Description

The genotypes of the animals provided may not reflect those discussed in the strain description or the mating scheme utilized by The Jackson Laboratory prior to cryopreservation. Please inquire for possible genotypes for this specific strain.

Strain Information

Type Congenic; Mutant Strain; Targeted Mutation; Additional information on Genetically Engineered and Mutant Mice. Visit our online Nomenclature tutorial. Additional information on Congenic nomenclature. Species laboratory mouse Generation N?pN1 Generation Definitions   Donating Investigator Michel Nussenzweig,   The Rockefeller University

Description
Mice homozygous for this targeted mutation are viable and fertile and do not display any gross physical or behavioral abnormalities. In combination with immunoglobulin lambda light chain, this heavy chain variable (V) region produces antibody that binds hapten NP (4-hydroxy-3-nitrophenylacetyl). A Trp to Leu point mutation at codon 33 results in a 40-fold increase in antigen binding affinity (B1-8^hi). Despite the significantly enhanced affinity for NP, there is only a 2-3 fold difference in the T-independent proliferative response of B cells that carry high or low affinity receptors. In T cell-dependent responses there is no difference in the ability of B1-8 high vs. B1-8 low affinity cells to enter germinal center reactions. However, high affinity B cells were recruited preferentially in response to both T cell-dependent and T cell-independent antigens. Expression has been verified by immunostaining cells that carry the mutation. The phenotype of this mutation on the BALB/cBy background is not known to differ from that on the C57BL/6 background (Stock No. 007594).

Development
PCR was used to introduce a point mutation conferring higher affinity 4-hydroxy-3-nitrophenyl)acetyl (NP)-binding to Igh (V_HB1-8): TGG->TTG (codon 33 Trp->Leu). A targeting vector incorporating a 5' floxed neomycin cassette in addition to the point mutation was transfected into 129P2/OlaHsd-derived E14 embryonic stem (ES) cells. Positive clones were injected into C57BL/6 blastocysts, and the resulting chimeric males were bred to C57BL/6 EIIA-Cre females to delete the neomycin gene, and leave a loxP site. Mice were backcrossed to C57BL/6 congenic background CD45.1 (Ptprc^a) mice for at least 12 generations by the donating laboratory, then backcrossed to BALB/cBy for 10 generations. This strain does not carry the Ptprc^a allele.

Related Strains

Strains carrying   Igh^tm1Mnz allele

007594

B6.129P2-Ptrpca Ightm1Mnz/J

View Strains carrying   Igh^tm1Mnz     (1 strain)

Strains carrying other alleles of Igh

012642	B6.129P2(C)-Ightm2Cgn/J
007776	B6.129P2-Ightm2Mnz/J
001317	B6.Cg-Igha Thy1a Gpi1a/J
011074	C.129P2(B6)-Igktm1Rsky Ightm2Rsky/PldJ
012235	C.129P2(B6)-Igktm2Rsky Ightm2Rsky/J
008332	C.129S1-Ightm1(Myc)Janz/J
001109	C.AL-Igho/SmnJ
001107	C.BKa-Ighb/IcrSmnJ
004126	C.Cg-Cd19tm1(cre)Cgn Ighb/J

View Strains carrying other alleles of Igh     (9 strains)

Phenotype

Phenotype Information

View Mammalian Phenotype Terms

Mammalian Phenotype Terms provided by MGI

      assigned by genotype

The following phenotype information may relate to a genetic background differing from this JAX^® Mice strain.

Igh^tm1Mnz/Igh^tm1Mnz

        B6.129P2-Igh^tm1Mnz

• immune system phenotype
• abnormal B cell physiology
  • some mutant B cells that express Ig lambda differentiate into short-lived plasmacytes in red pulp of lymphoid follicles; plasmacyte response is greater than in Igh^tm2Mnz cells or wild-type   (MGI Ref ID J:75653)
  • fraction of mutant B cells differentiate into short lived germinal center (GC) cells; GC response is greater than in Igh^tm2Mnz cells   (MGI Ref ID J:75653)
  • when equal numbers of Igh^tm1Mnz and Igh^tm2Mnz B cells are transferred to wild-type recipient mice, after immunization with NP-Ficoll, Igh^tm1Mnz B cells preferentially expand and proliferation to make up ~46% of Ig lambda B cells whereas Igh^tm2Mnz B cells are not expanded   (MGI Ref ID J:75653)
  • after 5 days post immunization, 85% of plasmacytes and 60% of germinal center cells are Igh^tm1Mnz B cells (high affinity)   (MGI Ref ID J:75653)
  • mutant B cells with high affinity for antigen are preferentially selected during early phase of T1-2 immune response, over mutant B cells with low affinity for antigen   (MGI Ref ID J:75653)
• • increased B cell apoptosis
    • there are higher numbers of apoptotic mutant B cells than in wild-type or Igh^tm2Mnz B cells in spleens 3 and 5 days after immunization   (MGI Ref ID J:75653)
  • increased B cell proliferation
    • mutant B cells in mice challenged with a T1-2 antigen (NP-Ficoll) undergo rapid proliferative expansion (from 3 to 25% of lymphocytes by 5 days after immunization   (MGI Ref ID J:75653)
    • in immunized mice, on day 2 there is a much higher percentage of high-affinity B cells (58%) compared to wild-type cells (~3%)   (MGI Ref ID J:75653)
  • increased IgG level
    • 4-hydroxy-3-nitrophenyl)acetyl-specific (NP) IgM antibody production is greater than in Igh^tm2Mnz B cells or wild-type   (MGI Ref ID J:75653)
  • increased IgM level
    • NP-specific IgM antibody production is greater than in Igh^tm2Mnz B cells or wild-type   (MGI Ref ID J:75653)
• cellular phenotype
• abnormal cell cycle
  • absolute number of cells in cell cycle is always higher than in Igh^tm2Mnz or wild-type mice   (MGI Ref ID J:75653)
• increased B cell apoptosis
  • there are higher numbers of apoptotic mutant B cells than in wild-type or Igh^tm2Mnz B cells in spleens 3 and 5 days after immunization   (MGI Ref ID J:75653)
• increased B cell proliferation
  • mutant B cells in mice challenged with a T1-2 antigen (NP-Ficoll) undergo rapid proliferative expansion (from 3 to 25% of lymphocytes by 5 days after immunization   (MGI Ref ID J:75653)
  • in immunized mice, on day 2 there is a much higher percentage of high-affinity B cells (58%) compared to wild-type cells (~3%)   (MGI Ref ID J:75653)
• hematopoietic system phenotype
• increased B cell proliferation
  • mutant B cells in mice challenged with a T1-2 antigen (NP-Ficoll) undergo rapid proliferative expansion (from 3 to 25% of lymphocytes by 5 days after immunization   (MGI Ref ID J:75653)
  • in immunized mice, on day 2 there is a much higher percentage of high-affinity B cells (58%) compared to wild-type cells (~3%)   (MGI Ref ID J:75653)

View Research Applications

Research Applications

This mouse can be used to support research in many areas including:

Immunology, Inflammation and Autoimmunity Research

Genes & Alleles

Gene & Allele Information provided by MGI

Allele Symbol		Ightm1Mnz
Allele Name		targeted mutation 1, Michel C Nussenzweig
Allele Type		Targeted (knock-in)
Common Name(s)		B1-8hi;
Mutation Made By		Michel Nussenzweig,   The Rockefeller University
Strain of Origin		129P2/OlaHsd
ES Cell Line Name		E14
ES Cell Line Strain		129P2/OlaHsd
Promoter		Igh, immunoglobulin heavy chain complex, mouse, laboratory
Molecular Note		PCR was used to introduce a point mutation conferring higher affinity 4-hydroxy-3-nitrophenyl)acetyl (NP)-binding to Igh-V (VHB1-8): TGG->TTG (codon 33 Trp->Leu). A targeting vector incorporating a 5' floxed neomycin cassette in addition to the point mutation was transfected into 129P2/OlaHsd-derived E14 embryonic stem (ES) cells. [MGI Ref ID J:75653]

Genotyping

Genotyping Information

Genotyping Protocols

Igh^tm1Mnz, High Resolution Melting
Igh^tm1Mnz, Standard PCR

Helpful Links

Genotyping resources and troubleshooting

References

References provided by MGI

Selected Reference(s)

Shih TA; Roederer M; Nussenzweig MC. 2002. Role of antigen receptor affinity in T cell-independent antibody responses in vivo. Nat Immunol 3(4):399-406. [PubMed: 11896394]  [MGI Ref ID J:75653]

Additional References

Igh^tm1Mnz related

Aiba Y; Kometani K; Hamadate M; Moriyama S; Sakaue-Sawano A; Tomura M; Luche H; Fehling HJ; Casellas R; Kanagawa O; Miyawaki A; Kurosaki T. 2010. Preferential localization of IgG memory B cells adjacent to contracted germinal centers. Proc Natl Acad Sci U S A 107(27):12192-7. [PubMed: 20547847]  [MGI Ref ID J:162089]

Cadera EJ; Wan F; Amin RH; Nolla H; Lenardo MJ; Schlissel MS. 2009. NF-kappaB activity marks cells engaged in receptor editing. J Exp Med 206(8):1803-16. [PubMed: 19581408]  [MGI Ref ID J:151490]

Chappell CP; Draves KE; Giltiay NV; Clark EA. 2012. Extrafollicular B cell activation by marginal zone dendritic cells drives T cell-dependent antibody responses. J Exp Med 209(10):1825-40. [PubMed: 22966002]  [MGI Ref ID J:191423]

Crouch EE; Li Z; Takizawa M; Fichtner-Feigl S; Gourzi P; Montano C; Feigenbaum L; Wilson P; Janz S; Papavasiliou FN; Casellas R. 2007. Regulation of AID expression in the immune response. J Exp Med 204(5):1145-56. [PubMed: 17452520]  [MGI Ref ID J:125740]

Dominguez-Sola D; Victora GD; Ying CY; Phan RT; Saito M; Nussenzweig MC; Dalla-Favera R. 2012. The proto-oncogene MYC is required for selection in the germinal center and cyclic reentry. Nat Immunol 13(11):1083-91. [PubMed: 23001145]  [MGI Ref ID J:188565]

Draghi NA; Denzin LK. 2010. H2-O, a MHC class II-like protein, sets a threshold for B-cell entry into germinal centers. Proc Natl Acad Sci U S A 107(38):16607-12. [PubMed: 20807742]  [MGI Ref ID J:164357]

Kamphorst AO; Guermonprez P; Dudziak D; Nussenzweig MC. 2010. Route of antigen uptake differentially impacts presentation by dendritic cells and activated monocytes. J Immunol 185(6):3426-35. [PubMed: 20729332]  [MGI Ref ID J:163535]

King IL; Fortier A; Tighe M; Dibble J; Watts GF; Veerapen N; Haberman AM; Besra GS; Mohrs M; Brenner MB; Leadbetter EA. 2011. Invariant natural killer T cells direct B cell responses to cognate lipid antigen in an IL-21-dependent manner. Nat Immunol 13(1):44-50. [PubMed: 22120118]  [MGI Ref ID J:178990]

Kitano M; Moriyama S; Ando Y; Hikida M; Mori Y; Kurosaki T; Okada T. 2011. Bcl6 protein expression shapes pre-germinal center B cell dynamics and follicular helper T cell heterogeneity. Immunity 34(6):961-72. [PubMed: 21636294]  [MGI Ref ID J:174014]

Mohr E; Cunningham AF; Toellner KM; Bobat S; Coughlan RE; Bird RA; MacLennan IC; Serre K. 2010. IFN-{gamma} produced by CD8 T cells induces T-bet-dependent and -independent class switching in B cells in responses to alum-precipitated protein vaccine. Proc Natl Acad Sci U S A 107(40):17292-7. [PubMed: 20855629]  [MGI Ref ID J:165414]

Ouchida R; Kurosaki T; Wang JY. 2010. A role for lysosomal-associated protein transmembrane 5 in the negative regulation of surface B cell receptor levels and B cell activation. J Immunol 185(1):294-301. [PubMed: 20519653]  [MGI Ref ID J:161622]

Reina-San-Martin B; Difilippantonio S; Hanitsch L; Masilamani RF; Nussenzweig A; Nussenzweig MC. 2003. H2AX is required for recombination between immunoglobulin switch regions but not for intra-switch region recombination or somatic hypermutation. J Exp Med 197(12):1767-78. [PubMed: 12810694]  [MGI Ref ID J:120658]

Robbiani DF; Bunting S; Feldhahn N; Bothmer A; Camps J; Deroubaix S; McBride KM; Klein IA; Stone G; Eisenreich TR; Ried T; Nussenzweig A; Nussenzweig MC. 2009. AID produces DNA double-strand breaks in non-Ig genes and mature B cell lymphomas with reciprocal chromosome translocations. Mol Cell 36(4):631-41. [PubMed: 19941823]  [MGI Ref ID J:154731]

Schwickert TA; Alabyev B; Manser T; Nussenzweig MC. 2009. Germinal center reutilization by newly activated B cells. J Exp Med 206(13):2907-14. [PubMed: 19934021]  [MGI Ref ID J:155831]

Serre K; Cunningham AF; Coughlan RE; Lino AC; Rot A; Hub E; Moser K; Manz R; Ferraro A; Bird R; Toellner KM; Demengeot J; MacLennan IC; Mohr E. 2012. CD8 T cells induce T-bet-dependent migration toward CXCR3 ligands by differentiated B cells produced during responses to alum-protein vaccines. Blood 120(23):4552-9. [PubMed: 23065152]  [MGI Ref ID J:190901]

Victora GD; Schwickert TA; Fooksman DR; Kamphorst AO; Meyer-Hermann M; Dustin ML; Nussenzweig MC. 2010. Germinal center dynamics revealed by multiphoton microscopy with a photoactivatable fluorescent reporter. Cell 143(4):592-605. [PubMed: 21074050]  [MGI Ref ID J:166836]

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Production of mice from cryopreserved embryos or sperm occurs in a maximum barrier room, G200.

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The Jackson Laboratory has rigorous genetic quality control and mutant gene genotyping programs to ensure the genetic background of JAX^® Mice strains as well as the genotypes of strains with identified molecular mutations. JAX^® Mice strains are only made available to researchers after meeting our standards. However, the phenotype of each strain may not be fully characterized and/or captured in the strain data sheets. Therefore, we cannot guarantee a strain's phenotype will meet all expectations. To ensure that JAX^® Mice will meet the needs of individual research projects or when requesting a strain that is new to your research, we suggest ordering and performing tests on a small number of mice to determine suitability for your particular project.

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