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Germline Structure and Differential Utilization of Igh^a and Igh^b V_H10 Genes¹

Immunology Program, Sackler School of Graduate Biomedical Sciences, and Department of Pathology, Tufts University School of Medicine, Boston, MA 02111

Ab heavy chains encoded by mouse V_H10 genes have been of particular interest due to their frequent association with DNA binding. We reported previously that V_H10 sequences are over-represented in the preimmune repertoire considering the apparent number of germline-encoded V_H10 gene segments. In this report, we show that the V_H10 family consists of three and two germline genes in the Igh^a and Igh^b haplotypes, respectively. The complete nucleotide sequences of these five genes, including promoters and recombination signal sequences, were determined and allow unambiguous assignment of allelic relationships. The usage of individual V_H10 genes varied significantly and ranged from 0.2% to an extraordinary 7.2% of the V_H genes expressed by splenic B cells. Since the promoter and recombination signal sequence elements of all five V_H10 genes are identical, we suggest that the few amino acid differences encoded by these five germline V_H10 genes determine their representation in the preimmune repertoire. Rearrangements of the most frequently used V_H10 gene have an apparent bias for histidine at position 95 of complementarity-determining region-3 (CDR3). These CDR3s are also biased for asparagine, an amino acid associated with the CDRs of DNA binding Abs. Together, these results suggest that high V_H10 gene use is the result of B cell receptor-mediated selection and may involve DNA and/or ligands that share antigenic features with DNA.

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