IMMUNOGLOBULIN HEAVY-CHAIN GENE REPLACEMENT - A MECHANISM OF RECEPTOREDITING

We have generated a site-directed transgenic (sd-tg) mouse model in wh ich the J(H) locus has been replaced with a rearranged VOJ coding for the heavy chain of an anti-DNA antibody. In these mice, B cells expres sing the anti-dsDNA specificity are negatively regulated. We observe a novel mechanism for B cell tolerance, receptor editing at the heavy c hain locus. In most sd-tg B cells, the inserted anti-DNA V-H gene has been replaced by the upstream endogenous V-H, or D-H, or both genes th rough recombination with the heptamer embedded at the 3' end of most V -H genes. Three types of recombination events have been identified: V- H-to-VDJ, D-H-to-VDJ, and V-H-to-D-H-VDJ. Analysis of the junctional s equences revealed features of classical V(D)J rearrangement, namely N sequence addition and nucleotide deletion. A conserved nonamer was fou nd 12 bp upstream of the embedded heptamer. This nonamer may represent a novel recombination signal sequence used for V-H editing. The sd-tg model thus provides direct evidence for secondary rearrangement at V- H-D-J(H). This process may play a role in tolerance by editing autorea ctive receptors and may also serve to diversify the V-H repertoire.