MARION, T.N., TILLMAN, D.M., KRISHNAN, M.K., DESAI, D.D., JOU, N.-T. and RUFF, M.B. Immunoglobulin Variable-Region Structures in Immunity and Autoimmunity to DNA. Tohoku J. Exp. Med., 1994, 173 (1), 43-63 - Important to the immunopathology associated with the autoimmune disease systemic lupus erythematosus, is the production of autoantibody to DNA. Crucial to understanding the immunological basis for autoimmunity to DNA is knowing whether the anti-DNA autoantibody is the product of clonally-selective, antigen-specific B cell stimulation or non-selective, polyclonal B cell activation. Structural analyses of the Immunoglobulin variable-regions of both early, IgM and late, IgG anti-DNA antibodies from lupus-prone (NZB×NZW) F₁ mice have indicated that both IgM and IgG anti-DNA autoantibodies are generated by clonally-selective B cell stimulation. Within individual autoimmune mice the later appearing, IgG anti-DNA autoantibodies are structurally similar to the earlier appearing, IgM antibodies, and in some cases both IgM and IgG may be produced by the same B cell clones. The variable-region structural data also suggest that DNA or complexes containing DNA may be the immunogenic stimuli for autoantibody to DNA. In support of this conclusion, normal mice immunized with immunogenic peptide-DNA complexes produce anti-DNA antibodies with structural and serological characteristics similar if not identical to those of autoimmune anti-DNA antibodies. Normal mice immunized with peptide-DNA complexes eventually develop immunopathology that resembles lupus nephritis. These results suggest that autoimmunity to DNA and subsequent autoimmune disease in SLE may result from a specific immune response to DNA containing antigens.