Primary structure of immunoglobulins and its relationship to antibody specificity

Previous evidence that the specificity of antibodies is determined by differences in their primary structure was based on the finding of characteristic differences in the average amino acid compositions of five purified rabbit antibodies. These differences were shown to be independent of those associated with the allotypic specificities of rabbit γ G‐immunoglobulins and independent of the charge on the determinant group of the antigens employed. Further support was provided by recent studies of the location of the amino acid differences in the antibody structures. (1) The differences were found to be distributed in both the light and heavy polypeptide chains, which correlated with immunological data indicating that both chains contribute to the formation of the active site. (2) The amino acid differences were all located in an active fragment obtained after cleavage of the C‐terminal half of the heavy chain with cyanogen bromide. Further fractionation of this active fragment showed that the amino acid differences observed in the heavy chains were localized in the N‐terminal half known to be involved in the active site. The simplest interpretation of these results is that antibody formation is a genetically controlled process. However, the finding that the light chain from any one antibody was heterogeneous with respect to its amino acid content despite its average characteristic composition raises the possibility that mechanism of antibody synthesis may not be analogous to that of other proteins. Proposed normal and abnormal mechanisms are discussed in relation to both these data on antibody primary structure and the data on the primary structure of the related myeloma proteins.