cellular
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• purified B cells from homozygous mutant mice display defective proliferative responses to various mitogenic signals
• however, under appropriate in vitro conditions, mutant B cells undergo normal B cell maturation to IgG secretion and heavy chain class switching
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• mutant PMN leukocytes display a 2.5-fold reduction in their capacity to phagocytose opsonized zymosan particles
• mutant thioglycolate-elicited peritoneal macrophages show reduced H2O2 production following stimulation with opsonized zymosan particles and PMA
• reduced neutrophil phagocytosis results in defective clearance of L. monocytogenes during early stages of infection
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mortality/aging
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• all homozygotes survive to birth; however, some homozygotes die prematurely
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hematopoietic system
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• purified B cells from homozygous mutant mice display defective proliferative responses to various mitogenic signals
• however, under appropriate in vitro conditions, mutant B cells undergo normal B cell maturation to IgG secretion and heavy chain class switching
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• mutant PMN leukocytes display a 2.5-fold reduction in their capacity to phagocytose opsonized zymosan particles
• mutant thioglycolate-elicited peritoneal macrophages show reduced H2O2 production following stimulation with opsonized zymosan particles and PMA
• reduced neutrophil phagocytosis results in defective clearance of L. monocytogenes during early stages of infection
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• homozygotes display a variable degree of thymic atrophy
• at >3 weeks, homozygotes show a ~30% reduction in thymus weight relative to wild-type mice
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• at >3 weeks, homozygotes show a ~30% reduction in the number of thymocytes
• the thymic medulla is more severely affected than the cortex
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• at P20+, homozygotes exhibit a 2- to 8-fold increase in spleen weight relative to age-matched wild-type mice
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• homozygotes display severely impaired erythropoiesis in the bone marrow
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• myeloid hyperplasia is associated with peripheral leukocytosis
• in contrast, erythrocyte counts, hematocrit, and hemoglobin concentrations per cell remain normal
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• at P10, homozygotes exhibit progressive extramedullary hematopoiesis in the liver and spleen due to an increase in erythroid precursors
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• homozygotes exhibit myeloid hyperplasia of the bone marrow which is first detected at P10 and becomes prominent by P20
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• in adulthood, myeloid hyperplasia is associated with a reduction in the number of erythroid precursors in the bone marrow
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• at >3 weeks, homozygotes display a significant reduction in the number of antigen-presenting medullary dendritic cells
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• homozygotes display normal lymphoid development and are able to mount an immune response with no major alterations in the B-cell compartment
• however, homozygotes exhibit a mild depletion of T cells in the spleen and lymph nodes
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• in adulthood, mutant spleens show a significant increase in the red pulp as a result of extramedullary hematopoiesis
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• in adulthood, mutant spleens show a significant reduction in the white pulp
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• unimmunized 6-week-old homozygotes show a 2- to 4-fold reduction in IgG2a, IgG2b, IgG3 and IgA resting serum levels, as well as a slight increase in IgG1 resting serum levels relative to wild-type mice
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• unimmunized 6-week-old homozygotes show a 18-fold increase in resting serum IgE levels relative to wild-type mice
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• unimmunized 6-week-old homozygotes show a 6-fold increase in resting IgM serum levels relative to wild-type mice
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• at 7 days post LCMV infection, homozygotes display a significantly reduced expansion of CD8+ T cells, suggesting an impaired CTL response
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• following in vitro stimulation with LPS plus IFN-gamma, mutant peritoneal macrophages show a ~30% reduction in nitric oxide production
• following in vitro stimulation with LPS or LPS plus IFN-gamma, mutant thioglycolate-elicited peritoneal macrophages display reduced TNF production
• in contrast, mutant thioglycolate-elicited peritoneal macrophages show increased H2O2 production following stimulation with opsonized zymosan particles and PMA
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immune system
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• myeloid hyperplasia is associated with peripheral leukocytosis
• in contrast, erythrocyte counts, hematocrit, and hemoglobin concentrations per cell remain normal
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• at >3 weeks, homozygotes display a significant reduction in the number of antigen-presenting medullary dendritic cells
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• homozygotes display normal lymphoid development and are able to mount an immune response with no major alterations in the B-cell compartment
• however, homozygotes exhibit a mild depletion of T cells in the spleen and lymph nodes
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• homozygotes display a variable degree of thymic atrophy
• at >3 weeks, homozygotes show a ~30% reduction in thymus weight relative to wild-type mice
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• at >3 weeks, homozygotes show a ~30% reduction in the number of thymocytes
• the thymic medulla is more severely affected than the cortex
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• at P20+, homozygotes exhibit a 2- to 8-fold increase in spleen weight relative to age-matched wild-type mice
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• in adulthood, mutant spleens show a significant increase in the red pulp as a result of extramedullary hematopoiesis
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• in adulthood, mutant spleens show a significant reduction in the white pulp
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• at P8-P10, mediastinal, mesenteric and sub-mandibular lymph nodes exhibit histopathologic alterations, typified by a mild lymphoid depletion and a relative increase in macrophage number
• by P20, the architecture of affected lymph nodes is largely effaced by a mixed inflammatory infiltrate, with a pronounced neutrophil component
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• at P20+, the architecture of mutant mesenteric lymph nodes is effaced by a mixed inflammatory infiltrate
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• older homozygotes exhibit a marked inflammatory cell infiltrate in the GI tract
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• 9 out of 12 older homozygotes have a marked inflammatory cell infiltrate in the salivary glands
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• 14 out of 15 older homozygotes show a notable inflammatory cell infiltrate in the stomach
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• 4 out of 7 older female homozygotes have a notable neutrophilic infiltrate in the ovaries and uterus
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• 12-day-old homozygotes exhibit increased expression of several pro-inflammatory cytokines, including CCL3 and CCL7, in the liver and lung
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• 12-day-old homozygotes exhibit increased IFN-gamma mRNA levels in the liver and lung
• in addition, homozygotes display increased serum IFN-gamma protein levels during L. monocytogenes infection
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• 12-day-old homozygotes exhibit increased IL-2 and IL-4 mRNA levels in the liver and lung
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• 12-day-old homozygotes exhibit increased TNF mRNA levels in the liver and lung
• however, following in vitro stimulation with LPS or LPS plus IFN-gamma, mutant thioglycolate-elicited peritoneal macrophages display reduced TNF production relative to wild-type
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• homozygotes exhibit thymic atrophy, a mild depletion of T cells in the spleen and lymh nodes, and an impaired DTH response, strongly suggesting an abnormal T cell-mediated immune function
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• purified B cells from homozygous mutant mice display defective proliferative responses to various mitogenic signals
• however, under appropriate in vitro conditions, mutant B cells undergo normal B cell maturation to IgG secretion and heavy chain class switching
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• mutant PMN leukocytes display a 2.5-fold reduction in their capacity to phagocytose opsonized zymosan particles
• mutant thioglycolate-elicited peritoneal macrophages show reduced H2O2 production following stimulation with opsonized zymosan particles and PMA
• reduced neutrophil phagocytosis results in defective clearance of L. monocytogenes during early stages of infection
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• at 7 days post LCMV infection, homozygotes display a significantly reduced expansion of CD8+ T cells, suggesting an impaired CTL response
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• following in vitro stimulation with LPS plus IFN-gamma, mutant peritoneal macrophages show a ~30% reduction in nitric oxide production
• following in vitro stimulation with LPS or LPS plus IFN-gamma, mutant thioglycolate-elicited peritoneal macrophages display reduced TNF production
• in contrast, mutant thioglycolate-elicited peritoneal macrophages show increased H2O2 production following stimulation with opsonized zymosan particles and PMA
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• ear lesions in sensitized homozygotes exhibit a reduced dermal edema and cell infiltrate, indicating an impaired delayed-type hypersensitivity reaction
(J:22675)
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• homozygotes display impaired antigen-specific IgG production in response to both T cell-dependent and -independent stimuli
• specifically, mutants exhibit reduced secretion of IgG1 in response to T-cell dependent antigen NP-KLH and impaired IgG3 production in response to T-cell independent antigen NP-LPS relative to wild-type mice
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• unimmunized 6-week-old homozygotes show a 2- to 4-fold reduction in IgG2a, IgG2b, IgG3 and IgA resting serum levels, as well as a slight increase in IgG1 resting serum levels relative to wild-type mice
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• unimmunized 6-week-old homozygotes show a 18-fold increase in resting serum IgE levels relative to wild-type mice
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• unimmunized 6-week-old homozygotes show a 6-fold increase in resting IgM serum levels relative to wild-type mice
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• at P10, mutant livers show a severe periportal mixed inflammatory infiltrate of lymphocytes and neutrophils
• by P20, the periportal mixed inflammatory infiltrate is more severe extending beyond the limiting plate
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• 6 out of 12 older homozygotes show a marked inflammatory cell infiltrate in skeletal muscles
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• at >6 weeks, all male homozygotes display a notable inflammatory cell infiltrate in the interstitium of the epididymis
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• at P8-P10, mutant lungs display a perivascular mononuclear cell infiltrate (mostly lymphocytes)
• by P20, perivascular mixed inflammation extends multifocally into the interstitium and adjacent alveoli, resulting in alveolar histiocytosis
• at P20+, many alveolar macrophages have a microvesiculated cytoplasm while others contain non-birefringent eosinophillic material or hemosiderin pigment
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• homozygotes are extremely susceptible to Listeria monocytogenes infection
• ~50% of homozygotes die 4 days post i.p. infection with a low dose (500 CFU) of L. monocytogenes, with >1000-fold titers in all tissues, whereas all wild-type and heterozygous mice remain alive
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• at 7 days p.i., homozygotes are unable to clear LCMV viral loads from various organs as efficiently as wild-type mice, partly due to a 5-fold reduction in the CD8+ to CD4+ ratio
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liver/biliary system
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• at P10, mutant livers show a severe periportal mixed inflammatory infiltrate of lymphocytes and neutrophils
• by P20, the periportal mixed inflammatory infiltrate is more severe extending beyond the limiting plate
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• at P20, homozygotes with severe liver inflammation display biliary hyperplasia and biliary epithelial mucoid metaplasia
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• at P20, homozygotes with severe liver inflammation display peribiliary as well as periportal fibrosis
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reproductive system
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• 4 out of 7 older female homozygotes have a notable neutrophilic infiltrate in the ovaries and uterus
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• at >6 weeks, all male homozygotes display a notable inflammatory cell infiltrate in the interstitium of the epididymis
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• both male and female homozygotes display severely reduced fertility
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respiratory system
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• at P8-P10, mutant lungs often display alveolar hemorrhage
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• at P8-P10, mutant lungs display a perivascular mononuclear cell infiltrate (mostly lymphocytes)
• by P20, perivascular mixed inflammation extends multifocally into the interstitium and adjacent alveoli, resulting in alveolar histiocytosis
• at P20+, many alveolar macrophages have a microvesiculated cytoplasm while others contain non-birefringent eosinophillic material or hemosiderin pigment
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• at P20+, perivascular mixed inflammation extends into the adjacent parenchyma and is associated with fibrosis or focal consolidation
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behavior/neurological
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• homozygotes appear normal at birth; however, at at 2-6 weeks, they develop a hunched posture
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growth/size/body
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• at 2-6 weeks after birth, homozygotes display slightly enlarged abdomens
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• at P20+, homozygotes exhibit a 2- to 8-fold increase in spleen weight relative to age-matched wild-type mice
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cardiovascular system
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• at P8-P10, mutant lungs often display alveolar hemorrhage
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digestive/alimentary system
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• older homozygotes exhibit a marked inflammatory cell infiltrate in the GI tract
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• 9 out of 12 older homozygotes have a marked inflammatory cell infiltrate in the salivary glands
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• 14 out of 15 older homozygotes show a notable inflammatory cell infiltrate in the stomach
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endocrine/exocrine glands
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• 9 out of 12 older homozygotes have a marked inflammatory cell infiltrate in the salivary glands
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• at P20, homozygotes with severe liver inflammation display biliary hyperplasia and biliary epithelial mucoid metaplasia
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• homozygotes display a variable degree of thymic atrophy
• at >3 weeks, homozygotes show a ~30% reduction in thymus weight relative to wild-type mice
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• at >3 weeks, homozygotes show a ~30% reduction in the number of thymocytes
• the thymic medulla is more severely affected than the cortex
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• 4 out of 7 older female homozygotes have a notable neutrophilic infiltrate in the ovaries and uterus
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muscle
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• 6 out of 12 older homozygotes show a marked inflammatory cell infiltrate in skeletal muscles
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homeostasis/metabolism
integument
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• at 2-6 weeks after birth, homozygotes appear disheveled relative to wild-type mice
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Analysis Tools