Phenotypes Associated with This Genotype

Genotype
MGI:2429606

• Allelic Composition: C3^tm1Crr/C3^tm1Crr
• Genetic Background: involves: 129S4/SvJae * C57BL/6

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

C3^tm1Crr/C3^tm1Crr exhibit protection from hepatic ischemia reperfusion injury

mortality/aging

abnormal induced morbidity/mortality ( J:152533 )

• poor survival (20%) after 30 minutes of ischemia while 70% partial hepatectomy performed

increased susceptibility to bacterial infection induced morbidity/mortality ( J:205353 )

• in mice infected with S. pneumoniae

increased susceptibility to induced morbidity/mortality ( J:44240 )

• caecal ligation and puncture (CLP) causes greater mortality in mutants than wild-type in the first 24 hours after CLP (100 vs 20% mortality)

• reconstitution of mice with ip. injection of purified human C3 (HuC3) reduces mortality from 100% to 40% in the first 24 hours

immune system

immune system phenotype ( J:64282 )

N • secondary immune responses are similar in wild-type and mutant mice, so helper T cell function is normal

N • B cells from deficient mice show normal proliferative effects in response to surface IgM crosslinking

abnormal immune system morphology ( J:44240 )

decreased mast cell number ( J:44240 )

• after CLP less peritoneal mast cells can be recovered from Cr3-deficient mice compared to controls

decreased neutrophil cell number ( J:44240 )

• 1 hour after CLP, 50% of peritoneal cells are neutrophils and after 3 hours, 90% are neutrophils while in C3-deficient mice, after 1 hour only 1% and 45% after 3 hours are neutrophils

decreased osteoclast cell number ( J:166640 )

• bone marrow cells incubated with 1,25(OH)2 vitamin D3 produce fewer osteoclasts than do cells from controls

abnormal spleen germinal center morphology ( J:64282 )

decreased spleen germinal center number ( J:64282 )

• after immunization, wild-type mice develop germinal centers (GC) in ~half of splenic follicles while ~10% of splenic follicles in C3-deficient mice contain GCs

decreased spleen germinal center size ( J:64282 )

• diameter of GCs are less than that observed in wild-type

abnormal immune system physiology ( J:44240 )

decreased circulating interleukin-6 level ( J:152533 , J:166640 )

• reduced levels at 6 and 24 hours after 6 and 24 hours of reperfusion (J:152533)

• Il-6 production after vitamin D3 stimulation is significantly reduced (J:166640)

abnormal tumor necrosis factor level ( J:44240 )

• levels of Tnfa in peritoneal lavage fluids are reduced in C3-deficient mice compared to controls at 1 hour (158 mg/pl vs 400 mg/pl) and 3 hours (218 mg/pl vs 663 pg/ml) after CLP

• treatment with HuC3 restores levels of Tnfa production in mutants to wild-type levels

decreased circulating tumor necrosis factor level ( J:152533 )

• reduced TNFalpha levels at 6 and 24 hours after 6 and 24 hours of reperfusion

abnormal cell-mediated immunity ( J:30152 )

• in an in vitro assay, opsonization with serum from C3-deficient mice and 1% immune rabbit serum only resulted in a 0.2 log10 reduction in GBS CFU compared to a 1.0 log10 reduction by normal mouse serum

abnormal mast cell physiology ( J:44240 )

• mast cells from mutants 1 or 3 hours after CLP show reduced degranulation compared to wild-type (75% of wild-type cells vs <50% of C3-deficient cells)

• treatment with HuC3 results in comparable levels of mast cell degranulation to wild-type

abnormal humoral immune response ( J:64282 )

• in response to immunization with bacteriophage (phiX174), a T cell dependent antigen, C3-deficient mice mount a weak Ig M response but fail to switch to IgG

• when immunized with a 10-fold higher amount of bacteriophage, mice show a weak IgG response but response is still 10-fold lower than wild-type

liver inflammation ( J:30152 )

• mild hepatitis is observed in a small number (1/11) of mice surviving systemic challenge with GBS doses of 10² to 10⁵ CFU upon necropsy 15 days post-challenge; there are aggregates of mononuclear or polymorphonuclear leukocytes in hepatic sinusoids; wild-type animals that receive higher doses of GBS showed similar lesions

increased susceptibility to bacterial infection ( J:30152 , J:44240 )

• mice challenged with group B Streptococci (GBS) infection become bacteremic within 3 days and die or clear bacteria and survive; C3-deficient mice challenged with GBS infection showed a decreased LD₅₀ dose compared to immunocompetent controls (LD₅₀ dose: control 6.3 x 10⁴ vs. 1.3 x 10³ in C3-deficient mice) (J:30152)

• increased mortality from GBS infection compared to controls is limited to the first 3 days after challenge (J:30152)

• when pregnant dams are immunized with immune rabbit serum, pups are not protected against lethal challenge on day 2 of life (15/20 pups die within 48 hours) (J:30152)

• at 1 or 3 hours after CLP, cytocentrifuge preparations or peritoneal fluid from C3-deficient mice have reduced neutrophil counts and large numbers of bacteria, compared to wild-type which have few or no bacteria (J:44240)

• treatment with HuC3 restore neutrophil numbers and enhance bacterial clearance to wild-type levels (J:44240)

increased susceptibility to bacterial infection induced morbidity/mortality ( J:205353 )

• in mice infected with S. pneumoniae

cardiovascular system

decreased vascular permeability ( J:78613 )

• upeon reperfusion of ischemic intestine (jejunum), permeability index (PI) of injured C3-deficient mice is reduced compared to control treated wild-type (PI of 2.25 vs 3.26 in controls)

digestive/alimentary system

abnormal intestine morphology ( J:78613 )

• mice show less evidence of infarction compared to controls

homeostasis/metabolism

increased circulating bilirubin level ( J:152533 )

• after 70% partial hepatectomy

decreased circulating interleukin-6 level ( J:152533 , J:166640 )

• reduced levels at 6 and 24 hours after 6 and 24 hours of reperfusion (J:152533)

• Il-6 production after vitamin D3 stimulation is significantly reduced (J:166640)

abnormal enzyme/coenzyme level ( J:152533 )

• lower levels of myeloperoxidase in livers at 6 and 24 hours of reperfusion

decreased circulating alanine transaminase level ( J:152533 )

• levels lower during reperfusion after ischemia than in controls

increased circulating alanine transaminase level ( J:152533 )

• after 70% partial hepatectomy

abnormal tumor necrosis factor level ( J:44240 )

• levels of Tnfa in peritoneal lavage fluids are reduced in C3-deficient mice compared to controls at 1 hour (158 mg/pl vs 400 mg/pl) and 3 hours (218 mg/pl vs 663 pg/ml) after CLP

• treatment with HuC3 restores levels of Tnfa production in mutants to wild-type levels

decreased circulating tumor necrosis factor level ( J:152533 )

• reduced TNFalpha levels at 6 and 24 hours after 6 and 24 hours of reperfusion

decreased susceptibility to injury ( J:120567 )

• mice are resistant to ischemia reperfusion-induced renal injury

• serum urea nitrogen is reduced 31% to 55% compared to wild-type mice subjected to ischemia reperfusion

• neutrophil infiltration at the site of injury was reduced

hematopoietic system

decreased mast cell number ( J:44240 )

• after CLP less peritoneal mast cells can be recovered from Cr3-deficient mice compared to controls

decreased neutrophil cell number ( J:44240 )

• 1 hour after CLP, 50% of peritoneal cells are neutrophils and after 3 hours, 90% are neutrophils while in C3-deficient mice, after 1 hour only 1% and 45% after 3 hours are neutrophils

decreased osteoclast cell number ( J:166640 )

• bone marrow cells incubated with 1,25(OH)2 vitamin D3 produce fewer osteoclasts than do cells from controls

abnormal spleen germinal center morphology ( J:64282 )

decreased spleen germinal center number ( J:64282 )

• after immunization, wild-type mice develop germinal centers (GC) in ~half of splenic follicles while ~10% of splenic follicles in C3-deficient mice contain GCs

decreased spleen germinal center size ( J:64282 )

• diameter of GCs are less than that observed in wild-type

abnormal mast cell physiology ( J:44240 )

• mast cells from mutants 1 or 3 hours after CLP show reduced degranulation compared to wild-type (75% of wild-type cells vs <50% of C3-deficient cells)

• treatment with HuC3 results in comparable levels of mast cell degranulation to wild-type

liver/biliary system

abnormal liver morphology ( J:152533 )

• histological evidence of injury after 6 and 24 hours of reperfusion following ischemia

focal hepatic necrosis ( J:152533 )

• after 70% partial hepatectomy

hepatic steatosis ( J:152533 )

• increased steatosis after 70% hepatectomy

abnormal liver physiology ( J:152533 )

decreased hepatocyte proliferation ( J:152533 )

• impaired hepatocyte proliferation after 30 minutes of ischemia during 70% partial hepatectomy

liver inflammation ( J:30152 )

• mild hepatitis is observed in a small number (1/11) of mice surviving systemic challenge with GBS doses of 10² to 10⁵ CFU upon necropsy 15 days post-challenge; there are aggregates of mononuclear or polymorphonuclear leukocytes in hepatic sinusoids; wild-type animals that receive higher doses of GBS showed similar lesions

impaired liver regeneration ( J:152533 )

• significant hepatic injury after 30 minutes of ischemia during 70% partial hepatectomy

• impaired regenerative response after 70% hepatectomy

nervous system

enhanced central nervous system regeneration ( J:112353 )

• locomotor recovery from spinal cord injury occurs more rapidly than in controls

• slight improvement in tissue at 24 hours after injury but considerably improved relative to controls by 72 hours

• grossly normal at 7 days after injury compared to controls which show marked areas of necrosis with vacuolization of cells at day 7 and less pronounced necrosis at day 21

skeleton

decreased osteoclast cell number ( J:166640 )

• bone marrow cells incubated with 1,25(OH)2 vitamin D3 produce fewer osteoclasts than do cells from controls

cellular

decreased hepatocyte proliferation ( J:152533 )

• impaired hepatocyte proliferation after 30 minutes of ischemia during 70% partial hepatectomy

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
complement component 3 deficiency		DOID:8354	OMIM:613779	J:30152