Phenotypes Associated with This Genotype

Genotype
MGI:3759849

cn9

• Allelic Composition: Itgav^tm2Hyn/Itgav^tm2.1Hyn; Tg(Tek-cre)1Ywa/?
• Genetic Background: involves: 129S2/SvPas * C57BL/6 * FVB * SJL

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

mortality/aging

premature death ( J:125508 )

• median lifespan is reduced to 44 weeks compared to wild-type mice that live past 80 weeks

• mice die of intestinal constriction

immune system

abnormal immune system morphology ( J:125508 )

abnormal leukocyte morphology ( J:125508 )

abnormal dendritic cell differentiation ( J:125508 )

• mesenteric lymph node dendritic cells cultured with CD4+CD25- T cells produce only 1% regulatory T cells compared to 4% to 5% by control dendritic cells

• CD11c^highCD103+ dendritic cells implicated in gut-homing are reduced in the mesenteric lymph nodes compared to in Itgav^tm2Hyn heterozygote controls

• however, bone marrow dendritic cells produce normal amount of regulatory T cells when cultured with CD4+CD25- T cells

decreased regulatory T cell number ( J:125508 )

• the number of regulatory T cells in the colon is decreased by 50% compared to in Itgav^tm2Hyn heterozygote controls and are predominantly adaptive regulatory T cells

increased regulatory T cell number ( J:125508 )

• the number of regulatory T cells in the spleen and mesenteric lymph nodes is increased compared to in Itgav^tm2Hyn heterozygote controls and are predominantly natural regulatory T cells

enlarged Peyer's patches ( J:125508 )

• Peyer's patches are enlarged and contain an increased proportion of activated CD4+ cells compared to control mice

enlarged mesenteric lymph nodes ( J:125508 )

• mesenteric lymph nodes are enlarged (15+/-1.1x10⁶ cells compared to 7.1+/-0.23 x10⁶ cells in Itgav^tm2Hyn heterozygote controls at 3 weeks ,and 34.2+/-6.7 x10⁶ cells compared to 8.6+/-1.6 x10⁶ cells in Itgav^tm2Hyn heterozygote controls at 12 weeks) and contain an increased proportion of activated CD4+ cells (20+/-0.81 x10⁶ cells compared to 11+/-1.3 x10⁶ cells in Itgav^tm2Hyn heterozygote controls at week 3, and 31.7+/-0.40 x10⁶ cells compared to 15+/-0.81 x10⁶ cells in Itgav^tm2Hyn heterozygote controls at week 12)

abnormal immune system physiology ( J:125508 )

impaired macrophage phagocytosis ( J:125508 )

• macrophages exhibit impaired ability to phagocytose and remove apoptotic cells with twice as many uncleared apoptotic cells present in the intestine

• macrophages are no longer sensitive to the inhibitory effects of RGD peptide

abnormal interferon level ( J:125508 )

• levels of interferon-gamma in serum and the intestine are elevated compared to in Itgav^tm2Hyn heterozygote controls

abnormal interleukin level ( J:125508 )

• IL-4 levels in serum and the intestine and IL-5 and IL-6 levels in the intestine are elevated compared to in Itgav^tm2Hyn heterozygote controls

• however, IL-12 and IL-23 levels in the intestine are normal

abnormal tumor necrosis factor level ( J:125508 )

• TNF-alpha levels in the intestine are elevated compared to in Itgav^tm2Hyn heterozygote controls

increased autoantibody level ( J:125508 )

• mice contain higher levels of autoantibodies including ones against tropomyosin, phosphotidylserine, double-stranded DNA and anti-nuclear antibodies compared to in Itgav^tm2Hyn heterozygote controls

increased inflammatory response ( J:125508 )

• mice develop inflammation in the peritoneum, in the liver, and 40% of mice nasal cavity and respiratory tract

large intestinal inflammation ( J:125508 )

• after 14 weeks of age, mice exhibit inflammation in the colon and cecum with infiltration of lymphocytes, monocytes and plasma cells

• inflammation is chronic and progressive leading to ulcers, acute inflammatory infiltrate and crypt abscesses by week 20 with extensive epithelial proliferation, regeneration and adenocarcinoma from 40 weeks

colitis ( J:125508 )

digestive/alimentary system

abnormal intestinal epithelium morphology ( J:125508 )

• by 20 weeks of age, mice exhibit extensive epithelial proliferation and regeneration

crypts of Lieberkuhn abscesses ( J:125508 )

• by 20 weeks of age

intestinal ulcer ( J:125508 )

• by 20 weeks of age

increased intestinal adenocarcinoma incidence ( J:125508 )

• after 40 weeks of age

large intestinal inflammation ( J:125508 )

• after 14 weeks of age, mice exhibit inflammation in the colon and cecum with infiltration of lymphocytes, monocytes and plasma cells

• inflammation is chronic and progressive leading to ulcers, acute inflammatory infiltrate and crypt abscesses by week 20 with extensive epithelial proliferation, regeneration and adenocarcinoma from 40 weeks

colitis ( J:125508 )

neoplasm

increased intestinal adenocarcinoma incidence ( J:125508 )

• after 40 weeks of age

growth/size/body

weight loss ( J:125508 )

• despite being born with normal weights and no developmental abnormalities, mice begin to lose weight and body condition at 12 weeks of age

hematopoietic system

impaired macrophage phagocytosis ( J:125508 )

• macrophages exhibit impaired ability to phagocytose and remove apoptotic cells with twice as many uncleared apoptotic cells present in the intestine

• macrophages are no longer sensitive to the inhibitory effects of RGD peptide

abnormal leukocyte morphology ( J:125508 )

abnormal dendritic cell differentiation ( J:125508 )

• mesenteric lymph node dendritic cells cultured with CD4+CD25- T cells produce only 1% regulatory T cells compared to 4% to 5% by control dendritic cells

• CD11c^highCD103+ dendritic cells implicated in gut-homing are reduced in the mesenteric lymph nodes compared to in Itgav^tm2Hyn heterozygote controls

• however, bone marrow dendritic cells produce normal amount of regulatory T cells when cultured with CD4+CD25- T cells

decreased regulatory T cell number ( J:125508 )

• the number of regulatory T cells in the colon is decreased by 50% compared to in Itgav^tm2Hyn heterozygote controls and are predominantly adaptive regulatory T cells

increased regulatory T cell number ( J:125508 )

• the number of regulatory T cells in the spleen and mesenteric lymph nodes is increased compared to in Itgav^tm2Hyn heterozygote controls and are predominantly natural regulatory T cells

endocrine/exocrine glands

crypts of Lieberkuhn abscesses ( J:125508 )

• by 20 weeks of age

homeostasis/metabolism

abnormal interferon level ( J:125508 )

• levels of interferon-gamma in serum and the intestine are elevated compared to in Itgav^tm2Hyn heterozygote controls

abnormal interleukin level ( J:125508 )

• IL-4 levels in serum and the intestine and IL-5 and IL-6 levels in the intestine are elevated compared to in Itgav^tm2Hyn heterozygote controls

• however, IL-12 and IL-23 levels in the intestine are normal

abnormal tumor necrosis factor level ( J:125508 )

• TNF-alpha levels in the intestine are elevated compared to in Itgav^tm2Hyn heterozygote controls

cellular

abnormal dendritic cell differentiation ( J:125508 )

• mesenteric lymph node dendritic cells cultured with CD4+CD25- T cells produce only 1% regulatory T cells compared to 4% to 5% by control dendritic cells

• CD11c^highCD103+ dendritic cells implicated in gut-homing are reduced in the mesenteric lymph nodes compared to in Itgav^tm2Hyn heterozygote controls

• however, bone marrow dendritic cells produce normal amount of regulatory T cells when cultured with CD4+CD25- T cells

impaired macrophage phagocytosis ( J:125508 )

• macrophages exhibit impaired ability to phagocytose and remove apoptotic cells with twice as many uncleared apoptotic cells present in the intestine

• macrophages are no longer sensitive to the inhibitory effects of RGD peptide