[Genetic origins of anti-DNA autoantibodies]

A detailed analysis of variable region sequences, derived from monoclonal lupus anti-DNA autoantibodies has led to several conclusions with respect to the etiology and pathogenesis of systemic lupus erythematosus (SLE). It was found that the gene elements which are expressed in anti-DNA heavy and light chains are present in the germ lines of normal and diseased animals. However, several VH gene segments are not normally expressed in antibodies to external antigens and may, therefore, be excluded by the regulatory mechanism of self-tolerance. The presence of somatic point mutations, which may serve to change antigenic specificity as well as to increase affinity, indicates that an antigen (DNA)-driven mechanism rather than a polyclonal activation is responsible for the autoimmune response in SLE. An additional unique motif of anti-DNA heavy chains was found to consist of an arginine-rich basic peptide in the third complementarity-determining (hypervariable) region. These data have enabled us to build a computer model of the anti-DNA binding site and to design specific inhibitors of the autoimmune reaction.