We have previously demonstrated that experimental expression of the polyomavirus transcription factor T-antigen has the potential to induce anti-DNA antibodies in mice. Two sets of independent evidences are presented here that demonstrate a biological relevance for this model.

Anti-dsDNA antibodies as a classification criterion and a diagnostic marker for systemic lupus erythematosus: critical remarks OTHER ARTICLES PUBLISHED IN THIS SERIESDying autologous cells as instructors of the immune system. Clinical and Experimental Immunology 2015, 179: 1-4. The effect of cell death in the initiation of lupus nephritis. Clinical and Experimental Immunology 2015, 179: 11-16 SummaryAntibodies to mammalian dsDNA have, for decades, been linked to systemic lupus erythematosus (SLE) and particularly to its most serious complication, lupus nephritis. This canonical view derives from studies on its strong association with disease. The dogma was particularly settled when the antibody was included in the classification criteria for SLE that developed during the 1970s, most prominently in the 1982 American College of Rheumatology (ACR), and recently in The Systemic Lupus International Collaborating Clinics (SLICC) classification criteria. There are several problems to be discussed before the anti-dsDNA antibody can be accepted without further distinction as a criterion to classify SLE. Old and contemporary knowledge make it clear that an anti-dsDNA antibody is not a unifying term. It embraces antibodies with a wide spectrum of fine molecular specificities, antibodies that are produced transiently in context of infections and persistently in the context of true autoimmunity, and also includes anti-dsDNA antibodies that have the potential to bind chromatin (accessible DNA structures) and not (specificity for DNA structures that are embedded in chromatin and therefore unaccessible for the antibodies). This critical review summarizes this knowledge and questions whether or not an anti-dsDNA antibody, as simply that, can be used to classify SLE.

Murine and human lupus nephritis are characterized by glomerular deposits of electron-dense structures (EDS). Dominant components of EDS are chromatin fragments and IgG antibodies. Whether glomerular EDS predispose for similar deposits in skin is unknown. We analysed (i) whether dermo-epidermal immune complex deposits have similar molecular composition as glomerular deposits, (ii) whether chromatin fragments bind dermo-epidermal structures, and (iii) whether deposits in nephritic glomeruli predispose for accumulation of similar deposits in skin. Paired skin and kidney biopsies from nephritic (NZBxNZW)F1 and MRL-lpr/lpr mice and from five patients with lupus nephritis were analysed by immunofluorescence, immune electron microscopy (IEM) and co-localization TUNEL IEM. Affinity of chromatin fragments for membrane structures was determined by surface plasmon resonance. Results demonstrated (i) presence of EDS containing chromatin fragments and IgG in both organs in nephritic patients, (ii) chromatin fragments possessed high affinity for dermo-epidermal laminins and collagens, (iii) glomerular immune complex deposits did not predict similar interstitial deposits in skin, although such complexes were present in capillary lumina in glomeruli and skin of all nephritic individuals. Thus, chromatin-IgG complexes accounting for lupus nephritis seem to reach skin through circulation, but other undetermined factors are required for these complexes to deposit within skin membranes.

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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.