The soluble isoform of human FcɛRI is an endogenous inhibitor of IgE-mediated mast cell responses

Allergy. 2019 Feb;74(2):236-245. doi: 10.1111/all.13567. Epub 2018 Nov 20.


Background: The soluble isoform of FcɛRI, the high-affinity IgE receptor (sFcεRI), is a protein of the IgE network with poorly defined functions.

Objective: To define cellular sources and signals that result in the production of human sFcεRI and study its in vivo functions.

Methods: FcεRI-transfected human cell lines (MelJuso), human monocyte-derived dendritic cells (moDCs), and murine bone marrow-derived mast cells (MC) were stimulated by FcεRI cross-linking and release of sFcεRI was analyzed (ELISA, Western Blot). Lysosomal-associated membrane protein 1 degranulation assays and human basophil activation tests (BATs) were used to study IgE-dependent activation. Recombinant sFcεRI (rsFcεRI) was used to assess its role in murine models of anaphylaxis with WT (wild-type) and IgE-/- (IgE-deficient) mice.

Results: Antigen-specific cross-linking of IgE-loaded FcɛRI on MelJuso cells that express the trimeric or tetrameric receptor isoform induced the production of sFcεRI. Using MCs and moDCs, we confirmed that IgE/FcɛRI activation induces sFcɛRI release. We demonstrated that generation of sFcɛRI requires Src phosphorylation and endo/lysosomal acidification. In experimental mouse models, sFcɛRI diminishes the severity of IgE-mediated anaphylaxis. BATs confirmed that, comparable to the anti-IgE monoclonal antibody omalizumab, sFcɛRI is an inhibitor of the human innate IgE effector axis, implying that sFcɛRI and omalizumab potentially inhibit each other in vivo.

Conclusion: sFcɛRI is produced after antigen-specific IgE/FcɛRI-mediated activation signals and functions as an endogenous inhibitor of IgE loading to FcɛRI and IgE-mediated activation. Our results imply, therefore, that sFcɛRI contributes to a negative regulatory feedback loop that aims at preventing overshooting responses after IgE-mediated immune activation.

Keywords: FcεRI; IgE receptor; allergy; mast cell; omalizumab.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basophils / immunology
  • Basophils / metabolism
  • Biomarkers
  • Cell Degranulation / immunology
  • Cell Line, Tumor
  • Dendritic Cells / immunology
  • Dendritic Cells / metabolism
  • Endosomes / metabolism
  • Humans
  • Immunoglobulin E / chemistry
  • Immunoglobulin E / immunology*
  • Immunoglobulin E / metabolism*
  • Lysosomes / metabolism
  • Mast Cells / immunology*
  • Mast Cells / metabolism*
  • Mice
  • Mice, Knockout
  • Protein Binding
  • Protein Isoforms
  • Protein Multimerization
  • Receptors, IgE / chemistry
  • Receptors, IgE / metabolism*


  • Biomarkers
  • Protein Isoforms
  • Receptors, IgE
  • Immunoglobulin E