Mechanism of allergenic cross-reactions—IV. Evidence for participation of aromatic residues in the ligand binding site of two multi-specific IgE monoclonal antibodies

Mechanism of Allergic Cross-Reactions

“…Thus, the degree of IgE specificity is related to the ex tent o f overlap between the recognized subsets o f ligandsand not a unique lock-and-key type interaction between Ig Es and allergens. These results show, on the one hand, that cross-reactivities o f anti-DNP IgEs are not restricted to aro matic compounds as discussed previously [5], and that mer cury-induced IgE 'auto-antibodies' are able to recognize natural allergens, in addition to self-components and hap tens [9; Bellon et al, in prep.]. Of the mercury-induced clones, clone Hgl2 was found to be truly 'polyreactive', with the exception of ragweed, it recognized all the aller gens tested.…”

“…1995 binding characteristics of these IgEs [5], Although the anti bodies recognized a large number of ligands that were struc turally unrelated to the immunizing haptens [2, 4-dinitrophenol (DNP) or 2 ,4 ,6-trinitrophenol (TNP)], the great ma jority of the interacting compounds found by screening [2] and mediator release [3] were aromatics. And since the li gand-binding regions were found to be irregular aromatic surfaces [5], the multispecific interactions of aromatic li gands could have been interpreted as 'mimicking interac tions' with the involvement of the same DNP-orTNP-binding pockets of these antibodies. To answer the question whether the reactivity of these IgEs are restricted to small aromatic molecules, we have now investigated the ability of 9 monoclonal IgE antibodies from various sources for their ability to mediate degranulation of RBL-2H3 cells upon exCorrespondence to: Dr. J. M. Varga…”

“…the cross-stimulation of rat ba sophilic leukemia (RBL-2H3) cells can be affected by structurally dissimilar compounds when the cells are sensi tized with the same multispecific monoclonal IgE [3], Sub sequently, two of the mouse monoclonal IgEs were cloned and sequenced [4], and from the amino acid sequence data 3-D images of the combining regions were reconstructed by computer-aided molecular modeling [5], Based on biophys ical studies and molecular modeling, it was suggested that an overabundance o f solvent-exposed aromatic residues in the.combining regions are responsible for the multispecific binding characteristics of these IgEs [5], Although the anti bodies recognized a large number of ligands that were struc turally unrelated to the immunizing haptens [2, 4-dinitrophenol (DNP) or 2 ,4 ,6-trinitrophenol (TNP)], the great ma jority of the interacting compounds found by screening [2] and mediator release [3] were aromatics. And since the li gand-binding regions were found to be irregular aromatic surfaces [5], the multispecific interactions of aromatic li gands could have been interpreted as 'mimicking interac tions' with the involvement of the same DNP-orTNP-binding pockets of these antibodies.…”

Paratope Plasticity in Diverse Modes Facilitates Molecular Mimicry in Antibody Response

“…The two Ags bind to the Ab 7C4 with high affinity and specificity mediated by interactions involving aromatic residues, especially tyrosine. Such interactions are known to broaden the specificity repertoires of not just Abs but have also been implicated in receptor-ligand, enzymesubstrate, and lectin-carbohydrate multispecificity (32)(33)(34)(35)(36)(37). Significance of aromatic residues in defining the specificity of epitopeparatope interaction has been extensively addressed, highlighting the importance of tyrosine residues.…”

Comparative docking studies on ligand binding to the multispecific antibodies IgE-La2 and IgE-Lb4

“…Here we focus on these questions by means of computer-aided molecular modeling, investigating the complexes of two monoclonal IgE-antibodies, La2 and Lb4. These two antibodies have been shown to exhibit multispecific binding properties [10]: they are originally anti-trinitrophenyl antibodies, but were early recognized to be 'heteroclitic', i.e., they react with higher affinity to haptens other than the immunizing one. Experimental screening tests indicated entire sets of molecules bound by one or both of the antibodies.…”