Human polyomavirus BK and immunogenicity of mammalian DNA: a conceptual framework

Although the origin of autoimmune antibodies to double-stranded DNA (dsDNA) is not known, the variable-region structures of such antibodies indicate that they are produced in response to antigen-selective stimulation. In accordance with this, results from experiments using artificial complexes of DNA and DNA-binding polypeptides for immunizations have indicated that DNA may induce these antibodies. The immunogenicity of DNA in vivo may therefore depend upon structures, or processes, that render DNA immunogenic. It is therefore crucial to determine the nature of the antigen(s) recognized by anti-DNA antibody-inducing Th cells. We describe here the results of a series of experiments using polyomavirus BK (BKV) inoculation as a model system for initiation of antibodies to DNA, including dsDNA, in animals. From the early observation that BKV had the potential to induce the linked production of antibodies to DNA and histones, we have investigated and described the molecular bases for how this virus may do so. The minimum requirement for DNA to act as an immunogen is the in vivo expression of the BKV early gene encoding the DNA-binding large T-antigen. In the context of in vivo expression of this gene, IgG antibodies to dsDNA, histones, and T-antigen were produced. Monoclonal anti-dsDNA antibodies derived from BKV immunized mice demonstrated variable-region structures highly similar to those of spontaneous anti-DNA antibodies in murine lupus. These results represent a conceptual advance in understanding a potential molecular basis for initiation of autoimmunity in systemic lupus erythematosus and establish a precedent for further studies on polyomavirus expression as one biological origin for anti-dsDNA antibodies in human lupus.