A high-affinity natural autoantibody from human cord blood defines a physiologically relevant epitope on the FcepsilonRIalpha.
Natural Abs represent the indigenous immune repertoire and are thus present at birth and persist throughout life. Previously, human autoantibodies to the alpha domain of the high-affinity IgE receptor (FcepsilonRIalpha) have been isolated from Ab libraries derived from normal donors and patients with chronic urticaria. To investigate whether these anti-FcepsilonRIalpha 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 FcepsilonRIalpha had the same sequence. This single IgM Ab, named CBMalpha8, was strictly in germline configuration and had high affinity and functional in vitro anaphylactogenic activity. Inhibition experiments indicated an overlapping epitope on the FcepsilonRIalpha recognized by both CBMalpha8 and the previously isolated anti-FcepsilonRIalpha Abs from autoimmune and healthy donors. This common epitope on FcepsilonRIalpha coincides with the binding site for IgE. Affinity measurements demonstrated the presence of Abs showing CBMalpha8-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-FcepsilonRIalpha Abs are rendered less likely to compete with IgE for binding to FcepsilonRIalpha.
Bobrzynski
Tomasz
T
Institute of Immunology, University of Bern, Bern, Switzerland.
Fux
Michaela
M
Vogel
Monique
M
Stadler
Michael B
MB
Stadler
Beda M
BM
Miescher
Sylvia M
SM
D000595:Amino Acid Sequence; D001323:Autoantibodies / Q000097:blood* / Q000235:genetics; D015550:Cell Degranulation / Q000276:immunology; D000939:Epitopes / Q000737:chemistry; D005312:Fetal Blood / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate; D007140:Immunoglobulin Fab Fragments / Q000097:blood / Q000235:genetics; D066298:In Vitro Techniques; D007231:Infant, Newborn; D008407:Mast Cells / Q000276:immunology; D008969:Molecular Sequence Data; D019151:Peptide Library; D017455:Receptors, IgE / Q000737:chemistry / Q000276:immunology*
D001323:Autoantibodies; D000939:Epitopes; D007140:Immunoglobulin Fab Fragments; D019151:Peptide Library; D017455:Receptors, IgE