Anti‐DNA autoantibodies are the hallmark of human and murine systemic lupus erythematosus (SLE), an autoimmune rheumatic disease of unknown etiology. Some of these antibodies are believed to be pathogenic for kidney tissue and to initiate immune glomerulonephritis. However, the mechanisms by which anti‐DNA antibodies participate in tissue injury remain controversial. We have studied the in vivo pathogenicity of anti‐DNA monoclonal antibodies in immune deficient mice, using a panel of murine B cell hybridomas. No consistent genetic or immunochemical differences were found between pathogenic and non‐pathogenic anti‐DNA antibodies. However, the two antibody populations differed in their cross‐reaction with the acidic actin‐binding protein, α‐actinin, that is known to play a major role in the structural integrity of glomerular filtration components. These results suggest that kidney dysfunction in SLE may be facilitated by protein‐nucleic acid antigenic mimicry.