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Somatic mutations can lead to a loss of superantigenic and polyreactive binding
Author(s) -
Oppezzo Pablo,
Dumas Gérard,
Bouvet JeanPierre,
Robello Carlos,
Cayota Alfonso,
Pizarro Juan Carlos,
Dighiero Guillaume,
Pritsch Otto
Publication year - 2004
Publication title -
european journal of immunology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.272
H-Index - 201
eISSN - 1521-4141
pISSN - 0014-2980
DOI - 10.1002/eji.200424936
Subject(s) - biology , antibody , somatic cell , germline , microbiology and biotechnology , somatic hypermutation , antigen , immunoglobulin m , germline mutation , kappa , mutation , recombinant dna , monoclonal antibody , gene , immunoglobulin g , genetics , b cell , linguistics , philosophy
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 V H 3–73 gene and displaying anti‐tubulin activity in a patient suffering from an immunocytic lymphoma. Despite its expression of a V H 3 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 V H 3–73 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.