Mouse Genome Informatics
hm1
    H2-Ab1tm1Gru/H2-Ab1tm1Gru
B6.129S2-H2-Ab1tm1Gru
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
• CD4 T cells are virtually absent in these mice with only a few detectable in the periphery
• lymphocytes fail to proliferate in response to restimulation with bovine insulin antigen
• B cells fail to adhere to surfaces coated with anti-MHC II antibodies

hematopoietic system
• CD4 T cells are virtually absent in these mice with only a few detectable in the periphery
• lymphocytes fail to proliferate in response to restimulation with bovine insulin antigen
• B cells fail to adhere to surfaces coated with anti-MHC II antibodies


Mouse Genome Informatics
hm2
    H2-Ab1tm1Gru/H2-Ab1tm1Gru
involves: 129S2/SvPas
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cardiovascular system
• mice exhibit impaired arteriogenesis following occlusion compared to in similarly treated wild-type mice


Mouse Genome Informatics
hm3
    H2-Ab1tm1Gru/H2-Ab1tm1Gru
involves: 129S2/SvPas * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
• peripheral CD4+ T cell numbers are reduced more than 10-fold
• CD4 single-positive thymocyte numbers are decreased to 2.1% of thymocytes compared to 7.6% in wild-type controls
• MHC II complex is not expressed on the surface of cells
• mice fail to produce measurable antigen specific IgG1 levels in response to T cell dependent antigens even after two doses
• mice fail to produce measurable antigen specific IgM levels in response to T cell dependent antigens

hematopoietic system
• peripheral CD4+ T cell numbers are reduced more than 10-fold
• CD4 single-positive thymocyte numbers are decreased to 2.1% of thymocytes compared to 7.6% in wild-type controls
• MHC II complex is not expressed on the surface of cells
• mice fail to produce measurable antigen specific IgG1 levels in response to T cell dependent antigens even after two doses
• mice fail to produce measurable antigen specific IgM levels in response to T cell dependent antigens


Mouse Genome Informatics
hm4
    H2-Ab1tm1Gru/H2-Ab1tm1Gru
involves: 129S2/SvPas * C57BL/6J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
• CD4+ T cell count is reduced in the periphery relative to controls, but there are reduced but detectable numbers (3.2%) in the thymus
• mice show elevated single-positive CD8+ T cells in the thymus and periphery relative to controls
• mutants do not mount a complete immune response to an antigen such as TNP-conjugated ovalbumin
• 12 days post-immunization, mutants have not produced IgG1, IgG2a, IgG2b or IgG3 specific for TNP
• mutants produce IgM antigen-specific antibodies with consistently higher titers than control littermates
• skin grafts from OVA expressing transgenic mice ( Tg(CAG-OVA)916Jen) are indistinguishable from wild-type donor skin grafts for the first 40 days
• rejection starts occurring after 40 days with 25% of the transgenic grafts being completely lost after 115 days

hematopoietic system
• CD4+ T cell count is reduced in the periphery relative to controls, but there are reduced but detectable numbers (3.2%) in the thymus
• mice show elevated single-positive CD8+ T cells in the thymus and periphery relative to controls
• 12 days post-immunization, mutants have not produced IgG1, IgG2a, IgG2b or IgG3 specific for TNP
• mutants produce IgM antigen-specific antibodies with consistently higher titers than control littermates


Mouse Genome Informatics
hm5
    H2-Ab1tm1Gru/H2-Ab1tm1Gru
NOD.129S2-H2-Ab1tm1Gru
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
N
• NOD mice homozygous for this targeted mutation alone show no indication of inflammation at any age (J:86540)

cardiovascular system
N
• NOD mice homozygous for this targeted mutation alone show no indication of cardiac enlargement or inflammation at any age (J:86540)


Mouse Genome Informatics
cn6
    H2-Ab1tm1Gru/H2-Ab1tm1Gru
Runx1tm1Toku/Runx1tm1Toku
Runx3tm1Itan/Runx3tm1Itan
Tg(Cd4-cre)1Cwi/0

involves: 129P2/OlaHsd * 129S2/SvPas * C57BL/6 * DBA/2
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
• mice have predominance of CD4+CD8- T cells in thymus and periphery, indicating that MHC I-restricted cells are forced to differentiate into CD4+CD8- T cells
• after TCR stimulation, interferon gamma production is absent from class I-restricted CD4+CD8- cells

hematopoietic system
• mice have predominance of CD4+CD8- T cells in thymus and periphery, indicating that MHC I-restricted cells are forced to differentiate into CD4+CD8- T cells


Mouse Genome Informatics
cx7
    H2-Ab1tm1Gru/H2-Ab1tm1Gru
Tg(Ab1TL)1Gru/0

B6.Cg-H2-Ab1tm1Gru Tg(Ab1TL)1Gru
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
hematopoietic system
• CD4+ T cell development is normal in these mice
• peritoneal macrophages have an impaired capacity to activate I-Ab-restricted T cell hybridomas when loaded with the cognate peptide

immune system
• CD4+ T cell development is normal in these mice
• splenic APC have an impaired capacity to activate I-Ab-restricted T cell hybridomas when loaded with the cognate peptide
• LPS-induced blasts and peritoneal macrophages are also poor stimulators
• these splenic APC are also poor stimulators for freshly isolated T cells collected from immunized mice
• chemically fixed APC are also poor stimulators to T cell hybridomas when cognate peptide is loaded under neutral pH conditions
• however, chemically fixed APC are excellent stimulators when cognate peptide is loaded under acidic (pH 5) conditions
• peritoneal macrophages have an impaired capacity to activate I-Ab-restricted T cell hybridomas when loaded with the cognate peptide


Mouse Genome Informatics
cx8
    H2-Ab1tm1Gru/H2-Ab1tm1Gru
Tg(HLA-DQA1,HLA-DQB1)1Dv/0
Tg(Ins2-CD80)3B7Flv/0

B6.Cg-H2-Ab1tm1Gru Tg(HLA-DQA1,HLA-DQB1)1Dv Tg(Ins2-CD80)3B7Flv
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
• diabetic transgenic mice display sialadenitis
• over 80% of transgenic mice develop diabetes (positive urine glucose test and >250 mg/dl blood glucose) beginning at 4 months of age

homeostasis/metabolism
• over 80% have blood glucose levels above 250 mg/dl
• seen in over 80% of mice

digestive/alimentary system
• diabetic transgenic mice display sialadenitis

endocrine/exocrine glands
• diabetic transgenic mice display sialadenitis

renal/urinary system
• seen in over 80% of mice

Mouse Models of Human Disease
OMIM IDRef(s)
Diabetes Mellitus, Insulin-Dependent; IDDM 222100 J:59245


Mouse Genome Informatics
cx9
    H2-Ab1tm1Gru/H2-Ab1tm1Gru
Themistm1Lov/Themistm1Lov

involves: 129
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
• the number of transitional CD4+CD8int thymocytes is low in these mice when normally MHC-II deficient mice have high numbers of this population

hematopoietic system
• the number of transitional CD4+CD8int thymocytes is low in these mice when normally MHC-II deficient mice have high numbers of this population


Mouse Genome Informatics
cx10
    H2-Ab1tm1Gru/H2-Ab1tm1Gru
Tespa1tm1Lrgl/Tespa1tm1Lrgl

involves: 129 * 129S2/SvPas * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
• in the thymus compared with H2-Ab1tm1Gru homozygotes
• in the thymus compared with H2-Ab1tm1Gru homozygotes

hematopoietic system
• in the thymus compared with H2-Ab1tm1Gru homozygotes
• in the thymus compared with H2-Ab1tm1Gru homozygotes


Mouse Genome Informatics
cx11
    Cd8atm1Asin/Cd8atm1Asin
Cd8b1tm1Litt/Cd8b1tm1Litt
H2-Ab1tm1Gru/H2-Ab1tm1Gru

involves: 129 * FVB/N
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
• these cells are almost absent in the thymus and the lymph nodes
• 1.6 fold increase in number of these cells in the lymph nodes, compared to mice that have a wild-type allele for Cd8a on this mutant background

hematopoietic system
• these cells are almost absent in the thymus and the lymph nodes
• 1.6 fold increase in number of these cells in the lymph nodes, compared to mice that have a wild-type allele for Cd8a on this mutant background


Mouse Genome Informatics
cx12
    Cd4tm1.1Yzo/Cd4tm1.1Yzo
H2-Ab1tm1Gru/H2-Ab1tm1Gru

involves: 129P2/OlaHsd * 129S2/SvPas
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
• the peripheral CD4+CD8+ double positive T cells observed in Cd4 homozygotes are also present in these mice demonstrating Class II-independence of this cell population

hematopoietic system
• the peripheral CD4+CD8+ double positive T cells observed in Cd4 homozygotes are also present in these mice demonstrating Class II-independence of this cell population


Mouse Genome Informatics
cx13
    Cd4tm3.2Litt/Cd4tm3.2Litt
H2-Ab1tm1Gru/H2-Ab1tm1Gru

involves: 129P2/OlaHsd * 129S2/SvPas * FVB/N
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
N
• the expression of CD4 in post-selection thymocytes is normal (J:158962)
• the ratio of CD4 single positive to CD8 single positive T cells is inverted compared to in wild-type mice
• mature CD4 single positive and peripheral CD4lo T cell populations are largely lost unlike in wild-type mice

hematopoietic system
• the ratio of CD4 single positive to CD8 single positive T cells is inverted compared to in wild-type mice
• mature CD4 single positive and peripheral CD4lo T cell populations are largely lost unlike in wild-type mice


Mouse Genome Informatics
cx14
    H2-Ab1tm1Gru/H2-Ab1tm1Gru
Tg(HLA-DQA1,HLA-DQB1)1Dv/0
Tg(Ins2-CD80)3B7Flv/0

involves: 129S2/SvPas * C57BL/6 * C57BL/10SnJ * CBA
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
• stimulated CD4+ T cells secrete increased levels of Ifng compared to either DR4-transgenic or double transgenic MHC class II-deficient mice
• stimulated CD4+ T cells secrete low levels of Il-6 compared to either DR4-transgenic or double transgenic MHC class II-deficient mice
• 73% of mice expressing the transgene develop diabetes (blood glucose >250 mg/dl) compared to 0% of nontransgenic MHC class II-deficient mice

homeostasis/metabolism
• 73% display blood glucose levels above 250 mg/dl
• seen in 73% of mice

renal/urinary system
• seen in 73% of mice


Mouse Genome Informatics
cx15
    H2-Ab1tm1Gru/H2-Ab1tm1Gru
Tg(HLA-DQA1,HLA-DQB1)1Dv/0
Tg(HLA-DRB1)31Dmz/0
Tg(Ins2-CD80)3B7Flv/0

involves: 129S2/SvPas * C57BL/6 * C57BL/10SnJ * CBA * SJL
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
• transgenic mice develop sialadenitis and severity is associated with diabetes development
• coexpression of DR4 and DQ8 transgenes increases CD4+ T cell numbers 2-fold compared to either DR4 or DQ8 single transgenic line
• there are fewer CD8+ T cells in pancreatic infiltrates than in MHC class II-deficient mice expressing only DQ8
• incidence of diabetes (blood glucose >250 mg/dl; 5/22, 23%) is lowered from incidence in MHC class II-deficient mice expressing the DQ8 transgene (73%) and similar to deficient mice transgenic for DR4

endocrine/exocrine glands
• transgenic mice develop sialadenitis and severity is associated with diabetes development

hematopoietic system
• coexpression of DR4 and DQ8 transgenes increases CD4+ T cell numbers 2-fold compared to either DR4 or DQ8 single transgenic line
• there are fewer CD8+ T cells in pancreatic infiltrates than in MHC class II-deficient mice expressing only DQ8

digestive/alimentary system
• transgenic mice develop sialadenitis and severity is associated with diabetes development

Mouse Models of Human Disease
OMIM IDRef(s)
Diabetes Mellitus, Insulin-Dependent; IDDM 222100 J:68641


Mouse Genome Informatics
cx16
    H2-Ab1tm1Gru/H2-Ab1tm1Gru
Tg(Ins2-CD80)3B7Flv/0

involves: 129S2/SvPas * C57BL/6 * CBA
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
• only one of the MHC class II-deficient mice developed diabetes (blood glucose >250 mg/dl)


Mouse Genome Informatics
cx17
    H2-Ab1tm1Gru/H2-Ab1tm1Gru
Tg(HLA-DRB1)31Dmz/0
Tg(Ins2-CD80)3B7Flv/0

involves: 129S2/SvPas * C57BL/6 * CBA * SJL
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
endocrine/exocrine glands
• transgenic mice develop sialadenitis and severity is associated with diabetes development

immune system
• transgenic mice develop sialadenitis and severity is associated with diabetes development
• expression of the DR4 transgene increases CD4+ T cell numbers compared to the H2-Ab1-deficient Tg(Ins2-CD80)3B7Flv mice
• there are fewer CD8+ T cells in pancreatic infiltrates than in MHC class II-deficient mice expressing only DQ8
• incidence of diabetes (5/20) is lower than in MHC class II-deficient mice expressing the DQ8 transgene where incidence is 3-fold higher (73%)

hematopoietic system
• expression of the DR4 transgene increases CD4+ T cell numbers compared to the H2-Ab1-deficient Tg(Ins2-CD80)3B7Flv mice
• there are fewer CD8+ T cells in pancreatic infiltrates than in MHC class II-deficient mice expressing only DQ8

digestive/alimentary system
• transgenic mice develop sialadenitis and severity is associated with diabetes development

Mouse Models of Human Disease
OMIM IDRef(s)
Diabetes Mellitus, Insulin-Dependent; IDDM 222100 J:68641


Mouse Genome Informatics
cx18
    B2mtm1Unc/B2mtm1Unc
H2-Ab1tm1Gru/H2-Ab1tm1Gru
Tg(CD2-CD4,HLA-DQA1,HLA-DQB1)1Ell/Tg(CD2-CD4,HLA-DQA1,HLA-DQB1)1Ell

NOD.Cg-B2mtm1Unc H2-Ab1tm1Gru Tg(CD2-CD4,HLA-DQA1,HLA-DQB1)1Ell
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cardiovascular system
N
• at 22 weeks, no animals show cardiac enlargement or significant mononuclear cell infiltrates (J:113267)
• only animal developed first degree heart block by 24 weeks of age, and no animals develop complete heart block


Mouse Genome Informatics
cx19
    H2-Ab1tm1Gru/H2-Ab1tm1Gru
Tg(CD2-CD4,HLA-DQA1,HLA-DQB1)1Ell/Tg(CD2-CD4,HLA-DQA1,HLA-DQB1)1Ell

NOD.Cg-H2-Ab1tm1Gru Tg(CD2-CD4,HLA-DQA1,HLA-DQB1)1Ell
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• doubly homozygous mice die between 20 and 60 weeks of age; the female survival curve lags behind the male curve by about 1 week

immune system
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 (J:87013)
• 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 (J:87013)
• immunization of homozygous mutant/transgenic NOD mice with human GAD2 (GAD65) in complete Freund's adjuvant produces strong antibody responses versus GAD2 (J:87013)
• 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)
• rare, isolated foci of mononuclear cell infiltration may be seen in salivary glands of mice older than 30 weeks
• 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)
• 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
• mice produce high titers of autoantibodies against cardiac myosin at 12 weeks of age
• rare, isolated foci of mononuclear cell invasion may be observed in skeletal muscle 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

hematopoietic system
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 (J:87013)

homeostasis/metabolism
N
• NOD mice homozygous for both the mutation and the transgene do not spontaneously develop diabetes, even by one year of age (J:87013)
• NOD mice homozygous for both the mutation and the transgene are resistant to induction of diabetes by one or two doses of cyclophosphamide (J:87013)

cardiovascular system
• 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
• echocardiography of older animals reveals mitral regurgitation
• 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
• end-stage atria are grossly dilated, their walls composed primarily of fibrotic tissue, extremely thin in places and containing few live cardiomyocytes
• 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
• echocardiography of pre-terminal mice older than 20 weeks reveals extremely weak contraction of both ventricles
• 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
• nearly all of the mice develop heart block (prolongation of the PR interval) by 24 weeks of age
• some older animals present uncommon ECG profiles, e.g., torsade de pointes
• 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)

muscle
• 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
• echocardiography of pre-terminal mice older than 20 weeks reveals extremely weak contraction of both ventricles
• rare, isolated foci of mononuclear cell invasion may be observed in skeletal muscle of mice older than 30 weeks

digestive/alimentary system
• rare, isolated foci of mononuclear cell infiltration may be seen in salivary glands of mice older than 30 weeks

endocrine/exocrine glands
• rare, isolated foci of mononuclear cell infiltration may be seen in salivary glands of mice older than 30 weeks

respiratory system
• 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

Mouse Models of Human Disease
OMIM IDRef(s)
NOT Diabetes Mellitus, Insulin-Dependent; IDDM 222100 J:87013


Mouse Genome Informatics
cx20
    H2-Ab1tm1Gru/H2-Ab1tm1Gru
Tg(CD4,HLA-DQA1,HLA-DQB1)N8Ell/Tg(CD4,HLA-DQA1,HLA-DQB1)N8Ell

NOD.Cg-H2-Ab1tm1Gru Tg(CD4,HLA-DQA1,HLA-DQB1)N8Ell
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cardiovascular system
N
• no mice develop heart block at any age (J:113267)

immune system
N
• mice do not develop cardiac autoantibodies, or diabetes at any age (J:113267)
• mice do not develop cardiac myosin autoantibodies, but 100% develop thyroid autoantibodies by 55 weeks of age

endocrine/exocrine glands
• 25% of mice with thyroiditis develop thyroid gland enlargement and goiter

homeostasis/metabolism
• a subset of mice with an enlarged thyroid gland develop thyroid failure with elevated serum TSH levels


Mouse Genome Informatics
cx21
    H2-Ab1tm1Gru/H2-Ab1tm1Gru
Tg(HLA-DQA1,HLA-DQB1)70Myl/0

NOD.Cg-H2-Ab1tm1Gru Tg(HLA-DQA1,HLA-DQB1)70Myl
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cardiovascular system
• associated with myocarditis with lymphocytic infiltrates
• hearts show extensive mononuclear infiltrates in the atria; ventricles show focal infiltrates
• myocarditis development is transgene- and NOD-specific; the transgenics all exhibit myocarditis

digestive/alimentary system
• observed in transgenic and non-transgenic littermates with equal frequency

endocrine/exocrine glands
• observed in transgenic and non-transgenic littermates with equal frequency
• transgenic mice show insulitis, but pancreatic beta cell damage is not sufficient to result in clinical diabetes

immune system
• hearts show extensive mononuclear infiltrates in the atria; ventricles show focal infiltrates
• myocarditis development is transgene- and NOD-specific; the transgenics all exhibit myocarditis
• observed in transgenic and non-transgenic littermates with equal frequency
• transgenic mice show insulitis, but pancreatic beta cell damage is not sufficient to result in clinical diabetes
• transgenic mice line 73 show the highest prevalence and titers of cardiac tissue autoantibodies (16/18 mice are positive), while only 5/24 line 70 transgenics are positive and have lower antibody titers


Mouse Genome Informatics
cx22
    H2-Ab1tm1Gru/H2-Ab1tm1Gru
Tg(HLA-DQA1,HLA-DQB1)73Myl/0

NOD.Cg-H2-Ab1tm1Gru Tg(HLA-DQA1,HLA-DQB1)73Myl
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• >50% of transgenics (lines 73 and 275) die by 40 weeks of age; line 70 mice do not show significant premature death

homeostasis/metabolism
• massive mural thrombi adjacent to damaged tissue in atria are observed
• consistent with congestive heart failure
• consistent with congestive heart failure
• upon necropsy, diseased mice show varying degrees of pleural effusions

cardiovascular system
• myocyte degeneration and vacuolization are observed in atria, consistent with myocarditis
• associated with myocarditis with lymphocytic infiltrates
• diseased mice upon death are found to have enlarged hearts with ischemic coloration
• most healthy-appearing mice display marked cardiac enlargement at 40 weeks
• ventricular inflammatory lesions are composed of large numbers of CD4+ and CD8+ T cells with many F4/80 macrophages and few B cells
• enlarged livers show changes characteristic of centrilobular hepatic necrosis and hemorrhage
• many transgenic mice display symptoms of congestive heart failure; line 70 transgenics do not develop symptoms of congestive heart failure
• hearts show extensive mononuclear infiltrates in the atria; ventricles show focal infiltrates
• myocarditis development is transgene- and NOD-specific; the transgenics all exhibit myocarditis

endocrine/exocrine glands
• observed in transgenic and non-transgenic littermates with equal frequency
• transgenic mice show insulitis, but pancreatic beta cell damage is not sufficient to result in clinical diabetes

immune system
• hearts show extensive mononuclear infiltrates in the atria; ventricles show focal infiltrates
• myocarditis development is transgene- and NOD-specific; the transgenics all exhibit myocarditis
• observed in transgenic and non-transgenic littermates with equal frequency
• transgenic mice show insulitis, but pancreatic beta cell damage is not sufficient to result in clinical diabetes
• transgenic mice line 73 show the highest prevalence and titers of cardiac tissue autoantibodies (16/18 mice are positive), while only 5/24 mice of line 70 are positive with lower antibody titers

liver/biliary system
• livers show pathological changes characteristic of severe cardiac insufficiency and centrilobular hepatic necrosis and hemorrhage
• enlarged livers show changes characteristic of centrilobular hepatic necrosis and hemorrhage
• upon necropsy, diseased mice show enlargement and darkening of the liver

digestive/alimentary system
• observed in transgenic and non-transgenic littermates with equal frequency

behavior/neurological
• consistent with congestive heart failure

muscle
• myocyte degeneration and vacuolization are observed in atria, consistent with myocarditis

respiratory system
• upon necropsy, diseased mice show varying degrees of pleural effusions
• mice show acute onset of labored breathing


Mouse Genome Informatics
cx23
    H2-Ab1tm1Gru/H2-Ab1tm1Gru
Ighmtm1Cgn/Ighmtm1Cgn
Tg(CD2-CD4,HLA-DQA1,HLA-DQB1)1Ell/Tg(CD2-CD4,HLA-DQA1,HLA-DQB1)1Ell

NOD.Cg-Ighmtm1Cgn H2-Ab1tm1Gru Tg(CD2-CD4,HLA-DQA1,HLA-DQB1)1Ell
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cardiovascular system
• magnitude of cardiac enlargement is similar to NOD transgenic H2-Ab1-null, Igh-6-sufficient mice
• appearance of heart block is not significantly different from NOD transgenic H2-Ab1-null, Igh-6-sufficient mice
• at 22 weeks, mice show mononuclear cell infiltrates in heart walls

immune system
• at 22 weeks, mice show mononuclear cell infiltrates in heart walls


Mouse Genome Informatics
cx24
    H2-Ab1tm1Gru/H2-Ab1tm1Gru
Rag1tm1Mom/Rag1tm1Mom
Tg(CD2-CD4,HLA-DQA1,HLA-DQB1)1Ell/Tg(CD2-CD4,HLA-DQA1,HLA-DQB1)1Ell

NOD.Cg-Rag1tm1Mom H2-Ab1tm1Gru Tg(CD2-CD4,HLA-DQA1,HLA-DQB1)1Ell
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cardiovascular system
N
• animals have normal sized hearts, normal ECG, and show no sign of autoimmune pathology (J:113267)
• recipient animals develop cardiomegaly by 12 weeks after transfer
• 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
• recipient animals develop mononuclear cell infiltrates within heart wall by 12 weeks after transplant
• when young mice receive splenic lymphocytes from older NOD.DQ8/H2Ab-1 mice with heart block, myocarditis is triggered in 100% of recipients

immune system
• recipient animals develop mononuclear cell infiltrates within heart wall by 12 weeks after transplant
• when young mice receive splenic lymphocytes from older NOD.DQ8/H2Ab-1 mice with heart block, myocarditis is triggered in 100% of recipients
• anticardiac myosin autoantibodies reach a titer of 1:10000 in recipient mice at 12 weeks posttransfer
• 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;


Mouse Genome Informatics
cx25
    H2-Ab1tm1Gru/H2-Ab1tm1Gru
Rag1tm1Mom/Rag1tm1Mom
Tg(HLA-DQA1,HLA-DQB1)73Myl/0

NOD.Cg-Rag1tm1Mom H2-Ab1tm1Gru Tg(HLA-DQA1,HLA-DQB1)73Myl
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cardiovascular system
• mice do not develop spontaneous myocarditis like NOD.B6-H2Ab1tm1Gru-Tg(HLA-DQA1,HLA-DQB1)73 mice

immune system
• mice do not develop spontaneous myocarditis like NOD.B6-H2Ab1tm1Gru-Tg(HLA-DQA1,HLA-DQB1)73 mice
• injection of splenocytes from myocarditis-affected donors into healthy transgenic mice results in acute onset of symptoms of severe heart failure 3 weeks post-transfer, reproducing symptoms of the donor mice
• injection of serum from diseased donors with high autoantibody titer does not result in myocarditis