4-positive, alpha-beta T cell number ( J:113557 )

• increase in number of CD4+ helper T cells compared to Fas^lpr homozygotes

abnormal B cell activation ( J:113557 )

• B cells have increased expression of activation markers CD44 and CD69 compared to Fas^lpr homozygotes, indicating increased B cell activation

increased IgG level ( J:113557 )

• increase in concentration of every IgG isotype compared to Fas^lpr homozygotes, with most prominent increases in IgG2a and IgG3

increased IgG2a level ( J:113557 )

• compared to Fas^lpr homozygotes

increased IgG3 level ( J:113557 )

• compared to Fas^lpr homozygotes

homeostasis/metabolism

increased circulating interferon-alpha level ( J:113557 )

• mice exhibit increased serum IFN-alpha concentration compared to Fas^lpr homozygotes

growth/size/body

enlarged spleen ( J:113557 )

• splenomegaly is increased more than in Fas^lpr homozygotes

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
systemic lupus erythematosus		DOID:9074	OMIM:152700 OMIM:300809 OMIM:605480 OMIM:608437 OMIM:609903 OMIM:609939 OMIM:610065 OMIM:610066 OMIM:612254 OMIM:612378 OMIM:613145 OMIM:614420	J:113557