The genetic origin of human autoantibodies.
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Biomedical subjects
Publications and source records attributed to I Sanz.
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To characterize the light chain gene segments involved in the murine immune response to keyhole limpet hemocyanin p-azophenylarsonate (Ars), we have determined the amino acid and/or nucleotide sequences of several anti-arsonate antibodies of the Ars-A family in the A/J, C.AL-20, and BALB/c strains. These structures have been compared to certain BALB/c anti-phenyloxazolone and anti-levan antibodies previously sequenced and to the A/J V kappa 10-Ars-A genomic sequence (where V kappa = kappa chain variable). These primary structural studies were complemented by Southern filter hybridization analyses utilizing V kappa and kappa chain joining (J kappa) molecular probes. We found a surprising uniformity of structure among these antibody light chains derived from different murine strains. Thus, in contrast to the heavy chain variable (Vh) regions of the Ars-A antibody family where the BALB/c strain lacks the VH gene segment utilized in the A/J Ars-A response, the light chain variable region gene segments at the V kappa 10-Ars-A locus appear to be identical between the two strains.
The germ-line elements for the variable (V) and joining (J) regions of the kappa chains (V kappa-Ars, J kappa 1) that give rise to the productive allele for the A/J mouse light chains of Ars-A monoclonal antibodies (directed against the hapten p-azophenylarsonate) have been cloned and sequenced as well as a rearranged Ars-A light chain gene. Using the V kappa-Ars gene as a hybridization probe, we provide evidence that the V kappa 10 family is relatively small and that only one member gives rise to the productive allele in all Ars-A antibodies. An unusual feature of Ars-A light chains is that all contain an arginine at position 96, the V-J junctional position. We had shown by chain recombination that arginine-96 was essential for antigen binding. In the present study, an arginine codon was not found either at the 3' end of the V kappa-Ars gene segment or at the 5' end of J kappa 1. However, an arginine codon (CGG) can easily be generated by recombination between these two germ-line elements. Thus, we document that junctional diversity through intracodonic recombination can be crucial to the antibody binding function of the resulting molecule.
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