GENETIC-ANALYSIS OF THE VARIABLE REGION GENES ENCODING A MONOSPECIFICHUMAN NATURAL ANTI-DNA ANTIBODY

Recent evidence suggests that natural autoantibodies may play an integ ral role in the development of the normal immune repertoire. To explor e the genetic origins of these antibodies, we have isolated and sequen ced the variable (V) region genes encoding both the heavy (H) and ligh t (L) chains of a natural anti-DNA antibody, Kim11.4. The genes appear to be derived from the V(H)4.18 (subgroup V(H)IV), J(H)5, Hum1L1 (sub group VlambdaI) and Jlambda3 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 rev erse orientations. Both the Kim11.4 V(H) and V(L) genes share signific ant degrees of similarity with those utilized in other autoantibodies, indicating that at least some degree of V restriction may exist in hu man autoreactive B cells. The pattern of nucleotide differences betwee n the Kim 11.4 V(H) and V(L) genes and their putative germline counter parts suggests that the Kim 11.4 genes may have undergone somatic muta tion and arisen as a result of antigen selection.