title: IgG4 inhibits peanut-induced basophil and mast cell activation in peanut-tolerant children sensitized to peanut major allergens.
abstract: 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 IgG4 (P-sIgG4), 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 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.
  
  
  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-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).
  
  
  CONCLUSIONS
  Differences 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.
authors: Department of Pediatric Allergy, Division of Asthma, Allergy & Lung Biology, King's College London, London, United Kingdom; MRC & Asthma UK Centre in Allergic Mechanisms of Asthma, London, United Kingdom; Immunoallergology Department, Coimbra University Hospital, Coimbra, Portugal; Gulbenkian Programme for Advanced Medical Education, Lisbon, Portugal.
authors: Alexandra F
authors: AF
authors: Santos
authors: MRC & Asthma UK Centre in Allergic Mechanisms of Asthma, London, United Kingdom; Randall Division of Cell and Molecular Biophysics, King's College London, London, United Kingdom.
authors: Louisa K
authors: LK
authors: James
authors: Independent Biostatistician, Chapel Hill, NC.
authors: Henry T
authors: HT
authors: Bahnson
authors: MRC & Asthma UK Centre in Allergic Mechanisms of Asthma, London, United Kingdom; Allergy and Clinical Immunology, MRC & Asthma UK Centre for Allergic Mechanisms of Asthma Faculty of Medicine, National Heart and Lung Institute, Imperial College London, London, United Kingdom.
authors: Mohammed H
authors: MH
authors: Shamji
authors: Department of Pediatric Allergy, Division of Asthma, Allergy & Lung Biology, King's College London, London, United Kingdom; MRC & Asthma UK Centre in Allergic Mechanisms of Asthma, London, United Kingdom.
authors: Natália C
authors: NC
authors: Couto-Francisco
authors: Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom.
authors: Sabita
authors: S
authors: Islam
authors: Pathology Partnership at Cambridge University Hospitals, Cambridge, United Kingdom.
authors: Sally
authors: S
authors: Houghton
authors: Department of Allergy, Cambridge University Hospitals NHS Foundation Trust, Addenbrooke's Hospital, Cambridge, United Kingdom.
authors: Andrew T
authors: AT
authors: Clark
authors: Department of Pediatric Allergy, Division of Asthma, Allergy & Lung Biology, King's College London, London, United Kingdom; MRC & Asthma UK Centre in Allergic Mechanisms of Asthma, London, United Kingdom.
authors: Alick
authors: A
authors: Stephens
authors: Department of Pediatric Allergy, Division of Asthma, Allergy & Lung Biology, King's College London, London, United Kingdom; MRC & Asthma UK Centre in Allergic Mechanisms of Asthma, London, United Kingdom.
authors: Victor
authors: V
authors: Turcanu
authors: MRC & Asthma UK Centre in Allergic Mechanisms of Asthma, London, United Kingdom; Allergy and Clinical Immunology, MRC & Asthma UK Centre for Allergic Mechanisms of Asthma Faculty of Medicine, National Heart and Lung Institute, Imperial College London, London, United Kingdom.
authors: Stephen R
authors: SR
authors: Durham
authors: MRC & Asthma UK Centre in Allergic Mechanisms of Asthma, London, United Kingdom; Randall Division of Cell and Molecular Biophysics, King's College London, London, United Kingdom.
authors: Hannah J
authors: HJ
authors: Gould
authors: Department of Pediatric Allergy, Division of Asthma, Allergy & Lung Biology, King's College London, London, United Kingdom; MRC & Asthma UK Centre in Allergic Mechanisms of Asthma, London, United Kingdom. Electronic address: gideon.lack@kcl.ac.uk.
authors: Gideon
authors: G
authors: Lack
mesh_terms: D000485:Allergens / Q000276:immunology*; D000918:Antibody Specificity; D052179:Antigens, Plant; D010367:Arachis / Q000009:adverse effects*; D001491:Basophils / Q000276:immunology*; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007108:Immune Tolerance; D007073:Immunoglobulin E / Q000276:immunology; D007074:Immunoglobulin G / Q000276:immunology*; D008297:Male; D008407:Mast Cells / Q000276:immunology*; D021183:Peanut Hypersensitivity / Q000276:immunology*
chemical_list: D000485:Allergens; D052179:Antigens, Plant; D007074:Immunoglobulin G; D007073:Immunoglobulin E
keywords: Ara h 2; IgE inhibition; IgG(4); basophil; basophil activation test; blocking antibodies; mast cells; peanut; peanut allergy; tolerance