The importance of somatic mutations in the V-lambda gene 2a2 in human monoclonal anti-DNA antibodies

2a2 is the most commonly rearranged gene in the human V-lambda locus. It ha s been postulated that certain immunoglobulin genes (including 2a2) are rea rranged preferentially because their germline sequences encode structures c apable of binding to a range of antigens. Somatic mutation could then incre ase the specificity and affinity of binding to a particular antigen. We studied the properties of five IgG molecules in which the same heavy cha in was paired with different light chains derived from 2a2. The pattern of somatic mutations in 2a2 was shown to be crucial in conferring the ability to bind DNA, but two different patterns of mutation each conferred this abi lity. Computer-generated models of the three-dimensional structures of these anti bodies illustrate the ability of 2a2 to form a DNA binding site in differen t ways. Somatic mutations at the periphery of the DNA binding site were par ticularly important. In two different light chains, mutations to arginine a t different sites in the complementarity determining regions (CDRs) enhance d binding to DNA. In a third light chain, however, mutation to arginine at a different site blocked binding to DNA. (C) 2001 Academic Press.