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Cow’s milk protein β-lactoglobulin confers resilience against allergy by targeting complexed iron into immune cells

  • Franziska Roth-Walter
    Correspondence
    Corresponding author: Franziska Roth-Walter, PhD, Comparative Medicine, The Interuniversity Messerli Research Institute, University of Veterinary Medicine Vienna, Medical University of Vienna and University of Vienna, Veterinärplatz 1, A-1210 Vienna, Austria.
    Affiliations
    The Interuniversity Messerli Research Institute of the University of Veterinary Medicine Vienna, Medical University Vienna and University Vienna, Vienna, Austria

    Institute of Pathophysiology and Allergy Research, Center of Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
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  • Sheriene Moussa Afify
    Affiliations
    The Interuniversity Messerli Research Institute of the University of Veterinary Medicine Vienna, Medical University Vienna and University Vienna, Vienna, Austria

    Laboratory Medicine and Immunology Department, Faculty of Medicine, Menoufia University, Menoufia, Egypt
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  • Luis F. Pacios
    Affiliations
    Biotechnology Department, ETSIAAB, Center for Plant Biotechnology and Genomics, CBGP (UPM-INIA), Technical University of Madrid, Madrid, Spain
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  • Bart R. Blokhuis
    Affiliations
    Faculty of Science, Division of Pharmacology, Department of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands
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  • Frank Redegeld
    Affiliations
    Faculty of Science, Division of Pharmacology, Department of Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands
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  • Andreas Regner
    Affiliations
    The Interuniversity Messerli Research Institute of the University of Veterinary Medicine Vienna, Medical University Vienna and University Vienna, Vienna, Austria
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  • Lisa-Marie Petje
    Affiliations
    The Interuniversity Messerli Research Institute of the University of Veterinary Medicine Vienna, Medical University Vienna and University Vienna, Vienna, Austria
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  • Alessandro Fiocchi
    Affiliations
    Childrens Hospital Bambino Gesù, Rome, Italy
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  • Eva Untersmayr
    Affiliations
    Institute of Pathophysiology and Allergy Research, Center of Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
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  • Zdenek Dvorak
    Affiliations
    Department of Cell Biology and Genetics, Faculty of Science, Palacky University, Olomouc, Czech Republic
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  • Karin Hufnagl
    Affiliations
    The Interuniversity Messerli Research Institute of the University of Veterinary Medicine Vienna, Medical University Vienna and University Vienna, Vienna, Austria

    Institute of Pathophysiology and Allergy Research, Center of Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
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  • Isabella Pali-Schöll
    Affiliations
    The Interuniversity Messerli Research Institute of the University of Veterinary Medicine Vienna, Medical University Vienna and University Vienna, Vienna, Austria

    Institute of Pathophysiology and Allergy Research, Center of Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
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  • Erika Jensen-Jarolim
    Correspondence
    Erika Jensen-Jarolim, MD, Institute of Pathophysiology and Allergy Research, Center of Pathophysiology, Infectiology and Immunology, Medical University Vienna, Waehringer G. 18-20, 1090 Vienna, Austria.
    Affiliations
    The Interuniversity Messerli Research Institute of the University of Veterinary Medicine Vienna, Medical University Vienna and University Vienna, Vienna, Austria

    Institute of Pathophysiology and Allergy Research, Center of Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Vienna, Austria
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      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.

      Graphical abstract

      Key words

      Abbreviations used:

      AhR (Aryl hydrocarbon receptor), β-hex (β-hexosaminidase), BLG (β-Lactoglobulin), FeQ2 (Iron–quercetin 2), LCN (Lipocalin), SCF (Stem cell factor), TBS (Tris-buffered saline), Treg (Regulatory T), UV-VIS (Ultraviolet-visible spectroscopy)
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