Somatic mutations can lead to a loss of superantigenic and polyreactive binding

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Abstract
Although antibodies have been assumed to bind a specific antigen, evidence exists showing that a single antibody can bind to multiple unrelated antigens. We previously studied a human monoclonal antibody expressing a mutated form of the VH3–73 gene and displaying anti-tubulin activity in a patient suffering from an immunocytic lymphoma. Despite its expression of a VH3 family member, this immunoglobulin failed to react with protein A (SpA), suggesting that somatic mutations could account for its change in specificity. To examine this possibility, we produced recombinant Ig expressing germ-line (IgMκ-Germ) or the mutated form (IgMκ-PER) of the VH3–73 fragment. Comparison of the respective affinities of the two Ig demonstrated that IgMκ-Germ restores its SpA-binding capacity, and shows a moderate decrease in its affinity for tubulin. Interestingly, IgMκ-Germ displayed polyreactive specificity for different autoantigens, which contrasted to the monospecific binding of IgMκ-PER to tubulin. These results suggest that the monoreactive IgMκ-PER antibody may be derived from a natural polyreactive antibody through somatic mutation. In addition, both temperature modification and mild denaturation succeeded in recovering the polyreactivity of IgMκ-PER, which favors the view that conformational modifications of the tertiary structure of antibodies may play a key role in the genesis of polyreactivity.