HUMAN POLYOMAVIRUS BK AND IMMUNOGENICITY OF MAMMALIAN DNA - A CONCEPTUAL-FRAMEWORK

Although the origin of autoimmune antibodies to double-stranded DNA (d sDNA) is not known, the variable-region structures of such antibodies indicate that they are produced in response to antigen-selective stimu lation. In accordance with this, results from experiments using artifi cial complexes of DNA and DNA-binding polypeptides for immunizations h ave indicated that DNA may induce these antibodies. The immunogenicity of DNA in vivo may therefore depend upon structures, or processes, th at render DNA immunogenic. It is therefore crucial to determine the na ture of the antigen(s) recognized by anti-DNA antibody-inducing Th cel ls. We describe here the results of a series of experiments using poly omavirus BK (BKV) inoculation as a model system for initiation of anti bodies to DNA, including dsDNA, in animals. From the early observation that BKV had the potential to induce the linked production of antibod ies to DNA and histones, we have investigated and described the molecu lar bases for how this virus may do so. The minimum requirement for DN A to act as an immunogen is the in vivo expression of the BKV early ge ne encoding the DNA-binding large T-antigen. In the context of in vivo expression of this gene, IgG antibodies to dsDNA, histones, and T-ant igen 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 res ults represent a conceptual advance in understanding a potential molec ular basis for initiation of autoimmunity in systemic lupus erythemato sus and establish a precedent for further studies on polyomavirus expr ession as one biological origin for anti-dsDNA antibodies in human lup us. (C) 1997 Academic Press, Inc.