Phenotypes associated with this allele

• Allele Symbol: Tnf⁺
• Allele Name: wild type
• Allele ID: MGI:2152815
• Summary: 37 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
ht1	Tnf^tm2Gkl/Tnf^+	B6.129S-Tnf^tm2Gkl/Jarn	MGI:5702925
ht2	Tnf^M1Btlr/Tnf^+	C57BL/6J-Tnf^M1Btlr	MGI:3722938
ht3	Tnf^M2Btlr/Tnf^+	C57BL/6J-Tnf^M2Btlr	MGI:5582754
ht4	Tnf^em4Boui/Tnf^+	C57BL/6-Tnf^em4Boui	MGI:6730101
ht5	Tnf^Bpsm1/Tnf^+	C.Cg-Tnf^Bpsm1	MGI:6272038
ht6	Tnf^tm1Ljo/Tnf^+	involves: 129S1/Sv	MGI:2175018
ht7	Lta/Tnf^tm1Fda/Tnf^+	involves: 129S1/Sv * 129X1/SvJ	MGI:3768394
ht8	Tnf^tm2Gkl/Tnf^+	involves: 129S/SvEv * C57BL/6	MGI:3622061
ht9	Tnf^tm2Gkl/Tnf^+	involves: 129S/SvEv * C57BL/6 * CBA	MGI:3775436
ht10	Tnf^tm2Gkl/Tnf^+	involves: 129S/SvEv * C57BL/6J	MGI:3629514
ht11	Tnf^tm2Gkl/Tnf^+	involves: 129S/SvEv * C57BL/6 * SPRET/Ei	MGI:3622071
ht12	Tnf^Bpsm1/Tnf^+	involves: C57BL/6	MGI:6272035
cn13	Tnf^tm2.1Gkl/Tnf^+ Lyz2^tm1(cre)Ifo/Lyz2^+	involves: 129P2/OlaHsd * 129S/SvEv * 129S6/SvEvTac * C57BL/6J	MGI:3629610
cn14	Tnf^tm2Gkl/Tnf^+ Tnfrsf1b^tm1.1Gkl/Tnfrsf1b^tm1.1Gkl Tg(Col6a1-cre)1Gkl/0	involves: 129S/SvEv * C57BL/6 * C57BL/6J * CBA	MGI:6195612
cn15	Tnf^tm2Gkl/Tnf^+ Tnfrsf1a^tm2Gkl/Tnfrsf1a^tm2Gkl Tg(Col6a1-cre)1Gkl/0	involves: 129S/SvEv * C57BL/6 * C57BL/6J * CBA	MGI:6195614
cn16	Tnf^tm2Gkl/Tnf^+ Tnfrsf1a^tm2Gkl/Tnfrsf1a^tm2Gkl Tg(Col6a1-cre)1Gkl/?	involves: 129S/SvEv * C57BL/6 * CBA	MGI:3775437
cx17	Mapk11^tm1Jsca/Mapk11^tm1Jsca Tnf^tm2Gkl/Tnf^+	involves: 129P2/OlaHsd * 129S/SvEv * C57BL/6	MGI:3622058
cx18	Tcrd^tm1Mom/Tcrd^tm1Mom Tnf^tm2Gkl/Tnf^+	involves: 129P2/OlaHsd * 129S/SvEv * C57BL/6J	MGI:3629523
cx19	Mapk9^tm1Flv/Mapk9^tm1Flv Tnf^tm2Gkl/Tnf^+	involves: 129P2/OlaHsd * 129S/SvEv * C57BL/6J	MGI:3629608
cx20	Mapkapk2^tm1Mgl/Mapkapk2^tm1Mgl Tnf^tm2Gkl/Tnf^+	involves: 129P2/OlaHsd * 129S/SvEv * C57BL/6J	MGI:3629603
cx21	Map3k8^tm1Pnt/Map3k8^tm1Pnt Tnf^tm2Gkl/Tnf^+	involves: 129P2/OlaHsd * 129S/SvEv * C57BL/6J	MGI:3629606
cx22	Tnf^tm1Ljo/Tnf^+ Tnip1^tm1.1Ama/Tnip1^tm1.1Ama	involves: 129S1/Sv * C57BL/6J	MGI:3835807
cx23	Tnf^Bpsm1/Tnf^+ Tnfrsf1a^tm1Mak/Tnfrsf1a^tm1Mak	involves: 129S2/SvPas * C57BL/6	MGI:6272040
cx24	Tnf^em5Boui/Tnf^+ Tnfrsf1a^tm1Mak/Tnfrsf1a^+	involves: 129S2/SvPas * C57BL/6	MGI:6730103
cx25	Cd44^tm1Hbg/Cd44^tm1Hbg Tnf^tm2Gkl/Tnf^+	involves: 129S/SvEv * 129S1/Sv * 129X1/SvJ * C57BL/6	MGI:5702938
cx26	Cd44^tm1Hbg/Cd44^+ Tnf^tm2Gkl/Tnf^+	involves: 129S/SvEv * 129S1/Sv * 129X1/SvJ * C57BL/6	MGI:5702939
cx27	Il12b^tm1Jm/Il12b^tm1Jm Tnf^tm2Gkl/Tnf^+	involves: 129S/SvEv * 129S1/Sv * C57BL/6J	MGI:3629590
cx28	Ccr9^tm1.1Mal/Ccr9^tm1.1Mal Tnf^tm2Gkl/Tnf^+	involves: 129S/SvEv * 129S2/SvPas * C57BL/6	MGI:3799634
cx29	Ccl25^tm1.1Mal/Ccl25^tm1.1Mal Tnf^tm2Gkl/Tnf^+	involves: 129S/SvEv * 129S2/SvPas * C57BL/6	MGI:3799633
cx30	Tnf^tm2Gkl/Tnf^+ Tnfrsf1b^tm1Mwm/Tnfrsf1b^tm1Mwm	involves: 129S/SvEv * 129S2/SvPas * C57BL/6	MGI:3622064
cx31	Ighm^tm1Cgn/Ighm^tm1Cgn Tnf^tm2Gkl/Tnf^+	involves: 129S/SvEv * 129S2/SvPas * C57BL/6J	MGI:3629519
cx32	Cd4^tm1Mak/Cd4^tm1Mak Tnf^tm2Gkl/Tnf^+	involves: 129S/SvEv * 129S2/SvPas * C57BL/6J	MGI:3629516
cx33	B2m^tm1Jae/B2m^tm1Jae Tnf^tm2Gkl/Tnf^+	involves: 129S/SvEv * 129S2/SvPas * C57BL/6J	MGI:3629515
cx34	Rag1^tm1Mom/Rag1^tm1Mom Tnf^tm2Gkl/Tnf^+	involves: 129S/SvEv * 129S7/SvEvBrd * C57BL/6	MGI:3622066
cx35	Ifng^tm1Ts/Ifng^tm1Ts Tnf^tm2Gkl/Tnf^+	involves: 129S/SvEv * 129S7/SvEvBrd * C57BL/6J	MGI:3629594
cx36	Itgb7^tm1Cgn/Itgb7^tm1Cgn Tnf^tm2Gkl/Tnf^+	involves: 129S/SvEv * C57BL/6	MGI:3799636
cx37	Tnf^tm2Gkl/Tnf^+ Tnfrsf1b^tm1.2Gkl/Tnfrsf1b^tm1.2Gkl	involves: 129S/SvEv * C57BL/6 * C57BL/6J	MGI:6195613

Genotype
MGI:5702925

ht1

• Allelic Composition: Tnf^tm2Gkl/Tnf⁺
• Genetic Background: B6.129S-Tnf^tm2Gkl/Jarn

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

immune system

ileum inflammation ( J:131978 , J:145626 )

• antibody depletion of CD8+ T cells does not improve ileitis (J:131978)

• with increased levels of soluble hyaluronan (J:145626)

increased CD4-positive, alpha-beta T cell number ( J:145626 )

• increased percentage of CD4+/CD44^high T cells in populations from the spleen, mesenteric lymph nodes and lamina propria by 20 weeks of age

increased CD4-positive, alpha-beta memory T cell number ( J:145626 )

abnormal CD8-positive, alpha beta T cell morphology ( J:131978 )

• CD8+ population polarized into CD44^high/CD103^low and CD44^low/CD103^high subsets in mice with advanced disease

abnormal CD4-positive, alpha-beta T cell physiology ( J:145626 )

• increased reactivity and rolling flux fraction

increased interferon-gamma secretion ( J:131978 )

• in CD8+/CD44^high T cells

increased interleukin-2 secretion ( J:145626 )

• in CD4+/CD44^high T cells

increased tumor necrosis factor secretion ( J:145626 )

• in CD4+/CD44^high T cells

digestive/alimentary system

ileum inflammation ( J:131978 , J:145626 )

• antibody depletion of CD8+ T cells does not improve ileitis (J:131978)

• with increased levels of soluble hyaluronan (J:145626)

hematopoietic system

increased CD4-positive, alpha-beta T cell number ( J:145626 )

• increased percentage of CD4+/CD44^high T cells in populations from the spleen, mesenteric lymph nodes and lamina propria by 20 weeks of age

increased CD4-positive, alpha-beta memory T cell number ( J:145626 )

abnormal CD8-positive, alpha beta T cell morphology ( J:131978 )

• CD8+ population polarized into CD44^high/CD103^low and CD44^low/CD103^high subsets in mice with advanced disease

abnormal CD4-positive, alpha-beta T cell physiology ( J:145626 )

• increased reactivity and rolling flux fraction

Genotype
MGI:3722938

ht2

• Allelic Composition: Tnf^M1Btlr/Tnf⁺
• Genetic Background: C57BL/6J-Tnf^M1Btlr

immune system

immune system phenotype ( J:124642 )

N • number and morphology of Peyer's patches, formation of germinal centers in the spleen, and survival after sublethal infection with Listeria monocytogenes are all similar to wild-type mice, unlike in Tnf^tm1Gkl homozygotes

decreased follicular dendritic cell number ( J:124642 )

• upon immunization with a T cell antigen, there are a reduced number of follicular dendritic cells in the spleen

Genotype
MGI:5582754

ht3

• Allelic Composition: Tnf^M2Btlr/Tnf⁺
• Genetic Background: C57BL/6J-Tnf^M2Btlr

immune system

decreased macrophage cytokine production ( J:213047 )

• decreased TNFalpha secretion in response to Toll-like receptor (TLR) ligands, LPS (TLR4) and R848 (TLR7/8)

decreased tumor necrosis factor secretion ( J:213047 )

• decreased TNFalpha secretion in response to Toll-like receptor (TLR) ligands, LPS (TLR4) and R848 (TLR7/8)

hematopoietic system

decreased macrophage cytokine production ( J:213047 )

• decreased TNFalpha secretion in response to Toll-like receptor (TLR) ligands, LPS (TLR4) and R848 (TLR7/8)

Genotype
MGI:6730101

ht4

• Allelic Composition: Tnf^em4Boui/Tnf⁺
• Genetic Background: C57BL/6-Tnf^em4Boui

cardiovascular system

cardiovalvulitis ( J:306876 )

digestive/alimentary system

colitis ( J:306876 )

ileum inflammation ( J:306876 )

esophageal inflammation ( J:306876 )

immune system

cardiovalvulitis ( J:306876 )

colitis ( J:306876 )

ileum inflammation ( J:306876 )

esophageal inflammation ( J:306876 )

autoimmune arthritis ( J:306876 )

mortality/aging

premature death ( J:306876 )

• most mice die by age 250 days

skeleton

autoimmune arthritis ( J:306876 )

Genotype
MGI:6272038

ht5

• Allelic Composition: Tnf^Bpsm1/Tnf⁺
• Genetic Background: C.Cg-Tnf^Bpsm1

cardiovascular system

aortic aneurysm ( J:226052 )

• Background Sensitivity: all mice exhibit aortic root aneurisms; aneurisms are much more pronounced on the BALB/c background than on a C57BL/6 background

thick mitral valve ( J:226052 )

thick aortic valve ( J:226052 )

cardiac fibrosis ( J:226052 )

• fibrosis involving the aortic and mitral valves

cardiac valve regurgitation ( J:226052 )

• valve disease manifests mainly as regurgitation, indicated by the presence of a backward aortic blood flow

cardiovalvulitis ( J:226052 )

• aortic and mitral valve inflammation

• however, the tricuspid and pulmonary valves are unaffected

aortic valve inflammation ( J:226052 )

mitral valve inflammation ( J:226052 )

immune system

cardiovalvulitis ( J:226052 )

• aortic and mitral valve inflammation

• however, the tricuspid and pulmonary valves are unaffected

aortic valve inflammation ( J:226052 )

mitral valve inflammation ( J:226052 )

mortality/aging

premature death ( J:226052 )

• Background Sensitivity: many mice die suddenly between 90 and 160 days of age on the BALB/c background unlike on a C57BL/6 background

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
heart valve disease		DOID:4079		J:226052

Genotype
MGI:2175018

ht6

• Allelic Composition: Tnf^tm1Ljo/Tnf⁺
• Genetic Background: involves: 129S1/Sv

immune system

increased susceptibility to bacterial infection ( J:41992 )

• exhibit increased susceptibility to high-dose LPS lethality

• exhibit delayed resolution of the Corynebacterium parvum induced inflammatory process lipopolysaccharide (LPS) lethality

increased susceptibility to fungal infection ( J:41992 )

• exhibit increased susceptibility to Candida albicans challenge; 60% die by 30 days post-infection

Genotype
MGI:3768394

ht7

• Allelic Composition: Lta/Tnf^tm1Fda/Tnf⁺
• Genetic Background: involves: 129S1/Sv * 129X1/SvJ

immune system

decreased tumor necrosis factor secretion ( J:39519 )

• mice produce 60-fold less TNF-alpha in response to treatment with 100 ug LPS than wild-type mice

decreased susceptibility to endotoxin shock ( J:39519 )

• at low doses of LPS and D-galactosamine lethality is 30% compared to 60% in wild-type mice and a high doses lethality is only increased slightly

increased susceptibility to bacterial infection ( J:39519 )

• bacterial load in the liver and spleen are 20- and 4-fold higher, respectively, than in wild-type mice but not as high as in homozygotes

Genotype
MGI:3622061

ht8

• Allelic Composition: Tnf^tm2Gkl/Tnf⁺
• Genetic Background: involves: 129S/SvEv * C57BL/6

immune system

intestinal inflammation ( J:136667 )

• elevated chronic and acute inflammatory indices

small intestinal inflammation ( J:54056 , J:92307 , J:204922 )

• first detected between 2 and 4 weeks of age as mucosal abnormalities with intestinal villous blunting and broadening generally confined to the terminal ileum (J:54056)

• becomes severe by 8 weeks, with increased numbers of submucosal lymphoid aggregates and follicles eventually penetrating deep into the muscular layers of the bowel wall (J:54056)

• by 4-7 months of age complete loss of villous structure and rudimental granulomata are seen (J:54056)

• at 9 months similar bowel inflammation extending into the mucosal layers and loss of crypt morphology is seen in mice on a mixed background with or without SPRET/Ei (J:92307)

• mutants on a high-fat diet develop accelerated onset of intestinal inflammation compared to wild-type mice (J:204922)

ileum inflammation ( J:204922 )

increased dendritic cell number ( J:204922 )

• mutants show higher numbers of CD11c+ dendritic cells in the ileal lamina propria when fed a high-fat diet compared to wild-type mice

abnormal T cell subpopulation ratio ( J:136667 )

• at 16 weeks of age, the CD8alpha alpha to CD8alpha beta ratio is significantly decreased in the lamina propria of the ileum

abnormal CD8-positive, alpha beta T cell morphology ( J:136667 )

• at 4 weeks of age, fewer CD8alpha alpha intraepithelial lymphocytes are present in the ileum

• however, no significant difference is seen in the number of CD8alpha beta intraepithelial lymphocytes

abnormal alpha-beta intraepithelial T cell morphology ( J:136667 )

• decrease in TCRalpha beta CD8alpha alpha and TCRalpha beta CD8alpha alpha CD4 numbers

abnormal T cell physiology ( J:136667 )

• increase in the number of TNF-producing cells in the lamina propria and intraepithelial lymphocyte subsets

abnormal CD4-positive, alpha-beta T cell physiology ( J:136667 )

• reduced expression of interferon gamma and increased expression of interleukin 17 and 10 in CD4+ lymphocytes in the lamina propria of the ileum

abnormal T-helper 17 cell physiology ( J:204922 )

• mutants show increased Th17-biased lymphocyte infiltration into the lamina propria of the ileum on a high-fat diet compared to wild-type mice

abnormal circulating chemokine level ( J:204922 )

• mutants exhibit increased plasma CCL20 levels on both a regular or high-fat diet compared to wild-type mice

increased circulating tumor necrosis factor level ( J:54056 , J:204922 )

• at 6 weeks of age circulating levels of TNF are up between 90 and 430 pg/ml compared to undetectable levels in wild-type mice (J:54056)

• TNF plasma levels are increased at 12 weeks of age in mutants compared to wild-type mice, however high-fat diet does not result in a further increase (J:204922)

decreased inflammatory response ( J:204922 )

• expression analysis indicates that mutants do not show adipose tissue inflammation when fed a high-fat diet as seen in wild-type mice

autoimmune arthritis ( J:92307 , J:136667 )

• Background Sensitivity: at 9 months arthritis is severe enough to reduce mobility unlike in mice on a mixed background including SPRET/Ei (J:92307)

• at 9 months joints show extensive lymphocytic infiltration, thickening of the synovial lining, pannus formation, and abnormal ingrowth of the synovial lining (J:92307)

rheumatoid arthritis ( J:54056 )

digestive/alimentary system

steatorrhea ( J:204922 )

• mutants show elevated fecal energy content when fed a high-fat diet, suggesting steatorrhea, which is not seen in wild-type mice

abnormal intestine physiology ( J:204922 )

• mutants show increased intestinal permeability when fed a high-fat diet

intestinal inflammation ( J:136667 )

• elevated chronic and acute inflammatory indices

small intestinal inflammation ( J:54056 , J:92307 , J:204922 )

• first detected between 2 and 4 weeks of age as mucosal abnormalities with intestinal villous blunting and broadening generally confined to the terminal ileum (J:54056)

• becomes severe by 8 weeks, with increased numbers of submucosal lymphoid aggregates and follicles eventually penetrating deep into the muscular layers of the bowel wall (J:54056)

• by 4-7 months of age complete loss of villous structure and rudimental granulomata are seen (J:54056)

• at 9 months similar bowel inflammation extending into the mucosal layers and loss of crypt morphology is seen in mice on a mixed background with or without SPRET/Ei (J:92307)

• mutants on a high-fat diet develop accelerated onset of intestinal inflammation compared to wild-type mice (J:204922)

ileum inflammation ( J:204922 )

skeleton

autoimmune arthritis ( J:92307 , J:136667 )

• Background Sensitivity: at 9 months arthritis is severe enough to reduce mobility unlike in mice on a mixed background including SPRET/Ei (J:92307)

• at 9 months joints show extensive lymphocytic infiltration, thickening of the synovial lining, pannus formation, and abnormal ingrowth of the synovial lining (J:92307)

rheumatoid arthritis ( J:54056 )

homeostasis/metabolism

steatorrhea ( J:204922 )

• mutants show elevated fecal energy content when fed a high-fat diet, suggesting steatorrhea, which is not seen in wild-type mice

decreased susceptibility to diet-induced obesity ( J:204922 )

• mutants do not develop obesity on a high-fat diet as seen in wild-type mice

• mutants on a high-fat diet do not show increased fat depots or enlarged adipocytes as seen in wild-type mice

abnormal circulating leptin level ( J:204922 )

• mutants on high-fat diet do not exhibit an increase in plasma leptin levels as seen in wild-type mice

abnormal circulating chemokine level ( J:204922 )

• mutants exhibit increased plasma CCL20 levels on both a regular or high-fat diet compared to wild-type mice

increased circulating tumor necrosis factor level ( J:54056 , J:204922 )

• at 6 weeks of age circulating levels of TNF are up between 90 and 430 pg/ml compared to undetectable levels in wild-type mice (J:54056)

• TNF plasma levels are increased at 12 weeks of age in mutants compared to wild-type mice, however high-fat diet does not result in a further increase (J:204922)

abnormal glucose homeostasis ( J:204922 )

• glucose homeostasis remains normal in mutants fed a high-fat diet unlike in wild-type mice which show impaired glucose tolerance and elevated fasting blood glucose

hematopoietic system

increased dendritic cell number ( J:204922 )

• mutants show higher numbers of CD11c+ dendritic cells in the ileal lamina propria when fed a high-fat diet compared to wild-type mice

abnormal T cell subpopulation ratio ( J:136667 )

• at 16 weeks of age, the CD8alpha alpha to CD8alpha beta ratio is significantly decreased in the lamina propria of the ileum

abnormal CD8-positive, alpha beta T cell morphology ( J:136667 )

• at 4 weeks of age, fewer CD8alpha alpha intraepithelial lymphocytes are present in the ileum

• however, no significant difference is seen in the number of CD8alpha beta intraepithelial lymphocytes

abnormal alpha-beta intraepithelial T cell morphology ( J:136667 )

• decrease in TCRalpha beta CD8alpha alpha and TCRalpha beta CD8alpha alpha CD4 numbers

abnormal T cell physiology ( J:136667 )

• increase in the number of TNF-producing cells in the lamina propria and intraepithelial lymphocyte subsets

abnormal CD4-positive, alpha-beta T cell physiology ( J:136667 )

• reduced expression of interferon gamma and increased expression of interleukin 17 and 10 in CD4+ lymphocytes in the lamina propria of the ileum

abnormal T-helper 17 cell physiology ( J:204922 )

• mutants show increased Th17-biased lymphocyte infiltration into the lamina propria of the ileum on a high-fat diet compared to wild-type mice

integument

alopecia ( J:92307 )

• at 9 months of age

behavior/neurological

abnormal food intake ( J:204922 )

• mutants exhibit increased energy intake on a high-fat diet

growth/size/body

decreased susceptibility to diet-induced obesity ( J:204922 )

• mutants do not develop obesity on a high-fat diet as seen in wild-type mice

• mutants on a high-fat diet do not show increased fat depots or enlarged adipocytes as seen in wild-type mice

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
inflammatory bowel disease		DOID:0050589	OMIM:PS266600	J:136667 , J:204922 , J:54056
rheumatoid arthritis		DOID:7148	OMIM:180300	J:54056

Genotype
MGI:3775436

ht9

• Allelic Composition: Tnf^tm2Gkl/Tnf⁺
• Genetic Background: involves: 129S/SvEv * C57BL/6 * CBA

immune system

autoimmune arthritis ( J:131930 )

• bilaterial inflammation of the sacroiliac joints occurs starting at 4 weeks of age

• the fibrocartilagenous portion of the joint is invaded by mononuclear cells that protrude into the bone marrow

skeleton

autoimmune arthritis ( J:131930 )

• bilaterial inflammation of the sacroiliac joints occurs starting at 4 weeks of age

• the fibrocartilagenous portion of the joint is invaded by mononuclear cells that protrude into the bone marrow

Genotype
MGI:3629514

ht10

• Allelic Composition: Tnf^tm2Gkl/Tnf⁺
• Genetic Background: involves: 129S/SvEv * C57BL/6J

skeleton

abnormal joint morphology ( J:264147 )

• cultured synovial fibroblasts are bipolar rather than multipolar and exhibit a more complex and denser actin filament network

cellular

increased apoptosis ( J:108572 )

• mice display high levels of apoptosis in the ilea at 3 months of age

increased cell migration ( J:264147 )

• valvular interstitial cells show 70-80% closure of a wound in culture compared to around 20% in wild-type cells, indicating increased migration

increased fibroblast cell migration ( J:264147 )

• synovial fibroblasts show 70-80% closure of a wound in culture compared to around 20% in wild-type cells, indicating increased migration

increased cell proliferation ( J:264147 )

• valvular interstitial cells display a 2- to 3-fold increase in proliferation

increased fibroblast proliferation ( J:264147 )

• synovial fibroblasts display a 2- to 3-fold increase in proliferation

cardiovascular system

abnormal aorta bulb morphology ( J:264147 )

• by 16 weeks of age, the aortic root is thickened to about 10-15 times compared with wild-type

abnormal aortic valve morphology ( J:264147 )

• cultured valvular interstitial cells are bipolar rather than multipolar and exhibit a more complex and denser actin filament network

thick aortic valve cusps ( J:264147 )

• by 16 weeks of age, the aortic valve leaflets are thickened to about 10-15 times compared with wild-type

aortic valve stenosis ( J:264147 )

• mice progressively develop stenosis of the aortic valve leaflets starting at 8 weeks of age with 100% incidence

• treatment with an anti-TNF, etanercept (enbrel), and prophylactic regimen for 10 weeks upon disease initiation prevents the development of aortic valve stenosis and fibrosis

cardiac fibrosis ( J:264147 )

• thickened valves develop fibrosis but show very little immune cell infiltration

• treatment with an anti-TNF, etanercept (enbrel), and prophylactic regimen for 10 weeks upon disease initiation prevents the development of aortic valve fibrosis

decreased cardiac output ( J:264147 )

• cardiac output is reduced at 4 months of age

decreased heart left ventricle muscle contractility ( J:264147 )

• mice exhibit a mild, but significant, reduction in left ventricular ejection fraction

abnormal aortic valve flow ( J:264147 )

• mice exhibit a higher peak aortic valve flow

decreased heart rate ( J:264147 )

• heart rate is reduced at 4 months of age

prolonged QT interval ( J:264147 )

• mice exhibit prolonged heart rate corrected time from the start of the Q wave to the end of the T wave on the ECG trace (QTc) interval prolongation

homeostasis/metabolism

increased circulating tumor necrosis factor level ( J:264147 )

• circulating TNF levels are elevated

enhanced wound healing ( J:264147 )

• synovial fibroblasts and valvular interstitial cells show 70-80% closure of a wound in culture compared to around 20% in wild-type cells

immune system

small intestinal inflammation ( J:108572 )

• inflammatory bowel disease develops between 4-8 weeks of age

enlarged spleen ( J:108572 )

• mild splenomegaly development correlates with inflammatory bowel disease (IBD) development and becomes significant by 4 months of age

abnormal myelopoiesis ( J:108572 )

• splenocyte counts past 2 months of age show increases in CD11b+ myeloid cells

increased CD8-positive, alpha-beta T cell number ( J:108572 )

• there is a significant increase in CD8+ T cell number in Tnf^tm2Gkl mice past 2 months of age

abnormal cytotoxic T cell physiology ( J:108572 )

• T lymphocytes show a high degree of target cell lysis of syngeneic targets

• in allogeneic mixed lymphocyte reactions, splenocytes show enhanced proliferation compared to wild-type controls

increased circulating tumor necrosis factor level ( J:264147 )

• circulating TNF levels are elevated

increased tumor necrosis factor secretion ( J:264147 )

• levels of secreted TNF-alpha in supernatants of cultured synovial fibroblasts and valvular interstitial cells are elevated

abnormal response to transplant ( J:108572 )

• when lethality irradiated heterozygotes (that had also received anti-Tnf antibody treatment) receive bone marrow from wild-type mice only display mild villus blunting 9 weeks after removal of antibody treatment

hematopoietic system

enlarged spleen ( J:108572 )

• mild splenomegaly development correlates with inflammatory bowel disease (IBD) development and becomes significant by 4 months of age

abnormal myelopoiesis ( J:108572 )

• splenocyte counts past 2 months of age show increases in CD11b+ myeloid cells

increased CD8-positive, alpha-beta T cell number ( J:108572 )

• there is a significant increase in CD8+ T cell number in Tnf^tm2Gkl mice past 2 months of age

abnormal cytotoxic T cell physiology ( J:108572 )

• T lymphocytes show a high degree of target cell lysis of syngeneic targets

• in allogeneic mixed lymphocyte reactions, splenocytes show enhanced proliferation compared to wild-type controls

muscle

decreased heart left ventricle muscle contractility ( J:264147 )

• mice exhibit a mild, but significant, reduction in left ventricular ejection fraction

digestive/alimentary system

small intestinal inflammation ( J:108572 )

• inflammatory bowel disease develops between 4-8 weeks of age

growth/size/body

enlarged spleen ( J:108572 )

• mild splenomegaly development correlates with inflammatory bowel disease (IBD) development and becomes significant by 4 months of age

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
aortic valve stenosis		DOID:1712		J:264147
rheumatoid arthritis		DOID:7148	OMIM:180300	J:264147
spondyloarthropathy		DOID:1123		J:264147

Genotype
MGI:3622071

ht11

• Allelic Composition: Tnf^tm2Gkl/Tnf⁺
• Genetic Background: involves: 129S/SvEv * C57BL/6 * SPRET/Ei

immune system

small intestinal inflammation ( J:92307 )

• at 9 months similar bowel inflammation extending into the mucosal layers and loss of crypt morphology is seen in mice on a mixed background with or without SPRET/Ei

autoimmune arthritis ( J:92307 )

• Background Sensitivity: at 9 months arthritis is not severe enough to reduce mobility unlike in mice on a mixed background that does not include SPRET/Ei

digestive/alimentary system

small intestinal inflammation ( J:92307 )

• at 9 months similar bowel inflammation extending into the mucosal layers and loss of crypt morphology is seen in mice on a mixed background with or without SPRET/Ei

skeleton

autoimmune arthritis ( J:92307 )

• Background Sensitivity: at 9 months arthritis is not severe enough to reduce mobility unlike in mice on a mixed background that does not include SPRET/Ei

integument

alopecia ( J:92307 )

• at 9 months of age

Genotype
MGI:6272035

ht12

• Allelic Composition: Tnf^Bpsm1/Tnf⁺
• Genetic Background: involves: C57BL/6

behavior/neurological

decreased grip strength ( J:226052 )

• mice gradually lose grasping strength

hindlimb paralysis ( J:226052 )

• progressive paralysis of the hindlimbs

cardiovascular system

aortic aneurysm ( J:226052 )

• Background Sensitivity: aortic aneurism is much less pronounced on the C57BL/6 background than in mice on a BALB/c background

aortic valve inflammation ( J:226052 )

mitral valve inflammation ( J:226052 )

homeostasis/metabolism

increased circulating tumor necrosis factor level ( J:226052 )

• increase in circulating TNF levels

• however, circulating levels of IL1 beta, IL6, IL18, and IL23 are normal

immune system

aortic valve inflammation ( J:226052 )

mitral valve inflammation ( J:226052 )

increased circulating tumor necrosis factor level ( J:226052 )

• increase in circulating TNF levels

• however, circulating levels of IL1 beta, IL6, IL18, and IL23 are normal

rheumatoid arthritis ( J:226052 )

• mice exhibit a severe symmetrical, erosive chronic polyarthritis that predominately affects the peripheral joints and less severe damage in central joints

• joints show extensive pannus invasion, bone destruction and cartilage erosion

• bone erosion is maximal in joints with the highest load factor

• lethally irradiated wild-type mice transplanted with mutant bone marrow develop arthritis within 5 months

• 5 week old mutant mice transplanted with wild-type bone marrow do not develop arthritis over the following 5 months

• however, mice do not contain IgM or IgG rheumatoid factors and no inflammation is seen in the skin, liver, blood vessels, eyes or gut and no evidence for cartilage or bone repair is seen

increased synovial pannus formation ( J:226052 )

• joints show extensive pannus invasion

• pannus tissue is mostly F4.80 cells and most affected joints are devoid of lymphocytes and neutrophils

limbs/digits/tail

abnormal limb morphology ( J:226052 )

• limbs are deformed and mice gradually show forelimbs that become angled at the wrist level and hind-limb digits become immobile

mortality/aging

mortality/aging ( J:226052 )

N • Background Sensitivity: no mice on the C57BL/6 background die up to 200 days of age while sudden death is seen on the BALB/c background

skeleton

rheumatoid arthritis ( J:226052 )

• mice exhibit a severe symmetrical, erosive chronic polyarthritis that predominately affects the peripheral joints and less severe damage in central joints

• joints show extensive pannus invasion, bone destruction and cartilage erosion

• bone erosion is maximal in joints with the highest load factor

• lethally irradiated wild-type mice transplanted with mutant bone marrow develop arthritis within 5 months

• 5 week old mutant mice transplanted with wild-type bone marrow do not develop arthritis over the following 5 months

• however, mice do not contain IgM or IgG rheumatoid factors and no inflammation is seen in the skin, liver, blood vessels, eyes or gut and no evidence for cartilage or bone repair is seen

increased synovial pannus formation ( J:226052 )

• joints show extensive pannus invasion

• pannus tissue is mostly F4.80 cells and most affected joints are devoid of lymphocytes and neutrophils

abnormal rib joint morphology ( J:226052 )

• the 13th (floating) ribs enter the neural canal instead of being attached to the centrum

abnormal thoracic vertebrae morphology ( J:226052 )

• hunchback is due to erosion of the T10-T13 thoracic vertebrae

abnormal spine curvature ( J:226052 )

• abnormal curvature of the spine at the level of the rib cage

kyphosis ( J:226052 )

• a pronounced hunchback is seen at around 7 months of age associated with the progressive paralysis of hind limbs

joint dislocation ( J:226052 )

• hindpaws of 100 day old mice are luxated at the level of the ankle

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
rheumatoid arthritis		DOID:7148	OMIM:180300	J:226052

Genotype
MGI:3629610

cn13

• Allelic Composition: Tnf^tm2.1Gkl/Tnf⁺; Lyz2^tm1(cre)Ifo/Lyz2⁺
• Genetic Background: involves: 129P2/OlaHsd * 129S/SvEv * 129S6/SvEvTac * C57BL/6J

growth/size/body

weight loss ( J:108572 )

• past 4 months of age, mice display weight loss

Genotype
MGI:6195612

cn14

• Allelic Composition: Tnf^tm2Gkl/Tnf⁺; Tnfrsf1b^tm1.1Gkl/Tnfrsf1b^tm1.1Gkl; Tg(Col6a1-cre)1Gkl/0
• Genetic Background: involves: 129S/SvEv * C57BL/6 * C57BL/6J * CBA

cardiovascular system

cardiovascular system phenotype ( J:264147 )

N • mice show amelioration of the aortic valve stenosis seen in single Tnf^tm2Gkl heterozygotes, including a decrease of the leaflets surface area and reduction of fibrosis

skeleton

joint inflammation ( J:264147 )

• mice show reduced clinical features of arthritis compared to single Tnf^tm2Gkl heterozygotes, with a reduction of pannus formation and cartilage/bone destruction

cellular

abnormal cell physiology ( J:264147 )

• valvular interstitial cells fail to become activated

• however, cultured valvular interstitial cells appear similar to wild-type cells and exhibit normal proliferation

decreased cell adhesion ( J:264147 )

• synovial fibroblast and valvular interstitial cell adhesion to a fibronectin substrate is reduced by almost 50% compared to the levels in single Tnf^tm2Gkl heterozygotes but is somewhat higher than in wild-type cells

abnormal fibroblast physiology ( J:264147 )

• synovial fibroblasts fail to become activated

• however, cultured synovial fibroblasts appear similar to wild-type cells and exhibit normal proliferation

homeostasis/metabolism

increased circulating tumor necrosis factor level ( J:264147 )

• circulating TNF levels are elevated

abnormal wound healing ( J:264147 )

• synovial fibroblasts and valvular interstitial cells show only 40-45% closure of a wound in culture compared to 70-80% closure in single Tnf^tm2Gkl heterozygotes and about 20% in wild-type cells

immune system

increased circulating tumor necrosis factor level ( J:264147 )

• circulating TNF levels are elevated

increased tumor necrosis factor secretion ( J:264147 )

• levels of secreted TNF-alpha in supernatants of cultured synovial fibroblasts and valvular interstitial cells are elevated

joint inflammation ( J:264147 )

• mice show reduced clinical features of arthritis compared to single Tnf^tm2Gkl heterozygotes, with a reduction of pannus formation and cartilage/bone destruction

Genotype
MGI:6195614

cn15

• Allelic Composition: Tnf^tm2Gkl/Tnf⁺; Tnfrsf1a^tm2Gkl/Tnfrsf1a^tm2Gkl; Tg(Col6a1-cre)1Gkl/0
• Genetic Background: involves: 129S/SvEv * C57BL/6 * C57BL/6J * CBA

cardiovascular system

cardiovascular system phenotype ( J:264147 )

N • aortic valves appear normal at 16 weeks of age, showing no signs of disease

Genotype
MGI:3775437

cn16

• Allelic Composition: Tnf^tm2Gkl/Tnf⁺; Tnfrsf1a^tm2Gkl/Tnfrsf1a^tm2Gkl; Tg(Col6a1-cre)1Gkl/?
• Genetic Background: involves: 129S/SvEv * C57BL/6 * CBA

digestive/alimentary system

small intestinal inflammation ( J:131930 )

• the ileum contains inflammatory pathology reminiscent of Crohn's disease

• pathology includes blunting of intestinal villi, and infiltration of inflammation cells into the mucosal and submucosal layers

• 100% of mice have disease by 8 weeks of age

immune system

small intestinal inflammation ( J:131930 )

• the ileum contains inflammatory pathology reminiscent of Crohn's disease

• pathology includes blunting of intestinal villi, and infiltration of inflammation cells into the mucosal and submucosal layers

• 100% of mice have disease by 8 weeks of age

autoimmune arthritis ( J:131930 )

• 100% of mice have arthritis by 8 weeks of age

• joints are infiltrated by mononuclear cells

• mice also develop spondyloarthritis in their sacroiliac joints

skeleton

autoimmune arthritis ( J:131930 )

• 100% of mice have arthritis by 8 weeks of age

• joints are infiltrated by mononuclear cells

• mice also develop spondyloarthritis in their sacroiliac joints

Genotype
MGI:3622058

cx17

• Allelic Composition: Mapk11^tm1Jsca/Mapk11^tm1Jsca; Tnf^tm2Gkl/Tnf⁺
• Genetic Background: involves: 129P2/OlaHsd * 129S/SvEv * C57BL/6

immune system

ileum inflammation ( J:107771 )

• onset and severity of inflammation of the terminal ileum are similar to mice heterozygous for the Tnf allele only

autoimmune arthritis ( J:107771 )

• onset and severity of arthritis are similar to mice heterozygous for the Tnf allele only

digestive/alimentary system

ileum inflammation ( J:107771 )

• onset and severity of inflammation of the terminal ileum are similar to mice heterozygous for the Tnf allele only

skeleton

autoimmune arthritis ( J:107771 )

• onset and severity of arthritis are similar to mice heterozygous for the Tnf allele only

Genotype
MGI:3629523

cx18

• Allelic Composition: Tcrd^tm1Mom/Tcrd^tm1Mom; Tnf^tm2Gkl/Tnf⁺
• Genetic Background: involves: 129P2/OlaHsd * 129S/SvEv * C57BL/6J

immune system

small intestinal inflammation ( J:108572 )

• development and severity of inflammatory bowel disease are similar to Tnf^tm2Gkl/+, wild-type B2m controls

digestive/alimentary system

small intestinal inflammation ( J:108572 )

• development and severity of inflammatory bowel disease are similar to Tnf^tm2Gkl/+, wild-type B2m controls

Genotype
MGI:3629608

cx19

• Allelic Composition: Mapk9^tm1Flv/Mapk9^tm1Flv; Tnf^tm2Gkl/Tnf⁺
• Genetic Background: involves: 129P2/OlaHsd * 129S/SvEv * C57BL/6J

cellular

increased apoptosis ( J:108572 )

• mice have significantly higher numbers of apoptotic cells in the ilea compared to lower numbers in the infiltrate indicating a higher rate of apoptosis

immune system

immune system phenotype ( J:108572 )

N • there is no change in CD4+ to CD8+ ratios compared to findings in Tnf^tm2Gkl/+ single mutants

small intestinal inflammation ( J:108572 )

• there is a delayed onset and significant attenuation of disease

digestive/alimentary system

small intestinal inflammation ( J:108572 )

• there is a delayed onset and significant attenuation of disease

Genotype
MGI:3629603

cx20

• Allelic Composition: Mapkapk2^tm1Mgl/Mapkapk2^tm1Mgl; Tnf^tm2Gkl/Tnf⁺
• Genetic Background: involves: 129P2/OlaHsd * 129S/SvEv * C57BL/6J

mortality/aging

premature death ( J:108572 )

• increase in mortality from 8 weeks of age onward

cellular

decreased apoptosis ( J:108572 )

• mice have fewer apoptotic cells in inflamed ileal tissue compared to Tnf^tm2Gkl/+ controls

immune system

immune system phenotype ( J:108572 )

N • there is no change in CD4+ to CD8+ ratios compared to findings in Tnf^tm2Gkl/+ single mutants

small intestinal inflammation ( J:108572 )

• Tnf^tm2Gkl phenotype is exacerbated in these mice

granulomatous inflammation ( J:108572 )

• IBD is associated with early formation of multiple granulomas

digestive/alimentary system

small intestinal inflammation ( J:108572 )

• Tnf^tm2Gkl phenotype is exacerbated in these mice

Genotype
MGI:3629606

cx21

• Allelic Composition: Map3k8^tm1Pnt/Map3k8^tm1Pnt; Tnf^tm2Gkl/Tnf⁺
• Genetic Background: involves: 129P2/OlaHsd * 129S/SvEv * C57BL/6J

immune system

small intestinal inflammation ( J:108572 )

• there is a delayed onset and significant attenuation of disease compared to controls

increased CD8-positive, alpha-beta T cell number ( J:108572 )

• number of CD8+CD44^hi T cells is higher than in Tnf^tm2Gkl/+ controls

increased single-positive T cell number ( J:108572 )

• there is a significant increase in numbers of CD4+ and CD8+ cells

hematopoietic system

increased CD8-positive, alpha-beta T cell number ( J:108572 )

• number of CD8+CD44^hi T cells is higher than in Tnf^tm2Gkl/+ controls

increased single-positive T cell number ( J:108572 )

• there is a significant increase in numbers of CD4+ and CD8+ cells

digestive/alimentary system

small intestinal inflammation ( J:108572 )

• there is a delayed onset and significant attenuation of disease compared to controls

Genotype
MGI:3835807

cx22

• Allelic Composition: Tnf^tm1Ljo/Tnf⁺; Tnip1^tm1.1Ama/Tnip1^tm1.1Ama
• Genetic Background: involves: 129S1/Sv * C57BL/6J

mortality/aging

perinatal lethality, incomplete penetrance ( J:145539 )

• fewer than expected mice are born alive

Genotype
MGI:6272040

cx23

• Allelic Composition: Tnf^Bpsm1/Tnf⁺; Tnfrsf1a^tm1Mak/Tnfrsf1a^tm1Mak
• Genetic Background: involves: 129S2/SvPas * C57BL/6

homeostasis/metabolism

increased circulating tumor necrosis factor level ( J:226052 )

immune system

increased circulating tumor necrosis factor level ( J:226052 )

skeleton

skeleton phenotype ( J:226052 )

N • mice do not develop rheumatoid arthritis

Genotype
MGI:6730103

cx24

• Allelic Composition: Tnf^em5Boui/Tnf⁺; Tnfrsf1a^tm1Mak/Tnfrsf1a⁺
• Genetic Background: involves: 129S2/SvPas * C57BL/6

cardiovascular system

cardiovalvulitis ( J:306876 )

digestive/alimentary system

colitis ( J:306876 )

• inflammatory bowel disease (IBD) in gut in surviving mice at age P20

immune system

cardiovalvulitis ( J:306876 )

colitis ( J:306876 )

• inflammatory bowel disease (IBD) in gut in surviving mice at age P20

increased synovial pannus formation ( J:306876 )

• large pannus tissue invasion in synovial joints in surviving mice at age P20

autoimmune arthritis ( J:306876 )

• deformed ankles and wrists in surviving mice from age P7

mortality/aging

premature death ( J:306876 )

• surviving mice die by age 33 days

preweaning lethality, incomplete penetrance ( J:306876 )

• 80% of embryos die within hours of birth

respiratory system

abnormal lung morphology ( J:306876 )

• failure to initiate respiration: underinflated lungs in pups that died within hours of birth

skeleton

increased synovial pannus formation ( J:306876 )

• large pannus tissue invasion in synovial joints in surviving mice at age P20

autoimmune arthritis ( J:306876 )

• deformed ankles and wrists in surviving mice from age P7

Genotype
MGI:5702938

cx25

• Allelic Composition: Cd44^tm1Hbg/Cd44^tm1Hbg; Tnf^tm2Gkl/Tnf⁺
• Genetic Background: involves: 129S/SvEv * 129S1/Sv * 129X1/SvJ * C57BL/6

digestive/alimentary system

digestive/alimentary phenotype ( J:145626 )

N • mice exhibit attenuation of ileitis

immune system

immune system phenotype ( J:145626 )

N • mice exhibit attenuation of ileitis

Genotype
MGI:5702939

cx26

• Allelic Composition: Cd44^tm1Hbg/Cd44⁺; Tnf^tm2Gkl/Tnf⁺
• Genetic Background: involves: 129S/SvEv * 129S1/Sv * 129X1/SvJ * C57BL/6

digestive/alimentary system

ileum inflammation ( J:145626 )

• reduced ileitis compared with Tnf^tm2Gkl heterozygous mice

immune system

ileum inflammation ( J:145626 )

• reduced ileitis compared with Tnf^tm2Gkl heterozygous mice

Genotype
MGI:3629590

cx27

• Allelic Composition: Il12b^tm1Jm/Il12b^tm1Jm; Tnf^tm2Gkl/Tnf⁺
• Genetic Background: involves: 129S/SvEv * 129S1/Sv * C57BL/6J

immune system

small intestinal inflammation ( J:108572 )

• mice display delayed development and attenuation of inflammatory bowel disease

digestive/alimentary system

small intestinal inflammation ( J:108572 )

• mice display delayed development and attenuation of inflammatory bowel disease

Genotype
MGI:3799634

cx28

• Allelic Composition: Ccr9^tm1.1Mal/Ccr9^tm1.1Mal; Tnf^tm2Gkl/Tnf⁺
• Genetic Background: involves: 129S/SvEv * 129S2/SvPas * C57BL/6

immune system

intestinal inflammation ( J:136667 )

• develop inflammatory bowl disease with similar onset, progression, and severity as in littermates heterozygous for both alleles

• elevated acute and chronic inflammatory indices similar to littermates heterozygous for both alleles

abnormal T cell subpopulation ratio ( J:136667 )

• decrease in the CD8alpha alpha to CD8alpha beta ratio similar to that in mice heterozygous for Tnf^tm2Gkl alone

decreased gamma-delta intraepithelial T cell number ( J:136667 )

• more pronounced decrease in this subset early in the inflammatory disease process compared to mice heterozygous for Tnf^tm2Gkl alone

abnormal alpha-beta intraepithelial T cell morphology ( J:136667 )

• decrease in TCRalpha beta CD8alpha alpha and TCRalpha beta CD8alpha alpha CD4 numbers similar to mice heterozygous for Tnf^tm2Gkl alone

digestive/alimentary system

intestinal inflammation ( J:136667 )

• develop inflammatory bowl disease with similar onset, progression, and severity as in littermates heterozygous for both alleles

• elevated acute and chronic inflammatory indices similar to littermates heterozygous for both alleles

hematopoietic system

abnormal T cell subpopulation ratio ( J:136667 )

• decrease in the CD8alpha alpha to CD8alpha beta ratio similar to that in mice heterozygous for Tnf^tm2Gkl alone

decreased gamma-delta intraepithelial T cell number ( J:136667 )

• more pronounced decrease in this subset early in the inflammatory disease process compared to mice heterozygous for Tnf^tm2Gkl alone

abnormal alpha-beta intraepithelial T cell morphology ( J:136667 )

• decrease in TCRalpha beta CD8alpha alpha and TCRalpha beta CD8alpha alpha CD4 numbers similar to mice heterozygous for Tnf^tm2Gkl alone

Genotype
MGI:3799633

cx29

• Allelic Composition: Ccl25^tm1.1Mal/Ccl25^tm1.1Mal; Tnf^tm2Gkl/Tnf⁺
• Genetic Background: involves: 129S/SvEv * 129S2/SvPas * C57BL/6

immune system

intestinal inflammation ( J:136667 )

• develop inflammatory bowl disease with similar onset, progression, and severity as in littermates heterozygous for both alleles

• elevated acute and chronic inflammatory indices similar to littermates heterozygous for both alleles

abnormal T cell subpopulation ratio ( J:136667 )

• decrease in the CD8alpha alpha to CD8alpha beta ratio similar to that in mice heterozygous for Tnf^tm2Gkl alone

decreased gamma-delta intraepithelial T cell number ( J:136667 )

• more pronounced decrease in this subset early in the inflammatory disease process compared to mice heterozygous for Tnf^tm2Gkl alone

abnormal alpha-beta intraepithelial T cell morphology ( J:136667 )

• decrease in TCRalpha beta CD8alpha alpha and TCRalpha beta CD8alpha alpha CD4 numbers similar to mice heterozygous for Tnf^tm2Gkl alone

digestive/alimentary system

intestinal inflammation ( J:136667 )

• develop inflammatory bowl disease with similar onset, progression, and severity as in littermates heterozygous for both alleles

• elevated acute and chronic inflammatory indices similar to littermates heterozygous for both alleles

hematopoietic system

abnormal T cell subpopulation ratio ( J:136667 )

• decrease in the CD8alpha alpha to CD8alpha beta ratio similar to that in mice heterozygous for Tnf^tm2Gkl alone

decreased gamma-delta intraepithelial T cell number ( J:136667 )

• more pronounced decrease in this subset early in the inflammatory disease process compared to mice heterozygous for Tnf^tm2Gkl alone

abnormal alpha-beta intraepithelial T cell morphology ( J:136667 )

• decrease in TCRalpha beta CD8alpha alpha and TCRalpha beta CD8alpha alpha CD4 numbers similar to mice heterozygous for Tnf^tm2Gkl alone

Genotype
MGI:3622064

cx30

• Allelic Composition: Tnf^tm2Gkl/Tnf⁺; Tnfrsf1b^tm1Mwm/Tnfrsf1b^tm1Mwm
• Genetic Background: involves: 129S/SvEv * 129S2/SvPas * C57BL/6

immune system

small intestinal inflammation ( J:54056 )

• at 1-5 months of age, only mild intestinal inflammation and no signs of transmural inflammation are seen, unlike in mice heterozygous for Tnf^tm2Gkl only

rheumatoid arthritis ( J:54056 )

• arthritis is more aggressive and destructive than in mice heterozygous for Tnf^tm2Gkl only with increased swelling of the joints, synovial hyperplasia, numbers of polymorphonuclear infiltrates, and destruction of bone and cartilage

digestive/alimentary system

small intestinal inflammation ( J:54056 )

• at 1-5 months of age, only mild intestinal inflammation and no signs of transmural inflammation are seen, unlike in mice heterozygous for Tnf^tm2Gkl only

skeleton

rheumatoid arthritis ( J:54056 )

• arthritis is more aggressive and destructive than in mice heterozygous for Tnf^tm2Gkl only with increased swelling of the joints, synovial hyperplasia, numbers of polymorphonuclear infiltrates, and destruction of bone and cartilage

Genotype
MGI:3629519

cx31

• Allelic Composition: Ighm^tm1Cgn/Ighm^tm1Cgn; Tnf^tm2Gkl/Tnf⁺
• Genetic Background: involves: 129S/SvEv * 129S2/SvPas * C57BL/6J

immune system

small intestinal inflammation ( J:108572 )

• development and severity of inflammatory bowel disease are similar to Tnf^tm2Gkl/+, wild-type B2m controls

digestive/alimentary system

small intestinal inflammation ( J:108572 )

• development and severity of inflammatory bowel disease are similar to Tnf^tm2Gkl/+, wild-type B2m controls

Genotype
MGI:3629516

cx32

• Allelic Composition: Cd4^tm1Mak/Cd4^tm1Mak; Tnf^tm2Gkl/Tnf⁺
• Genetic Background: involves: 129S/SvEv * 129S2/SvPas * C57BL/6J

mortality/aging

premature death ( J:108572 )

• there is high incidence of mortality in mice by age of 2-3 months

immune system

small intestinal inflammation ( J:108572 )

• mice show exacerbation of IBD compared to Tnf^tm2Gkl/+ mice

digestive/alimentary system

small intestinal inflammation ( J:108572 )

• mice show exacerbation of IBD compared to Tnf^tm2Gkl/+ mice

Genotype
MGI:3629515

cx33

• Allelic Composition: B2m^tm1Jae/B2m^tm1Jae; Tnf^tm2Gkl/Tnf⁺
• Genetic Background: involves: 129S/SvEv * 129S2/SvPas * C57BL/6J

immune system

small intestinal inflammation ( J:108572 )

• mice display delayed development and attenuation of inflammatory bowel disease

digestive/alimentary system

small intestinal inflammation ( J:108572 )

• mice display delayed development and attenuation of inflammatory bowel disease

Genotype
MGI:3622066

cx34

• Allelic Composition: Rag1^tm1Mom/Rag1^tm1Mom; Tnf^tm2Gkl/Tnf⁺
• Genetic Background: involves: 129S/SvEv * 129S7/SvEvBrd * C57BL/6

immune system

small intestinal inflammation ( J:54056 )

• only minimal intestinal inflammation is seen, unlike in mice heterozygous for Tnf^tm2Gkl only

rheumatoid arthritis ( J:54056 )

• arthritis is similar to mice heterozygous for Tnf^tm2Gkl only

digestive/alimentary system

small intestinal inflammation ( J:54056 )

• only minimal intestinal inflammation is seen, unlike in mice heterozygous for Tnf^tm2Gkl only

skeleton

rheumatoid arthritis ( J:54056 )

• arthritis is similar to mice heterozygous for Tnf^tm2Gkl only

Genotype
MGI:3629594

cx35

• Allelic Composition: Ifng^tm1Ts/Ifng^tm1Ts; Tnf^tm2Gkl/Tnf⁺
• Genetic Background: involves: 129S/SvEv * 129S7/SvEvBrd * C57BL/6J

immune system

small intestinal inflammation ( J:108572 )

• development and severity of IBD are similar to Tnf^tm2Gkl/+, wild-type Ifng controls

digestive/alimentary system

small intestinal inflammation ( J:108572 )

• development and severity of IBD are similar to Tnf^tm2Gkl/+, wild-type Ifng controls

Genotype
MGI:3799636

cx36

• Allelic Composition: Itgb7^tm1Cgn/Itgb7^tm1Cgn; Tnf^tm2Gkl/Tnf⁺
• Genetic Background: involves: 129S/SvEv * C57BL/6

immune system

abnormal inflammatory response ( J:136667 )

• significant attenuation of the inflammatory bowel disease pathology with reduced acute and chronic inflammatory indices relative to mice heterozygous for Tnf^tm2Gkl alone

autoimmune arthritis ( J:136667 )

• chronic inflammatory arthritis is similar to mice heterozygous for Tnf^tm2Gkl alone

skeleton

autoimmune arthritis ( J:136667 )

• chronic inflammatory arthritis is similar to mice heterozygous for Tnf^tm2Gkl alone

Genotype
MGI:6195613

cx37

• Allelic Composition: Tnf^tm2Gkl/Tnf⁺; Tnfrsf1b^tm1.2Gkl/Tnfrsf1b^tm1.2Gkl
• Genetic Background: involves: 129S/SvEv * C57BL/6 * C57BL/6J

cardiovascular system

aortic valve stenosis ( J:264147 )

• mice exhibit an exacerbated aortic valve stenosis than seen in single Tnf^tm2Gkl heterozygotes, with an increase of valve leaflet surface area and fibrosis

• disease-manifestation in heart valve leaflets occurs at earlier time points than in single Tnf^tm2Gkl heterozygotes

• an increase of T and B cell infiltration is seen in late stages of the disease in the aortic valve leaflets compared to single Tnf^tm2Gkl heterozygotes

cardiac fibrosis ( J:264147 )

• mice exhibit exacerbated aortic valve fibrosis compared to in single Tnf^tm2Gkl heterozygotes

aortic valve inflammation ( J:264147 )

• an increase of T and B cell infiltration is seen in late stages of the disease in the aortic valve leaflets compared to single Tnf^tm2Gkl heterozygotes

skeleton

autoimmune arthritis ( J:264147 )

• mice exhibit a more aggressive and destructive type of arthritis, exacerbated synovial hyperplasia, and bone destruction compared to single Tnf^tm2Gkl heterozygotes

• disease-manifestation in joints occurs at earlier time points than in single Tnf^tm2Gkl heterozygotes

• an increase of T and B cell infiltration is seen in late stages of the disease in the ankle joint compared to single Tnf^tm2Gkl heterozygotes

cellular

abnormal cell physiology ( J:264147 )

• valvular interstitial cells fail to become activated

• however, cultured valvular interstitial cells appear similar to wild-type cells and exhibit normal proliferation

decreased cell adhesion ( J:264147 )

• synovial fibroblast and valvular interstitial cell adhesion to a fibronectin substrate is reduced by almost 50% compared to the levels in single Tnf^tm2Gkl heterozygotes but is higher than in wild-type cells

abnormal fibroblast physiology ( J:264147 )

• synovial fibroblasts fail to become activated

• however, cultured synovial fibroblasts appear similar to wild-type cells and exhibit normal proliferation

homeostasis/metabolism

increased circulating tumor necrosis factor level ( J:264147 )

• circulating TNF levels are elevated

abnormal wound healing ( J:264147 )

• synovial fibroblasts and valvular interstitial cells show only 40-45% closure of a wound in culture compared to 70-80% closure in single Tnf^tm2Gkl heterozygotes and about 20% closure in wild-type cells

immune system

aortic valve inflammation ( J:264147 )

• an increase of T and B cell infiltration is seen in late stages of the disease in the aortic valve leaflets compared to single Tnf^tm2Gkl heterozygotes

increased circulating tumor necrosis factor level ( J:264147 )

• circulating TNF levels are elevated

increased tumor necrosis factor secretion ( J:264147 )

• levels of secreted TNF-alpha in supernatants of cultured synovial fibroblasts and valvular interstitial cells are elevated

autoimmune arthritis ( J:264147 )

• mice exhibit a more aggressive and destructive type of arthritis, exacerbated synovial hyperplasia, and bone destruction compared to single Tnf^tm2Gkl heterozygotes

• disease-manifestation in joints occurs at earlier time points than in single Tnf^tm2Gkl heterozygotes

• an increase of T and B cell infiltration is seen in late stages of the disease in the ankle joint compared to single Tnf^tm2Gkl heterozygotes