Somatic mutations can lead to a loss of superantigenic and polyreactive binding.
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 (IgM kappa-Germ) or the mutated form (IgM kappa-PER) of the V(H)3-73 fragment. Comparison of the respective affinities of the two Ig demonstrated that IgM kappa-Germ restores its SpA-binding capacity, and shows a moderate decrease in its affinity for tubulin. Interestingly, IgM kappa-Germ displayed polyreactive specificity for different autoantigens, which contrasted to the monospecific binding of IgM kappa-PER to tubulin. These results suggest that the monoreactive IgM kappa-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 IgM kappa-PER, which favors the view that conformational modifications of the tertiary structure of antibodies may play a key role in the genesis of polyreactivity.
Oppezzo
Pablo
P
Unité d'Immuno-Hématologie et d'Immunopathologie, Institut Pasteur, Paris, France.
Dumas
Gérard
G
Bouvet
Jean-Pierre
JP
Robello
Carlos
C
Cayota
Alfonso
A
Pizarro
Juan Carlos
JC
Dighiero
Guillaume
G
Pritsch
Otto
O
D000595:Amino Acid Sequence; D006801:Humans; D007075:Immunoglobulin M / Q000235:genetics* / Q000276:immunology / Q000302:isolation & purification; D008969:Molecular Sequence Data; D009154:Mutation; D011485:Protein Binding / Q000276:immunology; D017434:Protein Structure, Tertiary; D018089:Superantigens / Q000276:immunology*; D013696:Temperature; D014404:Tubulin / Q000276:immunology
D007075:Immunoglobulin M; D018089:Superantigens; D014404:Tubulin