A high-affinity natural autoantibody from human cord blood defines a physiologically relevant epitope on the FcεRIα

Natural Abs represent the indigenous immune repertoire and are thus present at birth and persist throughout life. Previously, human autoantibodies to the a domain of the high-affinity IgE receptor (Fc epsilon RI alpha) have been isolated from Ab libraries derived from normal donors and patients with chronic urticaria. To investigate whether these anti-Fc epsilon RI alpha Abs are present in the germline repertoire, we constructed a phage Fab display library from human cord blood, which represents the naive immune repertoire before exposure to exogenous Ags. All isolated clones specific to the Fc epsilon RI alpha had the same sequence. This single IgM Ab, named CBM alpha 8, was strictly in germline configuration and had high affinity and functional in vitro anaphylactogenic activity. Inhibition experiments indicated an overlapping epitope on the Fc epsilon RI alpha recognized by both CBM alpha 8 and the previously isolated anti-Fc epsilon RI alpha Abs from autoimmune and healthy donors. This common epitope on Fc epsilon RI alpha coincides with the binding site for IgE. Affinity measurements demonstrated the presence of Abs showing CBM alpha 8-like specificity, but with a significantly lower affinity in i.v. Ig, a therapeutic multidonor IgG preparation. We propose a hypothesis of escape mutants, whereby the resulting lower affinity IgG anti-Fc epsilon RI alpha Abs are rendered less likely to compete with IgE for binding to Fc epsilon RI alpha.