IgG(4) inhibits peanut-induced basophil and mast cell activation in peanut-tolerant children sensitized to peanut major allergens

BACKGROUND: Most children with detectable peanut-specific IgE (P-sIgE) are not allergic to peanut. We addressed 2 non–mutually exclusive hypotheses for the discrepancy between allergy and sensitization: (1) differences in P-sIgE levels between children with peanut allergy (PA) and peanut-sensitized but tolerant (PS) children and (2) the presence of an IgE inhibitor, such as peanut-specific IgG(4) (P-sIgG(4)), in PS patients. METHODS: Two hundred twenty-eight children (108 patients with PA, 77 PS patients, and 43 nonsensitized nonallergic subjects) were studied. Levels of specific IgE and IgG(4) to peanut and its components were determined. IgE-stripped basophils or a mast cell line were used in passive sensitization activation and inhibition assays. Plasma of PS subjects and patients submitted to peanut oral immunotherapy (POIT) were depleted of IgG(4) and retested in inhibition assays. RESULTS: Basophils and mast cells sensitized with plasma from patients with PA but not PS patients showed dose-dependent activation in response to peanut. Levels of sIgE to peanut and its components could only partially explain differences in clinical reactivity between patients with PA and PS patients. P-sIgG(4) levels (P = .023) and P-sIgG(4)/P-sIgE (P < .001), Ara h 1–sIgG(4)/Ara h 1–sIgE (P = .050), Ara h 2–sIgG(4)/Ara h 2–sIgE (P = .004), and Ara h 3–sIgG(4)/Ara h 3–sIgE (P = .016) ratios were greater in PS children compared with those in children with PA. Peanut-induced activation was inhibited in the presence of plasma from PS children with detectable P-sIgG(4) levels and POIT but not from nonsensitized nonallergic children. Depletion of IgG(4) from plasma of children with PS (and POIT) sensitized to Ara h 1 to Ara h 3 partially restored peanut-induced mast cell activation (P = .007). CONCLUSIONS: Differences in sIgE levels and allergen specificity could not justify the clinical phenotype in all children with PA and PS children. Blocking IgG(4) antibodies provide an additional explanation for the absence of clinical reactivity in PS patients sensitized to major peanut allergens.