Cooperative binding by mouse IgG3 antibodies: implications for functional affinity, effector function, and isotype restriction

Variable-Region-Identical Antibodies Differing in Isotype Demonstrate Differences in Fine Specificity and Idiotype

“…Although for each assay it is conceivable to imagine that some of the differences in relative binding of the two families of switch variants are due to avidity for the Ags used, this explanation is difficult to reconcile with the finding that the different isotypes did not show the same relative binding for the different Ags analyzed. In this regard, murine IgG3 was shown to have higher apparent affinity for polysaccharides than other IgG subclasses, presumably as a result of increased avidity resulting from constantregion mediated polymerization after Ag binding (14,49).…”

The immunoglobulin constant region contributes to affinity and specificity

“…In this regard, small, stereochemically significant movements of Ab side chains upon Ag binding have been demonstrated by X-ray crystallography [20]. Possible examples of nontypical members of the Ag-binding site are amino acid residues in the C H domains that influence segmental flexibility [29], inter-Ab associations [30], and amino acid residues in the V region that are not contact residues but determine or influence the canonical conformations of the complementarity-determining regions (CDRs) [31].…”

“…Given that isotype could affect specificity, Ag binding to the B cell receptor could directly trigger clonal expansion of isotyperestricted Ag-specific cells. In this regard, the IgM and IgG2 (or IgG3 in mice) predominance in antipolysaccharide responses [30], the IgG1 predominance in pathogenic autoimmune Abs [59], and the IgG2a predominance in neutralizing Abs to viruses might reflect isotype-related effects on specificity [60] that, when combined with local stimuli that promote B cell switching to certain isotypes, result in isotype-restricted Ab responses.…”

Variable Region Identical IgA and IgE to Cryptococcus neoformans Capsular Polysaccharide Manifest Specificity Differences

“…At least two mechanisms have been proposed for this effect; 1) C region effects on V region paratope structure (15) before and/or during Ag binding and 2) subclass-mediated differences in functional affinity leading to the recognition of new epitopes (6). The latter is a mechanism that may apply to IgG 3 , which can self-aggregate through Fc-Fc receptor interactions to engage different epitopes through enhanced avidity (16). Although the molecular basis for these effects remains to be determined, a plausible mechanism involves C-mediated constraints on V region structure that affect the conformation of the Ig paratope.…”