The molecular origin of anti-DNA antibodies

The in vitro observation that a single point mutation in the protective anti-phosphorylcholine anti-bacterial antibody, S107, converts it into an autoantibody that reacts with dsDNA has focused our attention on the role of somatic mutation in generating autoantibodies. It has also led us to examine the significance of an individual's prior response to environmental antigens on the subsequent production of autoantibodies. The fact that genes of the S107 heavy chain variable region family could encode autoantibodies made it possible to clone and sequence the relevant germline genes of this small family from autoimmune (NZB x NZW)F1 mice and to compare these to the comparable genes in non-autoimmune mice. The germline genes from the normal and autoimmune mice are quite homologous and the small number of polymorphisms are not likely to predispose the autoimmune mice to the production of autoantibodies. (NZB x NZW)F1 mice respond to immunization with phosphorylcholine with a response that is largely encoded by the VH1 gene of the S107 family. However, when these same mice begin to make autoantibodies, their anti-DNA antibodies which are encoded by this family are in fact derived from the VH11 gene. The VH11 encoded anti-DNA antibodies which have been sequenced are all of the IgG2a subclass, react with dsDNA, and have undergone significant somatic diversification from the germline gene. Analysis of the ratio and location of the replacement and silent mutations suggests that the regulation of the autoantibody response differs from that of the normal response to foreign antigens. Our studies suggest that the utilization of a particular VH germline gene in the immune response to foreign antigens early in life does not lead to the preferential utilization of that same gene in the subsequent production of autoantibodies.