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Vkappa polymorphisms in NOD mice are spread throughout the entire immunoglobulin kappa locus and are shared by other autoimmune strains.
Henry RA, Kendall PL, Woodward EJ, Hulbert C, Thomas JW
(2010) Immunogenetics 62: 507-20
MeSH Terms: Amino Acid Substitution, Animals, Autoimmunity, B-Lymphocytes, Base Sequence, DNA Primers, Diabetes Mellitus, Type 1, Genes, Immunoglobulin Heavy Chain, Genes, Immunoglobulin Light Chain, Immunoglobulin Variable Region, Immunoglobulin kappa-Chains, Insulin, Mice, Mice, Inbred NOD, Mice, Transgenic, Molecular Sequence Data, Polymorphism, Genetic, Sequence Homology, Nucleic Acid, Species Specificity, T-Lymphocytes
Show Abstract · Added December 10, 2013
The diversity of immunoglobulin (Ig) and T cell receptor (TCR) genes available to form the lymphocyte repertoire has the capacity to produce a broad array of both protective and harmful specificities. In type 1 diabetes (T1D), the presence of antibodies to insulin and other islet antigens predicts disease development in both mice and humans, and demonstrate that immune tolerance is lost early in the disease process. Anti-insulin T cells isolated from T1D-prone non-obese diabetic (NOD) mice use polymorphic TCRalpha chains, suggesting that the available T cell repertoire is altered in these autoimmune mice. To probe whether insulin-binding B cells also possess polymorphic V genes, Ig light chains were isolated and sequenced from NOD mice that harbor an Ig heavy chain transgene. Three insulin-binding Vkappa genes were identified, all of which were polymorphic to the closest germline sequence matches present in the GenBank database. Additional analysis of over 300 light chain sequences from multiple sources, including germline DNA, shows that polymorphisms are spread throughout the entire NOD Igkappa locus, as these polymorphic sequences represent 43 distinct Vkappa genes which belong to 14 Vkappa families. Database searches reveal that a majority of polymorphic Vkappa genes identified in NOD are identical to Vkappa genes isolated from SLE-prone NZBxNZW F1 or MRL strains of mice, suggesting that a shared Igkappa haplotype may be present. Predicted amino acid changes preferentially occur in CDR, and thus could alter antigen recognition by the germline B cell repertoire of autoimmune versus non-autoimmune mouse strains.
2 Communities
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20 MeSH Terms
Regulation of IgH gene assembly: role of the intronic enhancer and 5'DQ52 region in targeting DHJH recombination.
Afshar R, Pierce S, Bolland DJ, Corcoran A, Oltz EM
(2006) J Immunol 176: 2439-47
MeSH Terms: Animals, B-Lymphocytes, Cell Differentiation, Enhancer Elements, Genetic, Gene Deletion, Gene Expression Regulation, Gene Rearrangement, B-Lymphocyte, Genes, Immunoglobulin Heavy Chain, Introns, Mice, Mice, Knockout, Mutation, Recombination, Genetic, Regulatory Sequences, Nucleic Acid, Transcription, Genetic
Show Abstract · Added August 13, 2010
The assembly of Ag receptor genes by V(D)J recombination is regulated by transcriptional promoters and enhancers which control chromatin accessibility at Ig and TCR gene segments to the RAG-1/RAG-2 recombinase complex. Paradoxically, germline deletions of the IgH enhancer (Emu) only modestly reduce D(H)-->J(H) rearrangements when assessed in peripheral B cells. However, deletion of Emu severely impairs recombination of V(H) gene segments, which are located over 100 kb away. We now test two alternative explanations for the minimal effect of Emu deletions on primary D(H)-->J(H) rearrangement: 1) Accessibility at the D(H)J(H) cluster is controlled by a redundant cis-element in the absence of Emu. One candidate for this element lies 5' to D(Q52) (PD(Q52)) and exhibits promoter/enhancer activity in pre-B cells. 2) In contrast to endpoint B cells, D(H)-->J(H) recombination may be significantly impaired in pro-B cells from enhancer-deficient mice. To elucidate the roles of PD(Q52) and Emu in the regulation of IgH locus accessibility, we generated mice with targeted deletions of these elements. We report that the defined PD(Q52) promoter is dispensable for germline transcription and recombination of the D(H)J(H) cluster. In contrast, we demonstrate that Emu directly regulates accessibility of the D(H)J(H) region. These findings reveal a significant role for Emu in the control mechanisms that activate IgH gene assembly and suggest that impaired V(H)-->D(H)J(H) rearrangement in enhancer-deficient cells may be a downstream consequence of the primary block in D(H)-->J(H) recombination.
1 Communities
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15 MeSH Terms