title: Distinct transcriptome profiles differentiate nonsteroidal anti-inflammatory drug-dependent from nonsteroidal anti-inflammatory drug-independent food-induced anaphylaxis.
abstract: BACKGROUND
  Lipid transfer protein (LTP), an abundant protein in fruits, vegetables, and nuts, is a common food allergen in Mediterranean areas causing diverse allergic reactions. Approximately 40% of food-related anaphylaxis induced by LTPs requires nonsteroidal anti-inflammatory drugs (NSAIDs) as a triggering cofactor.
  
  
  OBJECTIVE
  We sought to better understand the determinants of NSAID-dependent and NSAID-independent LTP-induced anaphylaxis (LTP-A).
  
  
  METHODS
  Selection of patients was based on a proved clinical history of NSAID-dependent or NSAID-independent anaphylaxis to LTPs, positive skin prick test response to LTPs, and serum LTP IgE. Whole-transcriptome (RNA sequencing) analysis of blood cells from 14 patients with NSAID-related LTP-A (NSAID-LTP-A), 7 patients with LTP-A, and 13 healthy control subjects was performed to identify distinct gene expression signatures.
  
  
  RESULTS
  Expression of genes regulating gastrointestinal epithelial renewal was altered in both patient sets, particularly in those with LTP-A, who also presented with gene expression profiles characteristic of an inflammatory syndrome. These included altered B-cell pathways, increased neutrophil activation markers, and increased reactive oxygen species levels. Increased expression of the IgG receptor (CD64) in patients with LTP-A was mirrored by the presence of LTP-specific IgG1 and IgG3. Conversely, patients with NSAID-LTP-A were characterized by reduced expression of IFN-γ-regulated genes and IFN-γ levels, as well as upregulated expression of adenosine receptor 3 (ADORA3) and genes related to adenosine metabolism.
  
  
  CONCLUSIONS
  Gene ontology analysis suggests disturbances in gut epithelial homeostasis in both groups with LTP-A, with potential integrity breaches in patients with LTP-A that might explain their distinct inflammatory signatures. Differential regulation in patients with LTP-A and those with NSAID-LTP-A of the IFN-γ pathway, IgG receptors, and ADORA3 might provide the pathogenic basis of their distinct responses.
authors.affiliation: Mast Cell Biology Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md; Unitat d'Al.lergia, Servei de Neumologia i Al.lergia Respiratoria, Hospital Clinic, Universitat de Barcelona, Barcelona, Spain; Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain. Electronic address: rmunoz@clinic.ub.es.
authors.forename: Rosa
authors.initials: R
authors.lastname: Muñoz-Cano
authors.affiliation: Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Servei d'Immunologia, CDB, Hospital Clinic, Universitat de Barcelona, Barcelona, Spain; Spanish Research Network on Adverse Reactions to Allergens and Drugs (RIRAAF: Red de Investigacion de Reacciones Adversas a Alergenos y Farmacos) of the Carlos III Health Institute, Madrid, Spain.
authors.forename: Mariona
authors.initials: M
authors.lastname: Pascal
authors.affiliation: Unitat d'Al.lergia, Servei de Neumologia i Al.lergia Respiratoria, Hospital Clinic, Universitat de Barcelona, Barcelona, Spain; Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Spanish Research Network on Adverse Reactions to Allergens and Drugs (RIRAAF: Red de Investigacion de Reacciones Adversas a Alergenos y Farmacos) of the Carlos III Health Institute, Madrid, Spain.
authors.forename: Joan
authors.initials: J
authors.lastname: Bartra
authors.affiliation: Unitat d'Al.lergia, Servei de Neumologia i Al.lergia Respiratoria, Hospital Clinic, Universitat de Barcelona, Barcelona, Spain; Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Cesar
authors.initials: C
authors.lastname: Picado
authors.affiliation: Unitat d'Al.lergia, Servei de Neumologia i Al.lergia Respiratoria, Hospital Clinic, Universitat de Barcelona, Barcelona, Spain; Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Valero
authors.affiliation: Mast Cell Biology Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
authors.forename: Do-Kyun
authors.initials: DK
authors.lastname: Kim
authors.affiliation: Office of Science and Technology and Translational Genetics and Genomics Unit, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Md.
authors.forename: Stephen
authors.initials: S
authors.lastname: Brooks
authors.affiliation: Office of Science and Technology and Translational Genetics and Genomics Unit, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Md.
authors.forename: Michael
authors.initials: M
authors.lastname: Ombrello
authors.affiliation: Mast Cell Biology Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
authors.forename: Dean D
authors.initials: DD
authors.lastname: Metcalfe
authors.affiliation: Laboratory of Molecular Immunogenetics, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Md.
authors.forename: Juan
authors.initials: J
authors.lastname: Rivera
authors.affiliation: Mast Cell Biology Section, Laboratory of Allergic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md.
authors.forename: Ana
authors.initials: A
authors.lastname: Olivera
mesh_terms: D000328:Adult; D000485:Allergens / Q000276:immunology*; D000707:Anaphylaxis / Q000235:genetics* / Q000276:immunology; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects*; D002352:Carrier Proteins / Q000276:immunology*; D005260:Female; D005512:Food Hypersensitivity / Q000235:genetics* / Q000276:immunology; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology; D008297:Male; D008875:Middle Aged; D043684:Receptor, Adenosine A3 / Q000235:genetics; D017452:Receptors, IgG / Q000235:genetics; D017423:Sequence Analysis, RNA; D059467:Transcriptome
chemical_list: D000485:Allergens; D000894:Anti-Inflammatory Agents, Non-Steroidal; D002352:Carrier Proteins; C489017:FCGR1A protein, human; D007074:Immunoglobulin G; D043684:Receptor, Adenosine A3; D017452:Receptors, IgG; C030363:lipid transfer protein; D007371:Interferon-gamma
keywords: Anaphylaxis; food allergy; lipid transfer protein syndrome; nonsteroidal anti-inflammatory drugs; transcriptome analysis