IgG4 inhibits peanut-induced basophil and mast cell activation in peanut-tolerant children sensitized to peanut major allergens

Abstract

BackgroundMost 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 IgG4 (P-sIgG4), in PS patients.MethodsTwo hundred twenty-eight children (108 patients with PA, 77 PS patients, and 43 nonsensitized nonallergic subjects) were studied. Levels of specific IgE and IgG4 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 IgG4 and retested in inhibition assays.ResultsBasophils 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-sIgG4 levels (P = .023) and P-sIgG4/P-sIgE (P < .001), Ara h 1–sIgG4/Ara h 1–sIgE (P = .050), Ara h 2–sIgG4/Ara h 2–sIgE (P = .004), and Ara h 3–sIgG4/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-sIgG4 levels and POIT but not from nonsensitized nonallergic children. Depletion of IgG4 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).ConclusionsDifferences in sIgE levels and allergen specificity could not justify the clinical phenotype in all children with PA and PS children. Blocking IgG4 antibodies provide an additional explanation for the absence of clinical reactivity in PS patients sensitized to major peanut allergens.

Markers of tolerance development to food allergens

“…Recent data support a relevant suppressive effect of IgG4 in patients that acquired tolerance to peanut or keep a status of tolerance despite sensitization. IgG4 from peanut-sensitized nonallergic individuals suppressed allergen-specific activation of mast cells and basophils loaded with IgE from allergic individuals (121), although other studies showed that allergen-specific IgG seems not to be involved in peanut natural clinical tolerance (111).…”

Asthma phenotypes and IgE responses

“…This absence of any IgE dose-response is also observed during omalizumab treatment of chronic urticaria [144]. This discrepancy could relate to the existence of neutralising antibodies towards IgE, which was recently established ex vivo [145,146], providing new evidence that the IgE level alone might not be sufficient to predict clinical outcome. It is also possible that IgE may act on mast cells independently of allergen-induced IgE/receptor cross-linking, to promote their survival and decrease their activation threshold by other stimuli, as suggested in the skin [147].…”

News in Cellular Allergology: A Review of the Human Mast Cell and Basophil Granulocyte Literature from January 2013 to May 2015

“…Supporting this, symptom severity during failed oral food challenges correlated with basophil reactivity [65]. Basophil and mast cell activity in vivo depends on both the IgE affinity and concentration, and also on competing IgG4 to the same allergen [66]. Although hydrolysates of peanut flower appeared to reduce the molecular weight of allergens, the basophil reactivity of peanut-allergic patients was not reduced by this treatment, suggesting that IgE epitopes were predominantly linear, and peptides containing IgE epitopes were resistant to degradation [67].…”