Retinoic acid prevents immunogenicity of milk lipocalin Bos d 5 through binding to its immunodominant T-cell epitope

Karin Hufnagl, Debajyoti Ghosh, Stefanie Wagner, Alessandro Fiocchi, Lamia Dahdah, Rodolfo Bianchini, Nina Braun, Ralf Steinborn, Martin Hofer, Marion Blaschitz, Georg A Roth, Gerlinde Hofstetter, Franziska Roth-Walter, Luis F Pacios, Erika Jensen-Jarolim

Research output: Contribution to journalArticle

Abstract

The major cow's milk allergen Bos d 5 belongs to the lipocalin protein family, with an intramolecular pocket for hydrophobic ligands. We investigated whether Bos d 5 when loaded with the active vitamin A metabolite retinoic acid (RA), would elicit differential immune responses compared to the unloaded state. By in silico docking an affinity energy of -7.8 kcal/mol was calculated for RA into Bos d 5. Loading of RA to Bos d 5 could be achieved in vitro, as demonstrated by ANS displacement assay, but had no effect on serum IgE binding in tolerant or challenge-positive milk allergic children. Bioinformatic analysis revealed that RA binds to the immunodominant T-cell epitope region of Bos d 5. In accordance, Bos d 5 significantly suppressed the CD3+ CD4+ cell numbers, proliferative response and IL-10, IL-13 and IFN-γ secretion from stimulated human PBMCs only when complexed with RA. This phenomenon was neither associated with apoptosis of T-cells nor with the activation of Foxp3+ T-cells, but correlated likely with enhanced stability to lysosomal digestion due to a predicted overlap of Cathepsin S cleavage sites with the RA binding site. Taken together, proper loading of Bos d 5 with RA may suppress its immunogenicity and prevent its allergenicity.

Original languageEnglish
Number of pages12
JournalScientific Reports
Volume8
Issue number1
DOIs
Publication statusPublished - Jan 25 2018

Keywords

  • Allergens/immunology
  • Animals
  • Cattle
  • Cell Proliferation/drug effects
  • Epitopes, T-Lymphocyte/metabolism
  • Humans
  • Immunoglobulin E/metabolism
  • Immunologic Factors/metabolism
  • Interferon-gamma/metabolism
  • Interleukin-10/metabolism
  • Interleukin-13/metabolism
  • Leukocytes, Mononuclear/immunology
  • Lipocalins/immunology
  • Lysosomes/metabolism
  • Molecular Docking Simulation
  • Protein Binding
  • Proteolysis
  • Tretinoin/metabolism

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    Hufnagl, K., Ghosh, D., Wagner, S., Fiocchi, A., Dahdah, L., Bianchini, R., Braun, N., Steinborn, R., Hofer, M., Blaschitz, M., Roth, G. A., Hofstetter, G., Roth-Walter, F., Pacios, L. F., & Jensen-Jarolim, E. (2018). Retinoic acid prevents immunogenicity of milk lipocalin Bos d 5 through binding to its immunodominant T-cell epitope. Scientific Reports, 8(1). https://doi.org/10.1038/s41598-018-19883-0