Mouse Genome Informatics
cn1
    Cd19tm1(cre)Cgn/Cd19+
Ptentm1Hwu/Ptentm1Hwu
Tg(IghelMD4)4Ccg/0
Tg(ML5sHEL)5Ccg/0

involves: 129P2/OlaHsd * 129S4/SvJae * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
• failed tolerance induction resulting in abundant autoantibody production, indicating that B cells are prevented from acquiring an anergic state
• B cells have about 10 fold lower bound HEL than in mutants with intact Pten, suggesting that receptor occupancy is reduced on mutant autoreactive B cells and that less HEL is available in adults for inducing and sustaining anergy
• increasing the concentration of free self-antigen confers an anergic phenotype on mutant B cells, but they remain long-lived


Mouse Genome Informatics
cn2
    Dicer1tm1Mmk/Dicer1tm1Mmk
Tg(IghelMD4)4Ccg/0
Cd79atm1(cre)Reth/Cd79a+

involves: BALB/c
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
• while B cell numbers are increased relative to in Cd79atm1(cre)Reth/Cd79a+ Dicer1tm1Mmk/Dicer1tm1Mmk mice, numbers are still lower than in wild-type mice

hematopoietic system
• while B cell numbers are increased relative to in Cd79atm1(cre)Reth/Cd79a+ Dicer1tm1Mmk/Dicer1tm1Mmk mice, numbers are still lower than in wild-type mice


Mouse Genome Informatics
cx3
    Tg(IghelMD4)4Ccg/0
Tg(KLK4mHEL)6Ccg/0

C57BL/6-Tg(IghelMD4)4Ccg Tg(KLK4mHEL)6Ccg
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
• the number of B cells found in the spleen is decreased by more than 6-fold compared to mice carrying just the antibody transgene
• very few of the remaining B cells expresses the transgenic antibody
• the number of B cells expressing the transgenic antibody is 5.9% of that found in singly transgenic NOD mice carrying only the antibody transgene

hematopoietic system
• the number of B cells found in the spleen is decreased by more than 6-fold compared to mice carrying just the antibody transgene
• very few of the remaining B cells expresses the transgenic antibody
• the number of B cells expressing the transgenic antibody is 5.9% of that found in singly transgenic NOD mice carrying only the antibody transgene


Mouse Genome Informatics
cx4
    Tg(IghelMD4)4Ccg/0
Tg(ML5sHEL)5Ccg/0

C57BL/6-Tg(IghelMD4)4Ccg Tg(ML5sHEL)5Ccg
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
• almost all of the B cells express the transgenic antibody
• the number of B cells expressing the transgenic antibody is 30% less than found in singly transgenic mice carrying just the antibody transgene
• this demonstrates that partial deletion occurs of B cells that recognize soluble self antigen
• there are reduced numbers of immature B cells bearing transgenic IgM in the bone marrow
• expression of IgM is 2- to 5- fold lower than on immature B cells found in mice carrying just the Tg(IghelMD4)4Ccg
• there are reduced numbers of pro-B cells bearing transgenic IgM in the bone marrow
• there is an increased percentage of mature B cells in the bone marrow
• B cells expressing the transgenic Ig are absent from the germinal center of the spleen and lymph nodes
• plasma cells producing transgenic Ig are found rarely in these mice
• splenic B cells bearing transgenic Ig are restricted to the follicular mantle zones
• very little IgM is detectable in the sera despite the presence of soluble antigen for the transgenic antibody (J:89156)
• B cells expressing the transgenic antibody are anergic as determined by the lack of HEL specific antibody found in the sera (J:89156)
• anergy occurs both centrally (i.e. in the bone marrow) and in the periphery (J:89156)
• this anergy can be reversed by stimulating B cells in vitro (J:89156)
• immature B cells in the bone marrow lack reactivity when transferred to irradiated host mice that are immunized with a HEL antigen

hematopoietic system
• almost all of the B cells express the transgenic antibody
• the number of B cells expressing the transgenic antibody is 30% less than found in singly transgenic mice carrying just the antibody transgene
• this demonstrates that partial deletion occurs of B cells that recognize soluble self antigen
• there are reduced numbers of immature B cells bearing transgenic IgM in the bone marrow
• expression of IgM is 2- to 5- fold lower than on immature B cells found in mice carrying just the Tg(IghelMD4)4Ccg
• there are reduced numbers of pro-B cells bearing transgenic IgM in the bone marrow
• there is an increased percentage of mature B cells in the bone marrow
• B cells expressing the transgenic Ig are absent from the germinal center of the spleen and lymph nodes
• plasma cells producing transgenic Ig are found rarely in these mice
• splenic B cells bearing transgenic Ig are restricted to the follicular mantle zones
• very little IgM is detectable in the sera despite the presence of soluble antigen for the transgenic antibody (J:89156)


Mouse Genome Informatics
cx5
    Tlr4Lps-d/Tlr4Lps-d
Tg(IghelMD4)4Ccg/0
Tg(KLK4mHEL)6Ccg/0

involves: 129P2/OlaHsd * C3H/HeJ * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
hematopoietic system
• a 35% reduction in number of recirculating mature autoreactive B cells is observed, compared to wild-type
• more B1 cells are detected among peritoneal lymphocytes in double transgenic mutants compared to Tg(IghelMD4)4Ccg single transgenic mutants

immune system
• a 35% reduction in number of recirculating mature autoreactive B cells is observed, compared to wild-type
• more B1 cells are detected among peritoneal lymphocytes in double transgenic mutants compared to Tg(IghelMD4)4Ccg single transgenic mutants


Mouse Genome Informatics
cx6
    Tlr9tm1Aki/Tlr9tm1Aki
Tg(IghelMD4)4Ccg/0
Tg(KLK4mHEL)6Ccg/0

involves: 129P2/OlaHsd * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
hematopoietic system
• a 37% reduction in number of recirculating mature autoreactive B cells is observed compared to wild-type
• more B1 cells are detected among peritoneal lymphocytes in double transgenic mutants compared to Tg(IghelMD4)4Ccg single transgenic mutants

immune system
• a 37% reduction in number of recirculating mature autoreactive B cells is observed compared to wild-type
• more B1 cells are detected among peritoneal lymphocytes in double transgenic mutants compared to Tg(IghelMD4)4Ccg single transgenic mutants


Mouse Genome Informatics
cx7
    Myd88tm1Aki/Myd88tm1Aki
Tg(IghelMD4)4Ccg/0
Tg(KLK4mHEL)6Ccg/0

involves: 129P2/OlaHsd * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
hematopoietic system
• a reduction in number of recirculating mature autoreactive B cells is observed compared to wild-type
• more B1 cells are detected among peritoneal lymphocytes in double transgenic mutants compared to Tg(IghelMD4)4Ccg single transgenic mutants

immune system
• a reduction in number of recirculating mature autoreactive B cells is observed compared to wild-type
• more B1 cells are detected among peritoneal lymphocytes in double transgenic mutants compared to Tg(IghelMD4)4Ccg single transgenic mutants


Mouse Genome Informatics
cx8
    Prkcdtm1Qxu/Prkcdtm1Qxu
Tg(IghelMD4)4Ccg/0
Tg(KLK4mHEL)6Ccg/0

involves: 129P2/OlaHsd * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
N
• mice exhibit the same number of B cells as in Tg(IghelMD4)4Ccg mice indicating normal clonal deletion (J:76134)


Mouse Genome Informatics
cx9
    Prkcdtm1Qxu/Prkcdtm1Qxu
Tg(IghelMD4)4Ccg/0
Tg(ML5sHEL)5Ccg/0

involves: 129P2/OlaHsd * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
N
• B cell activation in vitro and in vivo are normal (J:76134)
• peripheral B cells are reduced compared to in Prkcdtm1Qxu/Prkcdtm1Qxu Tg(IghelMD4)4Ccg mice
• the number of B follicles is increased compared to in Tg(IghelMD4)4Ccg Tg(ML5sHEL)5Ccg mice
• surface levels of IgMa are decreased 2-fold compared to in Prkcdtm1Qxu/Prkcdtm1Qxu Tg(IghelMD4)4Ccg mice
• B cells proliferate vigorously in response to HEL unlike Tg(IghelMD4)4Ccg Tg(ML5sHEL)5Ccg mice
• B cells switch to an autoreactive phenotype and fail to induce tolerance
• B cells proliferate vigorously in response to HEL unlike Tg(IghelMD4)4Ccg Tg(ML5sHEL)5Ccg mice
• mice exhibit an 80-fold increase in HEL-specific antibodies compared to in Tg(IghelMD4)4Ccg Tg(ML5sHEL)5Ccg mice

hematopoietic system
• peripheral B cells are reduced compared to in Prkcdtm1Qxu/Prkcdtm1Qxu Tg(IghelMD4)4Ccg mice
• the number of B follicles is increased compared to in Tg(IghelMD4)4Ccg Tg(ML5sHEL)5Ccg mice
• surface levels of IgMa are decreased 2-fold compared to in Prkcdtm1Qxu/Prkcdtm1Qxu Tg(IghelMD4)4Ccg mice
• B cells proliferate vigorously in response to HEL unlike Tg(IghelMD4)4Ccg Tg(ML5sHEL)5Ccg mice


Mouse Genome Informatics
cx10
    Lyntm1Ard/Lyntm1Ard
Tg(IghelMD4)4Ccg/0

involves: 129P2/OlaHsd * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
• B cells have altered kinetics of calcium fluxing upon BCR engagement with delayed influx but an ultimately higher peak intracellular concentration
• when mutant bone marrow is transferred to mice expressing hen egg lysozyme, B cell maturation is blocked at the immature B cell stage instead of anergy inducation in mature B cells as occurs with wild-type bone marrow
• mature B cells have 4-5 lower sIgM levels on their surface
• B1 B cells are absent in these mice
• hypersecretion of the transgenic IgM antibody occurs in these mice

hematopoietic system
• B cells have altered kinetics of calcium fluxing upon BCR engagement with delayed influx but an ultimately higher peak intracellular concentration
• when mutant bone marrow is transferred to mice expressing hen egg lysozyme, B cell maturation is blocked at the immature B cell stage instead of anergy inducation in mature B cells as occurs with wild-type bone marrow
• mature B cells have 4-5 lower sIgM levels on their surface
• B1 B cells are absent in these mice
• hypersecretion of the transgenic IgM antibody occurs in these mice


Mouse Genome Informatics
cx11
    Lyntm1Ard/Lyn+
Tg(IghelMD4)4Ccg/0

involves: 129P2/OlaHsd * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
• mature B cells have about 2-fold lower surface IgM levels

hematopoietic system
• mature B cells have about 2-fold lower surface IgM levels


Mouse Genome Informatics
cx12
    Ptpn6me-v/Ptpn6+
Tg(IghelMD4)4Ccg/0

involves: 129P2/OlaHsd * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
• mature B cells have about 2-fold lower surface IgM levels

hematopoietic system
• mature B cells have about 2-fold lower surface IgM levels


Mouse Genome Informatics
cx13
    Lyntm1Ard/Lyn+
Ptpn6me-v/Ptpn6+
Tg(IghelMD4)4Ccg/0

involves: 129P2/OlaHsd * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
hematopoietic system
• mature B cells have about 4-fold lower surface IgM levels

immune system
• mature B cells have about 4-fold lower surface IgM levels


Mouse Genome Informatics
cx14
    Cd22tm1Eac/Cd22+
Tg(IghelMD4)4Ccg/0

involves: 129P2/OlaHsd * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
• expression of CD22 on the surface of cells is half that of controls
• surface expression of IgM is about 70-80% of controls

hematopoietic system
• expression of CD22 on the surface of cells is half that of controls
• surface expression of IgM is about 70-80% of controls


Mouse Genome Informatics
cx15
    Cd22tm1Eac/Cd22+
Lyntm1Ard/Lyn+
Ptpn6me-v/Ptpn6+
Tg(IghelMD4)4Ccg/0

involves: 129P2/OlaHsd * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
• when mutant bone marrow is transferred to mice expressing hen egg lysozyme, B cell maturation is almost completely blocked at the immature B cell stage
• surface expression of IgM is only 15% of controls
• half the mice have a 15-fold increase in Hel-specific serum IgM

hematopoietic system
• when mutant bone marrow is transferred to mice expressing hen egg lysozyme, B cell maturation is almost completely blocked at the immature B cell stage
• surface expression of IgM is only 15% of controls
• half the mice have a 15-fold increase in Hel-specific serum IgM


Mouse Genome Informatics
cx16
    Cd22tm1Eac/Cd22+
Ptpn6me-v/Ptpn6+
Tg(IghelMD4)4Ccg/0

involves: 129P2/OlaHsd * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
• when mutant bone marrow is transferred to mice expressing hen egg lysozyme, B cell maturation is partially blocked at the immature B cell stage
• surface expression of IgM is less than half of controls

hematopoietic system
• when mutant bone marrow is transferred to mice expressing hen egg lysozyme, B cell maturation is partially blocked at the immature B cell stage
• surface expression of IgM is less than half of controls


Mouse Genome Informatics
cx17
    Cd22tm1Eac/Cd22+
Lyntm1Ard/Lyn+
Tg(IghelMD4)4Ccg/0

involves: 129P2/OlaHsd * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
• when mutant bone marrow is transferred to mice expressing hen egg lysozyme, B cell maturation is patially blocked at the immature B cell stage
• surface expression of IgM is less than half of controls

hematopoietic system
• when mutant bone marrow is transferred to mice expressing hen egg lysozyme, B cell maturation is patially blocked at the immature B cell stage
• surface expression of IgM is less than half of controls


Mouse Genome Informatics
cx18
    Cd19tm1(cre)Cgn/Cd19tm1(cre)Cgn
Tg(IghelMD4)4Ccg/0

involves: 129P2/OlaHsd * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
hematopoietic system
• modest reduction in peripheral B cell numbers

immune system
N
• tolerance mechanisms to prevent autoantibody production are intact and B cells are able to selectively downregulate IgM (J:155314)
• modest reduction in peripheral B cell numbers


Mouse Genome Informatics
cx19
    Cd19tm1(cre)Cgn/Cd19tm1(cre)Cgn
Tg(IghelMD4)4Ccg/0
Tg(ML5sHEL)5Ccg/0

involves: 129P2/OlaHsd * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
hematopoietic system
• low splenic and lymph node B cell numbers

immune system
N
• tolerance mechanisms to prevent autoantibody production are intact and B cells are able to selectively downregulate IgM (J:155314)
• low splenic and lymph node B cell numbers


Mouse Genome Informatics
cx20
    Fnip1Gt(RRM154)Byg/Fnip1Gt(RRM154)Byg
Tg(IghelMD4)4Ccg/0

involves: 129P2/OlaHsd * C57BL/6 * FVB/N * SJL
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
• absence of peripheral B cells
• in the bone marrow compared with Fnip1tm1.2Tes or Fnip1Gt(RRM154)Byg homozygotes

hematopoietic system
• absence of peripheral B cells
• in the bone marrow compared with Fnip1tm1.2Tes or Fnip1Gt(RRM154)Byg homozygotes


Mouse Genome Informatics
cx21
    Cd79btm1Mnz/Cd79btm1Mnz
Tg(IghelMD4)4Ccg/0
Tg(Rag2-Igb)1Mnz/0

involves: 129S1/Sv * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
hematopoietic system
• increase in apoptosis of immature B cells
• B cells fail to develop beyond the IgMlow immature B cell stage and no mature recirculating CD25-IgMhigh B cells are seen

immune system
• increase in apoptosis of immature B cells
• B cells fail to develop beyond the IgMlow immature B cell stage and no mature recirculating CD25-IgMhigh B cells are seen


Mouse Genome Informatics
cx22
    Cd79btm1Mnz/Cd79btm1Mnz
Tg(BCL2)22Wehi/0
Tg(IghelMD4)4Ccg/0
Tg(Rag2-Igb)1Mnz/0

involves: 129S1/Sv * C57BL/6 * C57BL/6JWehi * SJL/JWehi
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
hematopoietic system
• expression of Tg(BCL2)22Wehi rescues immature B cell apoptosis but immature B cell differentiation beyond the IgMlow immature B cell stage is still impaired and no mature recirculating CD25-IgMhigh B cells are seen

immune system
• expression of Tg(BCL2)22Wehi rescues immature B cell apoptosis but immature B cell differentiation beyond the IgMlow immature B cell stage is still impaired and no mature recirculating CD25-IgMhigh B cells are seen


Mouse Genome Informatics
cx23
    Tg(IghelMD4)4Ccg/0
Tg(ML5sHEL)5Ccg/0

involves: C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
• peripheral B cells are reduced compared to in Tg(IghelMD4)4Ccg mice
• very few B cells in the spleen have surface markers indicative of the marginal zone phenotype
• the number of B follicles is decreased compared to in Tg(IghelMD4)4Ccg mice
• surface levels of IgMa are decreased 7- to 11-fold compared to in Tg(IghelMD4)4Ccg mice
• B cells from these mice are unable to activate HEL-specific CD4 T cells from Tg(TcrHEL3A9)1Mmd mice when co-cultured together in the presence of HEL protein (J:73608)
• B cells are anergic when stimulated with HEL antigen as determined by reduced antibody production, no upregulation of activation markers CD69 and CD86, and failure to increase size (J:132538)

hematopoietic system
• peripheral B cells are reduced compared to in Tg(IghelMD4)4Ccg mice
• very few B cells in the spleen have surface markers indicative of the marginal zone phenotype
• the number of B follicles is decreased compared to in Tg(IghelMD4)4Ccg mice
• surface levels of IgMa are decreased 7- to 11-fold compared to in Tg(IghelMD4)4Ccg mice


Mouse Genome Informatics
cx24
    Tg(IghelMD4)4Ccg/?
Tg(KLK4mHEL)6Ccg/?

involves: C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
• mature B cells are reduced 5- to 20- fold in the bone marrow, spleen and lymph node
• the small number of mature B cells present have B cell receptors encoded by endogenous heavy chain
• a small increase occurs in the number of B220low immature B cells found in the bone marrow
• the immature B cells found in the bone marrow have low surface expression of IgM suggesting B cells have encountered antigen but failed to develop to a mature phenotype

hematopoietic system
• mature B cells are reduced 5- to 20- fold in the bone marrow, spleen and lymph node
• the small number of mature B cells present have B cell receptors encoded by endogenous heavy chain
• a small increase occurs in the number of B220low immature B cells found in the bone marrow
• the immature B cells found in the bone marrow have low surface expression of IgM suggesting B cells have encountered antigen but failed to develop to a mature phenotype


Mouse Genome Informatics
cx25
    Cr2tm2.1(HLA-A)Crr/Cr2tm2.1(HLA-A)Crr
Tg(IghelMD4)4Ccg/?

involves: C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
• B cells fail to react to sub-optimal doses of antigen coated in C3 complement
• B cells are also unresponsive to a suboptimal level of anti-IgM, anti-CD40, and C3d

hematopoietic system
• B cells fail to react to sub-optimal doses of antigen coated in C3 complement
• B cells are also unresponsive to a suboptimal level of anti-IgM, anti-CD40, and C3d


Mouse Genome Informatics
cx26
    Fnip1tm1.2Baba/Fnip1tm1.2Baba
Tg(IghelMD4)4Ccg/0

involves: C57BL/6 * C57BL/6J * FVB/N * SJL
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
hematopoietic system
• absence of peripheral B cells
• in the bone marrow compared with Fnip1tm1.2Tes or Fnip1Gt(RRM154)Byg homozygotes

immune system
• absence of peripheral B cells
• in the bone marrow compared with Fnip1tm1.2Tes or Fnip1Gt(RRM154)Byg homozygotes


Mouse Genome Informatics
cx27
    Atp11cambr/Y
Tg(IghelMD4)4Ccg/0

involves: C57BL/6 * C57BL/6JApb
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
hematopoietic system
• immature B cell numbers are partially rescued compared to in Atp11cambr hemizygotes (J:171924)
• pro-B cell numbers are partially rescued compared to in Tg(IghelMD4)4Ccg mice (J:171924)

immune system
• immature B cell numbers are partially rescued compared to in Atp11cambr hemizygotes (J:171924)
• pro-B cell numbers are partially rescued compared to in Tg(IghelMD4)4Ccg mice (J:171924)


Mouse Genome Informatics
cx28
    Bcl6tm1.1Toka/Bcl6tm1.1Toka
Tg(IghelMD4)4Ccg/0

involves: C57BL/6 * NZB
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
• B cells co-transferred with Tg(TcraTcrb)425Cbn cells into wild-type mice immunized with HEL-ovalbumin exhibit increased apoptosis compared with similarly treated heterozygous cells
• B cells co-transferred with Tg(TcraTcrb)425Cbn cells into wild-type mice immunized with HEL-ovalbumin exhibit impaired formation of germinal center B cell populations compared with similarly treated heterozygous cells

cellular
• B cells co-transferred with Tg(TcraTcrb)425Cbn cells into wild-type mice immunized with HEL-ovalbumin exhibit increased apoptosis compared with similarly treated heterozygous cells

hematopoietic system
• B cells co-transferred with Tg(TcraTcrb)425Cbn cells into wild-type mice immunized with HEL-ovalbumin exhibit increased apoptosis compared with similarly treated heterozygous cells
• B cells co-transferred with Tg(TcraTcrb)425Cbn cells into wild-type mice immunized with HEL-ovalbumin exhibit impaired formation of germinal center B cell populations compared with similarly treated heterozygous cells


Mouse Genome Informatics
cx29
    Tg(IghelMD4)4Ccg/0
Tg(KLK4mHEL)6Ccg/0

NOD.B6-Tg(IghelMD4)4Ccg Tg(KLK4mHEL)6Ccg/Dvs
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
• the number of B cells found in the spleen is decreased by more than 6-fold compared to NOD mice carrying just the antibody transgene
• very few of the remaining B cells expresses the transgenic antibody
• the number of B cells expressing the transgenic antibody is 1.1% of that found in singly transgenic NOD mice carrying only the antibody transgene

hematopoietic system
• the number of B cells found in the spleen is decreased by more than 6-fold compared to NOD mice carrying just the antibody transgene
• very few of the remaining B cells expresses the transgenic antibody
• the number of B cells expressing the transgenic antibody is 1.1% of that found in singly transgenic NOD mice carrying only the antibody transgene


Mouse Genome Informatics
cx30
    Tg(IghelMD4)4Ccg/0
Tg(ML5sHEL)5Ccg/0

NOD.B6-Tg(IghelMD4)4Ccg Tg(ML5sHEL)5Ccg/Dvs
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
• there is no decrease in the number of B cells expressing the transgenic antibody compared to singly transgenic NOD mice that carry just the antibody transgene
• this suggests defect in the NOD strain of deleting B cells that recognize soluble self antigens
• Background Sensitivity: the normal number of B cells found in these mice demonstrate a defect in the NOD strain of deleting B cells that recognize soluble self antigens
• very little IgM is detectable in the sera despite the presence of soluble antigen for the transgenic antibody
• B cells expressing the transgenic antibody are anergic as determined by the lack of HEL specific antibody found in the sera
• anergy occurs both centrally (i.e. in the bone marrow) and in the periphery
• this anergy can be reversed by stimulating B cells in vitro
• when compared to singly transgenic controls, antibody production following BCR and CD40 stimulation is less suppressed in doubly transgenic NOD mice than in doubly transgenic C57BL/6 mice (2.6-fold less vs 4.5 fold less)

hematopoietic system
• there is no decrease in the number of B cells expressing the transgenic antibody compared to singly transgenic NOD mice that carry just the antibody transgene
• this suggests defect in the NOD strain of deleting B cells that recognize soluble self antigens
• Background Sensitivity: the normal number of B cells found in these mice demonstrate a defect in the NOD strain of deleting B cells that recognize soluble self antigens
• very little IgM is detectable in the sera despite the presence of soluble antigen for the transgenic antibody


Mouse Genome Informatics
cx31
    Ighmtm1Cgn/Ighmtm1Cgn
Tg(IghelMD4)4Ccg/Tg(IghelMD4)4Ccg

NOD.Cg-Ighmtm1Cgn Tg(IghelMD4)4Ccg/DvsJ
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
• mice have low levels of insulitis starting at 12 weeks of age with a mean disease score of 1.62 compared to non-transgenic NOD mice that have a mean score of 3.01 at this age
• the number of CD8 T cells found in the spleen is half that of non-transgenic NOD mice
• the number but not the proportion of B cells found in the spleen is twice that of non-transgenic NOD mice
• all of the B cells express the transgenic IgM B cell receptor specific for hen egg lysozyme
• T cells fail to proliferate when splenocytes are cultured in vitro with the diabetes autoantigen GAD
• purified B cells fail to stimulate T cells from non-transgenic NOD mice when cultured together in the presence of the diabetes autoantigen GAD
• 16.7% of female mice develop diabetes by 21 weeks of age compared to control NOD mice that have an incidence rate of 95.5% at this age
• mice with lymphosarcomas were not included in the analysis

tumorigenesis
• lymphosarcomas are present in the majority of mice with development starting at 20 weeks of age

hematopoietic system
• the number of CD8 T cells found in the spleen is half that of non-transgenic NOD mice
• the number but not the proportion of B cells found in the spleen is twice that of non-transgenic NOD mice
• all of the B cells express the transgenic IgM B cell receptor specific for hen egg lysozyme
• T cells fail to proliferate when splenocytes are cultured in vitro with the diabetes autoantigen GAD
• purified B cells fail to stimulate T cells from non-transgenic NOD mice when cultured together in the presence of the diabetes autoantigen GAD

endocrine/exocrine glands
• mice have low levels of insulitis starting at 12 weeks of age with a mean disease score of 1.62 compared to non-transgenic NOD mice that have a mean score of 3.01 at this age

Mouse Models of Human Disease
OMIM IDRef(s)
NOT Diabetes Mellitus, Insulin-Dependent; IDDM 222100 J:80859


Mouse Genome Informatics
tg32
    Tg(IghelMD4)4Ccg/Tg(IghelMD4)4Ccg
involves: C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system

hematopoietic system


Mouse Genome Informatics
tg33
    Tg(IghelMD4)4Ccg/Tg(IghelMD4)4Ccg
NOD.B6-Tg(IghelMD4)4Ccg/DvsJ
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
• the number of CD8 T cells found in the spleen is half that of non-transgenic NOD mice
• the number but not the proportion of B cells found in the spleen is twice that of non-transgenic NOD mice (J:80859)
• 99.3% of these B cells express the transgenic IgM B cell receptor specific for hen egg lysozyme (J:80859)
• 8.4% of the B cells express endogenous IgM indicating there is some escape from allelic exclusion (J:80859)
• 98% of the B cells express the transgenic antibody that is specific for hen egg lysozyme (HEL) (J:89156)
• 94% of these B cells retain the ability to bind HEL protein (J:89156)
• T cells fail to proliferate when splenocytes are cultured in vitro with the diabetes autoantigen GAD
• 90% of female mice are diabetic by 30 weeks of age which is similar to the incidence rate in non-transgenic NOD mice
• there is a significant delay in time of onset compared to non-transgenic diabetic mice

hematopoietic system
• the number of CD8 T cells found in the spleen is half that of non-transgenic NOD mice
• the number but not the proportion of B cells found in the spleen is twice that of non-transgenic NOD mice (J:80859)
• 99.3% of these B cells express the transgenic IgM B cell receptor specific for hen egg lysozyme (J:80859)
• 8.4% of the B cells express endogenous IgM indicating there is some escape from allelic exclusion (J:80859)
• 98% of the B cells express the transgenic antibody that is specific for hen egg lysozyme (HEL) (J:89156)
• 94% of these B cells retain the ability to bind HEL protein (J:89156)
• T cells fail to proliferate when splenocytes are cultured in vitro with the diabetes autoantigen GAD

Mouse Models of Human Disease
OMIM IDRef(s)
Diabetes Mellitus, Insulin-Dependent; IDDM 222100 J:80859


Mouse Genome Informatics
tg34
    Tg(IghelMD4)4Ccg/0
C57BL/6-Tg(IghelMD4)4Ccg
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
• most peripheral B cells express the transgenic immunoglobulin (Ig) that binds hen egg lysozyme peptide (HEL) with a high affinity (J:109923)
• the few B cells expressing endogenous Ig in the spleen express high levels of IgM with little to no levels of IgD compared to splenic B cells from wild-type mice that are IgMlow IgDhigh (J:109923)
• over 90% of B cells express immunoglobulin that has a high affinity for hen egg lysozyme antigen (HEL) (J:132538)
• there are reduced numbers of immature B cells bearing transgenic IgM in the bone marrow
• three quarters of the B cells in the spleen are immature as indicated by the IgMhi IgDhi surface markers (J:78308)
• three quarters of the B cells in the spleen are immature as indicated by the IgMhi IgDhi surface markers (J:132538)
• there are reduced numbers of pro-B cells bearing transgenic IgM in the bone marrow
• 98% of the B cells express the transgenic antibody that is specific for hen egg lysozyme (HEL) (J:89156)
• 94% of these B cells retain the ability to bind HEL protein (J:89156)
• there is an increased percentage of mature B cells in the bone marrow (J:109923)
• all of the B cells found in the peritoneal cavity are of the B-2 lineage as determined by B220hi CD5lowexpression
• B cells expressing the transgenic Ig are absent from the germinal center of the spleen and lymph nodes
• plasma cells bearing endogenous Ig outnumber plasma cells bearing the transgenic Ig
• there are low levels of anti-HEL IgG2b in the sera of unimmunized mice
• there are high levels of anti-HEL IgM in the sera of unimmunized mice (J:78308)
• there are high levels of anti-HEL IgM in the sera of unimmunized mice (J:132538)

hematopoietic system
• most peripheral B cells express the transgenic immunoglobulin (Ig) that binds hen egg lysozyme peptide (HEL) with a high affinity (J:109923)
• the few B cells expressing endogenous Ig in the spleen express high levels of IgM with little to no levels of IgD compared to splenic B cells from wild-type mice that are IgMlow IgDhigh (J:109923)
• over 90% of B cells express immunoglobulin that has a high affinity for hen egg lysozyme antigen (HEL) (J:132538)
• there are reduced numbers of immature B cells bearing transgenic IgM in the bone marrow
• three quarters of the B cells in the spleen are immature as indicated by the IgMhi IgDhi surface markers (J:78308)
• three quarters of the B cells in the spleen are immature as indicated by the IgMhi IgDhi surface markers (J:132538)
• there are reduced numbers of pro-B cells bearing transgenic IgM in the bone marrow
• 98% of the B cells express the transgenic antibody that is specific for hen egg lysozyme (HEL) (J:89156)
• 94% of these B cells retain the ability to bind HEL protein (J:89156)
• there is an increased percentage of mature B cells in the bone marrow (J:109923)
• all of the B cells found in the peritoneal cavity are of the B-2 lineage as determined by B220hi CD5lowexpression
• B cells expressing the transgenic Ig are absent from the germinal center of the spleen and lymph nodes
• plasma cells bearing endogenous Ig outnumber plasma cells bearing the transgenic Ig
• there are low levels of anti-HEL IgG2b in the sera of unimmunized mice
• there are high levels of anti-HEL IgM in the sera of unimmunized mice (J:78308)
• there are high levels of anti-HEL IgM in the sera of unimmunized mice (J:132538)


Mouse Genome Informatics
tg35
    Tg(IghelMD4)4Ccg/0
involves: C3H/HeJ * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
hematopoietic system
• bone marrow contains fewer combined numbers of combined pro-pre B cells than on a B6 background
• bone marrow contains fewer combined numbers of combined pro-pre B cells than on a B6 background

immune system
• bone marrow contains fewer combined numbers of combined pro-pre B cells than on a B6 background
• bone marrow contains fewer combined numbers of combined pro-pre B cells than on a B6 background


Mouse Genome Informatics
tg36
    Tg(IghelMD4)4Ccg/0
involves: C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
• bone marrow contains fewer combined numbers of combined pro-pre B cells than on a B6 background
• B cells become activated when cultured with HEL protein and CD4 T cells from Tg(TcrHEL3A9)1Mmd transgenic mice
• B cells in this culture quickly upregulate CD44 and CD86
• by 48 hours in culture, B cells are greatly enlarged as they undergo blastogenesis
• B cells cultured without the T cells initially upregulate activation markers but then die
• when HEL peptide is used in culture, some B cells increase expression of activation markers but do not form large blast cells
• bone marrow contains fewer combined numbers of combined pro-pre B cells than on a B6 background

hematopoietic system
• bone marrow contains fewer combined numbers of combined pro-pre B cells than on a B6 background
• B cells become activated when cultured with HEL protein and CD4 T cells from Tg(TcrHEL3A9)1Mmd transgenic mice
• B cells in this culture quickly upregulate CD44 and CD86
• by 48 hours in culture, B cells are greatly enlarged as they undergo blastogenesis
• B cells cultured without the T cells initially upregulate activation markers but then die
• when HEL peptide is used in culture, some B cells increase expression of activation markers but do not form large blast cells
• bone marrow contains fewer combined numbers of combined pro-pre B cells than on a B6 background