LIGAND RECOGNITION BY MURINE ANTI-DNA AUTOANTIBODIES .2. GENETIC-ANALYSIS AND PATHOGENICITY

Although anti-DNA autoantibodies are an important hallmark of lupus, t he relationships among anti-DNA structure, reactivity, and pathogenici ty have not been fully elucidated, To further investigate these relati onships, we compare the variable genes and primary structure of eight anti-DNA mAbs previously obtained from an MRL.MpJ-lpr/lpr mouse along with the ability of three representative mAbs to induce nephritis in n onautoimmune mice using established adoptive transfer protocols. One m onospecific anti-single-stranded (ss) DNA (11F8) induces severe diffus e proliferative glomerulonephritis in nonautoimmune mice whereas anoth er anti-ssDNA with apparently similar in vitro binding properties (9F1 1) and an anti-double-stranded DNA (4B2) are essentially benign, These results establish a murine model of anti-DNA-induced glomerular injur y resembling the severe nephritis seen in lupus patients and provide d irect evidence that anti-ssDNA can be more pathogenic than anti-double -stranded DNA, In vitro binding experiments using both protein-DNA com plexes and naive kidney tissue indicate that glomerular localization o f 11F8 may occur by recognition of a planted antigen in vivo. Binding to this antigen is DNase sensitive which suggests that DNA or a DNA-co ntaining molecule is being recognized.