Molecular analysis of anti-DNA antibodies

There are two major reasons for interest in antibodies to DNA: autoantibodies to DNA are characteristic of the autoimmune disease systemic lupus erythematosus and contribute to its pathology; and both autoantibodies and experimentally induced antibodies to nucleic acids serve as useful biochemical reagents. Physical biochemistry and molecular biology are applied increasingly to questions of the structure and origin of antibodies to DNA and how antibodies recognize specific structures in DNA. Cloning of cDNA for Ig V regions of anti-DNA antibodies reveals that some cells making IgG disease-related autoantibodies are derived from precursor cells that produce natural autoantibodies unrelated to disease. In addition, some immunization-induced antibodies to DNA use gene segments similar to those found in autoantibodies. Cloning and expression of recombinant V regions allow detailed analysis of antibody structures required for DNA binding. Domain swapping and mutagenesis with vectors for bacterial expression of single chain Fv molecules revealed the importance of CDR3 sites of both H and L chain V regions for specific antigen binding by antibody to Z-DNA. In certain autoantibodies, the H chain plays a dominant role in determining DNA binding. Molecular analysis opens doors to studies of normal immune tolerance and its loss in autoimmune disease as well as to development of antibodies with modified specificity.