On the biological origin of anti‐double‐stranded (ds)DNA antibodies: systemic lupus erythematosus‐related anti‐dsDNA antibodies are induced by polyomavirus BK in lupus‐prone (NZBxNZW) F₁ hybrids, but not in normal mice

Abstract

We have recently demonstrated that polyomavirus BK and isolated BK double-stranded (ds)DNA have a strong potential for induction of anti-dsDNA antibodies. Here, data are presented that demonstrate that normal mice (a term used in this report for mice not predisposed to a lupus-like syndrome) of four different strains responded to both BK virus and BK dsDNA by producing transient antibodies binding preferentially to the viral dsDNA itself. These antibodies did not bind in the Crithidia luciliae assay, and did not seem to be of pathogenic significance, as neither signs of proteinuria nor immunochemical signs of glomerulonephritis developed in these mice. In contrast, 5-week-old (NZBxNZW)F1 mice developed strong and persistent anti-dsDNA antibodies in response to BK virus and BK dsDNA, with similar features to those of anti-dsDNA antibodies from individuals with systemic lupus erythematosus: they reacted strongly in the Crithidia luciliae assay and cross-reacted with viral as well as with mammalian dsDNA. Furthermore, persistent proteinuria and glomerulonephritis, with demonstrable heavy mesangial deposits of immune complexes containing IgG anti-dsDNA antibodies, developed 2-3 months earlier than in spontaneously autoimmune control mice. The relevance of these observations to a viral origin of anti-dsDNA antibodies in lupus is discussed.

Autoimmunity to DNA and Nucleosomes in Binary Tetracycline-Regulated Polyomavirus T-Ag Transgenic Mice

“…The titers of the Abs determined in solid-phase (conventional anti-dsDNA ELISA) and in solution-phase anti-DNA ELISA (SPADE) using linear and circular dsDNA molecules, compared well with those currently determined in autoimmune (NZBϫW)F 1 mice (manuscript in preparation), and with those determined by the same solid-and solution-phase assays recently published for human SLE-derived anti-dsDNA Abs (27), which differ significantly from the much higher titers reported for Abs to nonself proteins or to Z DNA, as discussed by Stollar (43). The results of these experiments directly demonstrated that T-Ag expression initiated a process that resulted in continuous stimulation of autoimmune dsDNA-specific B cells, most probably due to release of heterologous nucleosome-T-Ag complexes able to initiate cognate interaction between DNA-specific B cells and T-Ag-specific T cells (13)(14)(15)(16)(17)44). The exact process involved in release of nucleosome-T-Ag complexes after expression of T-Ag is not fully determined, but may be caused by cytotoxic CD8 ϩ T cells activated in context of T-Ag expression.…”

Structure and specificity of T cell receptors expressed by potentially pathogenic anti-DNA autoantibody-inducing T cells in human lupus.

“…Even methylated BSA carrier-specific T cells could help in the production of anti-DNA autoantibodies when B/W lupus mice were immunized with methylated BSA-DNA complex (65). However, herein we have determined which of the naturally occurring and abundant autoantigens could trigger the spontaneously arising Th cells of lupus that preferentially induce potentially pathogenic anti-DNA autoantibodies.…”

“…Deliberate immunization of mice with various DNA-binding proteins of exogenous or endogenous origin along with CFA leads to the production of anti-DNA autoantibodies, particularly in lupus-prone genetic backgrounds (63)(64)(65). Even methylated BSA carrier-specific T cells could help in the production of anti-DNA autoantibodies when B/W lupus mice were immunized with methylated BSA-DNA complex (65).…”

Critical comparative analyses of anti–α‐actinin and glomerulus‐bound antibodies in human and murine lupus nephritis

“…An enzyme-linked immunosorbent assay (ELISA) was performed to detect antibodies to nucleosomes, H1, dsDNA, DNase I, type IV collagen, heparan sulfate, and ␣-actinin, as described previously (27)(28)(29)(30). Essentially, microtiter plates (MaxiSorp; Nunc, Copenhagen, Denmark) were coated with nucleosomes (10 g/ml as DNA), dsDNA (10 g/ml), H1 (2 g/ml), heparan sulfate (10 g/ml), ␣-actinin (5 g/ml), DNase I (5 g/ml), and type IV collagen (5 g/ml).…”