Genetic mechanisms for dominant VH gene expression: the VHB512 Gene

Abstract

A total of 37 mAb with reactivity for dextran B512 have been studied; 30 of them were products of independent rearrangements and 21 made use of the same VH gene, the VHB512 gene. These results unambiguously established that the immune response to dextran in the high responder mouse strain C57BL/6 was restricted. Idiotypic determinants are located all over the Ig V region. Many but not all Id described so far can be ascribed to protein structures encoded by VH or VL gene segments. The expression of the major Id, 17-9 Id, in C57BL/6 was not absolutely correlated with the expression of the dominant VHB512 gene in the same mouse strain. Inspection of amino acid sequences of the CDR3 of idiotypic positive and negative clones suggested that idiotypic structures may be associated with the expression of Tyr at position 95 and Phe or Leu at position 96 in the H and L chains, respectively. Therefore the indiscriminate use of idiotypic markers to characterize VH genes and the relevance of idiotypic regulation in VH gene expression are questioned. Id-positive and Id-negative clones displayed similar affinity values for dextran, indicating that idiotypic and binding structures were probably separated. The exchange of Asp65 for Gly65 in one of the clones reduced affinity for dextran, suggesting the involvement of CDR2 in dextran binding. The dominant expression of VH genes can be explained by somatic and/or genetic mechanisms. Because somatic mechanisms such as idiotypic regulation or selection based on affinity for dextran did not seem to influence the expression of the VHB512 gene we favor a genetic alternative. We discuss a model based on the distance between VH genes and D and JH elements. This model is compatible with somatic and genetic regulation in other systems and provides a new theoretical approach to the understanding of immune VH dominance and low responsiveness.