Genetic analysis of the variable region genes encoding a monospecific human natural anti-DNA antibody

SUMMARY Recent evidence suggests that natural autoantibodies may play an integral rote in the development of the normal immune repertoire. To explore the genetic origins of these antibodies, we have isolated and sequenced the variable (V) region genes encoding both the heavy (H) and light (L) chains of a natural anti-DNA antibody, Kim It.4. The genes appear to be derived from the VH4.t8 (subgroup VHIV), JH5, Hum ILI (subgroup VλI) and Jλ3 germline genes. The origin of the H chain diversity gene is more obscure, being potentially derived from one or more of several germline genes, arranged in either the forward or reverse orientations. Both the Kim 11.4 VH and VL genes share significant degrees of similarity with those utilized in other autoantibodies, indicating that at least some degree of V restriction may exist in human autoreactive B cells. The pattern of nucleotide differences between the Kim 11.4 VH and VL genes and their putative germline counterparts suggests that the Kim 11.4 genes may have undergone somatic mutation and arisen as a result of antigen selection.