Diversity in the CDR3 region of V-H is sufficient for most antibody specificities

All rearranging antigen receptor genes have one or two highly diverse compl ementarity determining regions (CDRs) among the six that typically form the ligand binding surface. We report here that, in the case of antibodies, di versity at one of these regions, CDR3 of the V-H domain, is sufficient to p ermit otherwise identical IgM molecules to distinguish between a variety of hapten and protein antigens. Furthermore, we find that somatic mutation ca n allow such antibodies to achieve surprisingly high affinities. These resu lts are consistent with a model in which the highly diverse CDR3 loops are the key determinant of specificity in antigen recognition in both T cell re ceptors (TCR) and antibodies, whereas the germline-encoded CDR1 and CDR2 se quences are much more cross-reactive.