Analysis Tools
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• at 22 weeks, no animals show cardiac enlargement or significant mononuclear cell infiltrates
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• only animal developed first degree heart block by 24 weeks of age, and no animals develop complete heart block
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• doubly homozygous mice die between 20 and 60 weeks of age; the female survival curve lags behind the male curve by about 1 week
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| N |
• although CD4+ T cells are virtually absent in NOD mice lacking H2-AB1, homozygosity for the transgene restores this cell population in both the spleen and the periphery
• spleen and lymph node cells harvested from homozygous mutant/transgenic NOD mice 2-6 weeks after immunization with human GAD2 (GAD65) in complete Freund's adjuvant exhibit a strong in vitro proliferative response to GAD2
• immunization of homozygous mutant/transgenic NOD mice with human GAD2 (GAD65) in complete Freund's adjuvant produces strong antibody responses versus GAD2
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• histologic examination of end-stage hearts reveals pancarditis
(J:86540)
• at 5 weeks, doubly homozygous mice exhibit little or no mononuclear-cell cardiac infiltration; the rare positive cases involve only the sites where the great vessels enter/exit the atria
(J:86540)
• the mononuclear cells infiltrating hearts of end-stage and of pre-terminal, >20 week old doubly homozygous mice comprise mostly B lymphocytes and plasma cells, with fewer CD4+ and CD8+ T cells
(J:86540)
• older female mice homozygous for both the mutation and the transgene were found to have cardiac immunopathology
(J:87013)
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• rare, isolated foci of mononuclear cell infiltration may be seen in salivary glands of mice older than 30 weeks
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• sera from >25 week old mice with heart block strongly labels both nuclei and cytoplasm of cardiomyocytes by indirect immunofluorescence
(J:86540)
• serum from a 6 week old doubly homozygous mouse showed reactivity against mouse and porcine cardiac myosin, and to a lesser extent, skeletal muscle myosin in a western blot assay; serum from an AV-blocked 28 week old mouse gave much stronger signal and detected more bands, suggesting epitope spread over time
(J:86540)
• IgG titers measured using purified porcine myosin were significant in doubly homozygous mice at 3 weeks of age (presumably transferred in mothers' milk), dropped to a minimum by 5 weeks and then rose progressively to as high as 1:106 by 20 weeks of age
(J:86540)
• porcine cardiac myosin induces in vitro proliferation of splenocytes from doubly mutant mice; this reaction is blocked by an anti-HLA-DQ monoclonal antibody
(J:86540)
• irradiation of 5 week old doubly homozygous mice reduces the incidence of AV block at 17 weeks to approximately 25%, when at least 80% of unirradiated mice have AV block
(J:86540)
• transfer of splenocytes or splenocytes plus serum from older, AV-blocked mice into irradiated 5 week old mice restores the progression to AV block, whereas serum alone is no more effective than PBS in doing so
(J:86540)
• daily injection of doubly homozygous mice from weaning with cyclosporin A significantly delays progression to AV block, although it does not prevent progression to disease in all animals; discontinuation of the drug at 15 weeks leads to rapid disease progression
(J:86540)
• a single dose of complete Freund's adjuvant (CFA) administered to 4 week old doubly homozygous NOD mice accelerates progression to AV block, causing complete block in all animals by 12-13 weeks of age (paradoxically, as this treatment delays or prevents onset of autoimmune diabetes in wild-type NOD mice)
(J:86540)
• older female mice homozygous for both the mutation and the transgene were found to have cardiac immunopathology
(J:87013)
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• NOD mice homozygous for both the mutation and the transgene do not spontaneously develop diabetes, even by one year of age
• homozygous mutant/transgenic NOD mice fail to develop insulitis
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• mice produce high titers of autoantibodies against cardiac myosin at 12 weeks of age
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• rare, isolated foci of mononuclear cell invasion may be observed in skeletal muscle of mice older than 30 weeks
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• by 5 weeks of age, the lungs of doubly homozygous mice have marked lymphocytic infiltration specifically of the ensheathing cardiomyocytes that surround rodents' pulmonary veins, with injury and loss of muscle cells contacted by the invading cells; in older preterminal mice, the pulmonary vessels are completely denuded of ensheathing cardiomyocytes and the mononuclear cell infiltrate has resolved
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| N |
• although CD4+ T cells are virtually absent in NOD mice lacking H2-AB1, homozygosity for the transgene restores this cell population in both the spleen and the periphery
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| N |
• NOD mice homozygous for both the mutation and the transgene do not spontaneously develop diabetes, even by one year of age
• NOD mice homozygous for both the mutation and the transgene are resistant to induction of diabetes by one or two doses of cyclophosphamide
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• by 5 weeks of age, the lungs of doubly homozygous mice have marked lymphocytic infiltration specifically of the ensheathing cardiomyocytes that surround rodents' pulmonary veins, with injury and loss of muscle cells contacted by the invading cells; in older preterminal mice, the pulmonary vessels are completely denuded of ensheathing cardiomyocytes and the mononuclear cell infiltrate has resolved
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• walls of end-stage atria are infiltrated with mononuclear cells where cardiomyocytes remain, and the cardiomyocytes are dead or dying
• ventricles of terminal mice exhibit scattered aggregates of mononuclear cells associated with injured or dead muscle cells
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• end-stage atria are grossly dilated, their walls composed primarily of fibrotic tissue, extremely thin in places and containing few live cardiomyocytes
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• hearts of doubly homozygous mice are 3-4 times normal size at autopsy; significant enlargement is seen by in vivo echocardiography of pre-terminal mice older than 20 weeks
• high resolution M-mode echocardiography of pre-terminal mice older than 20 weeks reveals significant dilation, with the distance between anterior and posterior endocarial walls greater than twice that of wild-type NOD hearts
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• echocardiography of pre-terminal mice older than 20 weeks reveals extremely weak contraction of both ventricles
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• echocardiography of older animals reveals mitral regurgitation
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• serial ECGs showed that at 6 weeks of age, the heart function of doubly homozygous mice is similar to that of NOD controls; by 7 weeks, some mice begin to exhibit first degree atrioventricular (AV) block, which affects increasing numbers of mice and progresses with age such that by 18 weeks, most mice have developed second degree or complete AV block
• some older animals present uncommon ECG profiles, e.g., Wenckeback
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• nearly all of the mice develop heart block (prolongation of the PR interval) by 24 weeks of age
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• some older animals present uncommon ECG profiles, e.g., torsade de pointes
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• histologic examination of end-stage hearts reveals pancarditis
(J:86540)
• at 5 weeks, doubly homozygous mice exhibit little or no mononuclear-cell cardiac infiltration; the rare positive cases involve only the sites where the great vessels enter/exit the atria
(J:86540)
• the mononuclear cells infiltrating hearts of end-stage and of pre-terminal, >20 week old doubly homozygous mice comprise mostly B lymphocytes and plasma cells, with fewer CD4+ and CD8+ T cells
(J:86540)
• older female mice homozygous for both the mutation and the transgene were found to have cardiac immunopathology
(J:87013)
|
|
• walls of end-stage atria are infiltrated with mononuclear cells where cardiomyocytes remain, and the cardiomyocytes are dead or dying
• ventricles of terminal mice exhibit scattered aggregates of mononuclear cells associated with injured or dead muscle cells
|
|
• hearts of doubly homozygous mice are 3-4 times normal size at autopsy; significant enlargement is seen by in vivo echocardiography of pre-terminal mice older than 20 weeks
• high resolution M-mode echocardiography of pre-terminal mice older than 20 weeks reveals significant dilation, with the distance between anterior and posterior endocarial walls greater than twice that of wild-type NOD hearts
|
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• echocardiography of pre-terminal mice older than 20 weeks reveals extremely weak contraction of both ventricles
|
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• rare, isolated foci of mononuclear cell invasion may be observed in skeletal muscle of mice older than 30 weeks
|
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• rare, isolated foci of mononuclear cell infiltration may be seen in salivary glands of mice older than 30 weeks
|
|
• rare, isolated foci of mononuclear cell infiltration may be seen in salivary glands of mice older than 30 weeks
|
|
• by 5 weeks of age, the lungs of doubly homozygous mice have marked lymphocytic infiltration specifically of the ensheathing cardiomyocytes that surround rodents' pulmonary veins, with injury and loss of muscle cells contacted by the invading cells; in older preterminal mice, the pulmonary vessels are completely denuded of ensheathing cardiomyocytes and the mononuclear cell infiltrate has resolved
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Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| dilated cardiomyopathy 1A | DOID:0110425 |
OMIM:115200 |
J:86540 | |
| myocarditis | DOID:820 | J:86540 | ||
| NOT | type 1 diabetes mellitus | DOID:9744 |
OMIM:222100 |
J:87013 |
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• magnitude of cardiac enlargement is similar to NOD transgenic H2-Ab1-null, Igh-6-sufficient mice
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• appearance of heart block is not significantly different from NOD transgenic H2-Ab1-null, Igh-6-sufficient mice
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• at 22 weeks, mice show mononuclear cell infiltrates in heart walls
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• at 22 weeks, mice show mononuclear cell infiltrates in heart walls
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• magnitude of cardiac enlargement is similar to NOD transgenic H2-Ab1-null, Igh-6-sufficient mice
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
| N |
• animals have normal sized hearts, normal ECG, and show no sign of autoimmune pathology
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• recipient animals develop cardiomegaly by 12 weeks after transfer
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• mice receiving splenic lymphocytes from animals with heart block display first-degree heart block as early as 2 weeks after transfer, with 50% progressing to complete heart block in 8 weeks
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• recipient animals develop mononuclear cell infiltrates within heart wall by 12 weeks after transplant
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• when young mice receive splenic lymphocytes from older NOD.DQ8/H2Ab-1 mice with heart block, myocarditis is triggered in 100% of recipients
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• recipient animals develop mononuclear cell infiltrates within heart wall by 12 weeks after transplant
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• when young mice receive splenic lymphocytes from older NOD.DQ8/H2Ab-1 mice with heart block, myocarditis is triggered in 100% of recipients
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• anticardiac myosin autoantibodies reach a titer of 1:10000 in recipient mice at 12 weeks posttransfer
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• younger mice receiving splenic lymphocytes from older DQ8 transgenic, H2-Ab1-null mice with heart block develop heart block, myocarditis, and autoantibodies
• when younger mice receive serum from the same older animals, no cardiac pathology is observed
• recipient mice receiving CD4 T cells from older donor animals with heart block develop heart block as early as 4 weeks posttransfer; all animals are diseased by 12 weeks and upon necropsy, heart are enlarged
• mononuclear cells are more numerous and infiltrates more widespread than in animals that receive total splenocytes (containing CD4 T cells) in the myocardium
• disease onset is somewhat accelerated compared to recipients receiving total lymphocytes;
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• recipient animals develop cardiomegaly by 12 weeks after transfer
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• 85-90% of both transgenic and wild-type female NOD mice develop diabetes by 32 weeks of age
(J:86540)
• diabetes incidence is similar to that in wild-type NOD mice
(J:87013)
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| N |
• NOD mice homozygous for this transgene alone show no indication of cardiac enlargement or inflammation at any age
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| N |
• NOD mice homozygous for this transgene alone show no indication of cardiac inflammation at any age
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Mouse Genome Database (MGD), Gene Expression Database (GXD), Mouse Models of Human Cancer database (MMHCdb) (formerly Mouse Tumor Biology (MTB)), Gene Ontology (GO) |
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last database update 12/10/2024 MGI 6.24 |
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