Cow's milk protein β-lactoglobulin confers resilience against allergy by targeting complexed iron into immune cells: Journal of Allergy and Clinical Immunology

F. Roth-Walter, S.M. Afify, L.F. Pacios, B.R. Blokhuis, F. Redegeld, A. Regner, L.-M. Petje, A. Fiocchi, E. Untersmayr, Z. Dvorak, K. Hufnagl, I. Pali-Schöll, E. Jensen-Jarolim

Research output: Contribution to journalArticlepeer-review


Background: Beta-lactoglobulin (BLG) is a bovine lipocalin in milk with an innate defense function. The circumstances under which BLG is associated with tolerance of or allergy to milk are not understood. Objective: Our aims were to assess the capacity of ligand-free apoBLG versus loaded BLG (holoBLG) to protect mice against allergy by using an iron-quercetin complex as an exemplary ligand and to study the molecular mechanisms of this protection. Methods: Binding of iron-quercetin to BLG was modeled and confirmed by spectroscopy and docking calculations. Serum IgE binding to apoBLG and holoBLG in children allergic to milk and children tolerant of milk was assessed. Mice were intranasally treated with apoBLG versus holoBLG and analyzed immunologically after systemic challenge. Aryl hydrocarbon receptor (AhR) activation was evaluated with reporter cells and Cyp1A1 expression. Treated human PBMCs and human mast cells were assessed by fluorescence-activated cell sorting and degranulation, respectively. Results: Modeling predicted masking of major IgE and T-cell epitopes of BLG by ligand binding. In line with this modeling, IgE binding in children allergic to milk was reduced toward holoBLG, which also impaired degranulation of mast cells. In mice, only treatments with holoBLG prevented allergic sensitization and anaphylaxis, while sustaining regulatory T cells. BLG facilitated quercetin-dependent AhR activation and, downstream of AhR, lung Cyp1A1 expression. HoloBLG shuttled iron into monocytic cells and impaired their antigen presentation. Conclusion: The cargo of holoBLG is decisive in preventing allergy in vivo. BLG without cargo acted as an allergen in vivo and further primed human mast cells for degranulation in an antigen-independent fashion. Our data provide a mechanistic explanation why the same proteins can act either as tolerogens or as allergens. © 2020
Original languageEnglish
Pages (from-to)321
JournalJ. Allergy Clin. Immunol.
Issue number1
Publication statusPublished - 2021


  • Allergen
  • allergy
  • BLG
  • Bos d 5
  • cow's milk
  • iron
  • ligand
  • lipocalin
  • milk
  • quercetin
  • tolerance
  • β-lactoglobulin
  • aromatic hydrocarbon receptor
  • beta lactoglobulin
  • cytochrome P450 1A1
  • deferoxamine
  • gamma interferon
  • immunoglobulin A antibody
  • immunoglobulin E
  • immunoglobulin E antibody
  • immunoglobulin G1 antibody
  • immunoglobulin G2a antibody
  • interleukin 10
  • interleukin 13
  • retinoic acid
  • animal experiment
  • animal model
  • antibody production
  • antigen presentation
  • antigen specificity
  • Article
  • cell proliferation
  • complex formation
  • controlled study
  • cow milk
  • cytokine release
  • cytokine response
  • equilibrium constant
  • feedback system
  • female
  • flow cytometry
  • fluorescence activated cell sorting
  • Hep-G2 cell line
  • human
  • human cell
  • human tissue
  • immunocompetent cell
  • immunohistochemistry
  • immunological tolerance
  • in vitro study
  • in vivo study
  • innate immunity
  • iron overload
  • ligand binding
  • mast cell
  • milk allergy
  • mouse
  • nonhuman
  • peripheral blood mononuclear cell
  • priority journal
  • protein binding
  • protein expression
  • retrospective study
  • spectroscopy
  • surface property
  • T lymphocyte


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