Recent studies have demonstrated that anti-DNA antibodies share important genetical features with antibodies to exogenous antigens, suggesting that anti-DNA antibody responses may be (auto-) antigen driven. We have earlier defined three out of five rabbits as anti-dsDNA antibody responders based on reactivity with calf thymus (CT) dsDNA after inoculation with the human dsDNA virus BK. In the present study we demonstrate that all five animals that received BK virus inoculations produced antibodies to BK virus dsDNA. These antibodies did not cross-react with CT dsDNA, as shown by inhibition experiments. The anti-BK dsDNA antibodies persisted over time, in contrast to the anti-CT dsDNA antibodies that decreased shortly after a peak following the first boost of BK virus. While the anti-CT dsDNA antibodies decreased, the anti-BK dsDNA antibodies remained elevated, thus supporting the results of the inhibition experiments which showed that two independent antibody populations are produced after BK virus inoculations. In the three animals producing anti-mammalian dsDNA antibodies, antibodies recognizing CT dsDNA reappeared after intravenous administration of a complex of CT dsDNA and methylated bovine serum albumin (MBSA) without adjuvant. The latter anti-CT dsDNA antibodies did not cross-react with BK dsDNA. In contrast to earlier studies we conclude that mammalian dsDNA may be immunogenic, and that discrete molecular differences in DNA antigens from different sources may induce anti-dsDNA antibodies specific for dsDNA molecules of different origin.

The contemporary view concerning the origin of anti-dsDNA antibodies is that eukaryotic dsDNA is not immunogenic. Results presented here, however, show (1) that inoculation of rabbits with BK virus elicits antibodies to eukaryotic, including autologous, dsDNA, (2) that the transition from a non-immunogenic to an immunogenic state of autologous dsDNA depends on productive infection with BK virus, and (3) that inoculation with protein-free circular BK dsDNA initiates both infection in vivo and production of antibodies to autologous dsDNA. Non-infectious linearized BK dsDNA did not elicit any anti-dsDNA antibodies, while the same DNA molecule, when complexed with methylated bovine serum albumin, elicited anti-dsDNA antibodies solely recognizing BK dsDNA. Neither of the two linearized BK dsDNA preparations initiated infection. Using two different techniques, we could demonstrate that two separate sets of anti-dsDNA antibodies were produced during viral infection; one recognizing BK dsDNA, and the other recognizing autologous dsDNA. Thus, in contrast to previous assumptions, autologous dsDNA may be immunogenic. Based on the present results, we propose that autologous dsDNA can be rendered immunogenic through complex formation with viral DNA binding protein(s) such as the structural protein VP1 or the tumour antigen T. Such DNA-protein complexes may bypass a putative T-cell tolerance to autologous dsDNA.