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

Background: Ig , , and constant regions can affect Ag specificity, but this is unknown for IgE. Results: IgE and IgA variable regions differ in specificity and cleavage rates compared with each other and IgG subclasses. Conclusion: Like IgG subclasses, the IgA and IgE constant regions can affect Ag binding specificities. Significance: These results extend the principle that the constant region can affect variable region specificity to IgE.In recent years several groups have shown that isotype switching from IgM to IgG to IgA can affect the affinity and specificity of antibodies sharing identical variable (V) regions. However, whether the same applies to IgE is unknown. In this study we compared the fine specificity of V region-identical IgE and IgA to Cryptococcus neoformans capsular polysaccharide and found that these differed in specificity from each other. The IgE and IgA paratopes were probed by nuclear magnetic resonance spectroscopy with N-15-labeled peptide mimetics of cryptococcal polysaccharide antigen (Ag). IgE was found to cleave the peptide at a much faster rate than V region-identical IgG subclasses and IgA, consistent with an altered paratope. Both IgE and IgA were opsonic for C. neoformans and protected against infection in mice. In summary, V-region expression in the context of the E constant (C) region results in specificity changes that are greater than observed for comparable IgG subclasses. These results raise the possibility that expression of certain V regions in the context of and E C regions affects their function and contributes to the special properties of those isotypes.