The Ciita knock-out on the NOD background in these mice results in protection from diabetes.
Dr. Richard A. Flavell, Yale University School of Medicine
In humans, a non-functional C2ta (or Ciita) gene causes bare lymphocyte syndrome (BLS), which is characterized by the lack of HLA class II gene expression and a reduced number of mature CD4+ T cells in the periphery.
On the C57BL/6 congenic background (see Stock No. 003239) disruption of C2ta results in a lack of MHC Class II expression by splenic B cells, dendridic cells, and both resting and interferon gamma stimulated macrophages. However, thymic epithelium retains MHC class II expression. Homozygotes also exhibit a significant decrease in the levels of invariant chain and H-2M gene transcripts. Non-conventional MHC Class II molecules such as H-2O alpha and H-2O beta, are not affected by the disruption of C2ta. Despite the continued expression of MHC Class II molecules on cells of the thymic epithilium, few CD4 positive cells exist in the periphery of homozygotes. (Chang et al 1996)
Because of the role of CD4+ T cells in the onset of diabetes, the mutation was backcrossed onto the NOD/ShiLtJ background to characterize its impact on diabetes development. The resulting congenic mice (Stock No. 004448) homozygous for the mutation are completely protected from diabetes after 35 weeks of age. However, they do exhibit perivascular infiltration or periinsulitis at 15 weeks of age.. Like their C57BL/6 counterparts, NOD homozygotes exhibit a ten-fold decrease in CD4+ T cells in the periphery, while the number of CD8+ T cells in the spleen remains normal. Homozygous mice do not show defects in B cell function, as measured by immunoglobulin production after stimulation of B cells with Il4 in vitro. (Mora et al. 1999)
The C2ta (or Ciita) gene was isolated from a 129S2/SvPas genomic library and disrupted by replacement of exons critical for gene function with a neomycin resistance cassette. The vector containing disrupted C2ta was transfected into D3 ES cells (129S2/SvPas derived). Positive clones were injected into C57BL/6 blastocysts, and resulting chimeric mice were intercrossed to produce homozygotes. These homozygous individuals were backcrossed to C57BL/6 for at least 2 generations before being backcrossed to NOD/LtJ for 11 generations using PCR-assisted selection for NOD diabetes susceptibility loci. (Chang et al 1996, Mora et al 1999)
|Allele Name||targeted mutation 1, Cheong-Hee Chang|
|Allele Type||Targeted (Null/Knockout)|
|Allele Synonym(s)||C2tatm1Ccum; CIITA C-; CIITA-; MHC classII-|
|Gene Symbol and Name||Ciita, class II transactivator|
|Gene Synonym(s)||C2TA; C2ta; C2ta; CIITAIV; EG669998; Gm9475; Gm9475; MHC2TA; Mhc2ta; NLRA; predicted gene 9475; predicted gene, EG669998|
|Strain of Origin||129S2/SvPas|
|Molecular Note||A genomic fragment containing exons which encode critical regions of the protein was replaced with a neomycin selection gene. Northern blot analysis on RNA derived from homozygous mice demonstrated that no detectable protein was produced from this allele.|
|Mutations Made By|| |
Dr. Cheong-Hee Chang, Indiana University
When using the NOD.129S2(B6)-Ciitatm1Ccum/FlvJ mouse strain in a publication, please cite the originating article(s) and include JAX stock #004448 in your Materials and Methods section.
|Homozygous for �Ciita<tm1Ccum>|
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