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A High-Affinity Natural Autoantibody from Human Cord Blood Defines a Physiologically Relevant Epitope on the FcRI ¹

Tomasz Bobrzynski^*, Michaela Fux^*, Monique Vogel^*, Michael B. Stadler, Beda M. Stadler^* and Sylvia M. Miescher^2,*,

^* Institute of Immunology, University of Bern, Bern, Switzerland; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139; and ZLB Behring, Bern, Switzerland

Natural Abs represent the indigenous immune repertoire and are thus present at birth and persist throughout life. Previously, human autoantibodies to the domain of the high-affinity IgE receptor (FcRI) have been isolated from Ab libraries derived from normal donors and patients with chronic urticaria. To investigate whether these anti-FcRI 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 FcRI had the same sequence. This single IgM Ab, named CBM8, was strictly in germline configuration and had high affinity and functional in vitro anaphylactogenic activity. Inhibition experiments indicated an overlapping epitope on the FcRI recognized by both CBM8 and the previously isolated anti-FcRI Abs from autoimmune and healthy donors. This common epitope on FcRI coincides with the binding site for IgE. Affinity measurements demonstrated the presence of Abs showing CBM8-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-FcRI Abs are rendered less likely to compete with IgE for binding to FcRI.