Amino acid sequence diversity within the family of antibodies bearing the major antiarsonate cross-reactive idiotype of the A strain mouse.

VH region amino acid sequences are described for five A/J anti-p-azophenylarsonate (anti-Ars) hybridoma antibodies for which the VL region sequences have previously been determined, thus completing the V domain sequences of these molecules. These antibodies all belong to the family designated Ars-A which bears the major anti-arsonate cross-reactive idiotype (CRI) of the A strain mouse. However, they differ in the degree to which they express the CRI in standard competition radioimmunoassays. Although the sequences are closely related, all are different from each other. Replacements are distributed throughout the VH region and occur in positions of the chain encoded by all three gene segments, VH, DH, and JH. It is likely that somatic diversification processes play a dominant role in producing the sequence variability in each of these segments. The number of differences from the sequence encoded by the germline is smallest for antibodies that express the CRI most strongly, suggesting that somatic diversification is responsible for loss of the CRI in members of the Ars-A antibody family. There is an unusual degree of clustering of differences in both CDR2 and CDR3 and many of the substitutions are located in "hot spots" of variation. The large number of differences between the chains prohibits the unambiguous identification of positions at which alterations play a major role in reducing the expression of the CRI. However, the data suggest that the loss of the CRI is associated with a definable repertoire of somatic changes at a restricted number of highly variable sites.