title: Natural tolerance development in cow's milk allergic children: IgE and IgG4 epitope binding.
abstract: BACKGROUND
  Although most of cow's milk (CM) allergic children will outgrow their allergy, the pathomechanism of the natural development of tolerance remains poorly understood. It has been suggested that the balance between milk-specific IgE and IgG4 plays a major role.
  
  
  OBJECTIVE
  We aimed to investigate differences in IgE and IgG4 antibody binding to CM epitopes between patients with persistent CM allergy (CMA) and those that naturally became tolerant.
  
  
  METHODS
  Sera from 35 children with proven CMA (median age at inclusion of 10 months) were analyzed retrospectively; 22 patients have become tolerant (median age at tolerance acquisition of 51 months) during the study period as confirmed by a negative oral food challenge. IgE and IgG4 binding to sequential epitopes derived from five major CM proteins were measured with a peptide microarray-based immunoassay.
  
  
  RESULTS
  At baselines, greater intensity and broader diversity of IgE and IgG4 binding have been found in children with persistent CMA beyond 5 years of age compared to patients with transient CMA. Moreover, children with transient CMA had IgE and IgG4 antibodies that more often recognized the same epitopes, compared to those with persistent CMA. From baseline to the time of tolerance development, both IgE and IgG4 binding intensity decreased significantly, particularly in areas of α-s- and β-casein (P<.01, false discovery rate [FDR]<.1). Interestingly, differences between IgE and IgG4 binding intensity to CM peptides decreased when the patients became tolerant.
  
  
  CONCLUSIONS
  Our results suggest that the overlap between IgE and IgG4 might be important in natural tolerance acquisition. Further studies are needed to confirm our data and can eventually lead to development of more targeted treatment of food allergy.
authors.affiliation: Geneva University Hospital, Geneva, Switzerland.|Department of Pediatrics, Division of Allergy and Immunology, Jaffe Food Allergy Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: J C
authors.identifier: http://orcid.org/0000-0001-5006-5724
authors.initials: JC
authors.lastname: Caubet
authors.affiliation: Department of Pediatrics, Division of Allergy and Immunology, Jaffe Food Allergy Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.|Bioinformatics Institute, Institute of High Performance Computing, A*STAR, Singapore, Singapore.
authors.forename: J
authors.initials: J
authors.lastname: Lin
authors.affiliation: Department of Pediatric Pneumology and Immunology, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Ahrens
authors.affiliation: Department of Pediatrics, Division of Allergy and Immunology, Jaffe Food Allergy Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: G
authors.initials: G
authors.lastname: Gimenez
authors.affiliation: Department of Pediatrics, Division of Allergy and Immunology, Jaffe Food Allergy Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: L
authors.initials: L
authors.lastname: Bardina
authors.affiliation: Department of Pediatric Pneumology and Immunology, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Niggemann
authors.affiliation: Department of Pediatrics, Division of Allergy and Immunology, Jaffe Food Allergy Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: H A
authors.initials: HA
authors.lastname: Sampson
authors.affiliation: Department of Pediatrics, Division of Allergy and Immunology, Jaffe Food Allergy Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.|Department of Pediatric Pneumology and Immunology, Charité Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Beyer
mesh_terms: D000818:Animals; D000915:Antibody Affinity; D002417:Cattle; D000939:Epitopes / Q000378:metabolism; D006801:Humans; D007108:Immune Tolerance; D007073:Immunoglobulin E / Q000276:immunology / Q000378:metabolism; D007074:Immunoglobulin G / Q000276:immunology / Q000378:metabolism; D007223:Infant; D016269:Milk Hypersensitivity / Q000276:immunology*; D011485:Protein Binding
chemical_list: D000939:Epitopes; D007074:Immunoglobulin G; D007073:Immunoglobulin E
keywords: IgE; IgG4; food allergy; microarray; pediatrics