STRUCTURAL PATTERNS IN ANTI-DNA AUTOANTIBODIES - A MOLECULAR MODELINGSTUDY

Anti-DNA autoantibodies are the hallmark of the autoimmune disease sys temic lupus erythematosus. Although these antibodies are both diagnost ic and pathogenic, little is known about their structures and the mann er in which they recognize DNA antigens. To address the first of these points we have predicted the three-dimensional structures of 40 monoc lonal anti-DNA F(ab) fragments derived from lupus-prone mice. These an tibodies were chosen to encompass several different autoimmune strains along with the known variable region gene families that encode anti-D NA. We find that the structures of the antigen binding regions of thes e antibodies fall into three main classes, irrespective of both the mo use strain and genetic origins of the antibody. Specifically, high-aff inity anti-ssDNA appear to possess a narrow channel that is presumably used for ligand recognition, whereas the binding site on anti-dsDNA i s an open surface that is large enough to accommodate a DNA duplex. Th ese findings provide structural data to support the hypothesis that an ti-DNA arise by DNA-driven B cell activation and clonal expansion. (C) 1995 Academic Press, Inc.