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Molecular Modeling of an Anti-DNA Autoantibody (V-88) and Mapping of Its V Region Epitopes Recognized by Heterologous and Autoimmune Antibodies¹

Paul Hobby^*,, Francis J. Ward, Andrew N. Denbury, D. Gwyn Williams, Norman A. Staines and Brian J. Sutton^2,*

^* The Randall Institute, Biomedical Sciences Division and Infection and Immunity Research Group, Life Sciences Division, King’s College London, London, United Kingdom; and Renal Unit, Division of Medicine, United Medical and Dental Schools, Guy’s Hospital, London, United Kingdom

Anti-DNA autoantibodies are a characteristic feature of human systemic lupus erythematosus (SLE) and lupus diseases in the mouse. V-88 is an IgG1/ ssDNA-binding Ab, derived from a lupus mouse, that bears a cross-species, cross-reactive Id (CRI) that has been implicated in the pathogenesis of both human and murine disease. A linear epitope map of V-88 has been determined with anti-idiotypic antisera obtained from rabbits, and candidate sequences for the idiotopes of the CRI have been proposed. We now report the modeling of the three-dimensional structure of the V regions of Ab V-88, to map the location of these idiotopes. The V region framework structure was derived from those of crystallographically determined Ab structures, and the complementarity determining region (CDR) structures were based upon the set of canonical structures adopted by these loop regions in Abs of known structure. One of the idiotopes is an extensive, highly accessible epitope consisting of framework regions spatially adjacent to CDR2 in the heavy chain. Epitopes recognized by an anti-idiotypic rabbit antiserum were compared with those recognized by autoimmune sera from SLE-prone mice, and common features were identified. By analogy with the crystal structure of an anti-DNA Ab BV04-01 complexed with a trinucleotide, the modeled structure also suggests a mode of binding of ssDNA to V-88. The location of the candidate CRI, although within the framework region of V_H, is such that it could influence Ag specificity.

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