期刊
ALLERGY
卷 74, 期 2, 页码 236-245出版社
WILEY
DOI: 10.1111/all.13567
关键词
allergy; Fc epsilon RI; IgE receptor; mast cell; omalizumab
资金
- Research Council of Boston Children's Hospital
- Austrian Science Fund [DK W 1248-B13]
- NIH Research Project Grant Program [1R01AI119918]
- Harvard Digestive Diseases Center [P30DK034854]
- Chron's & Colitis Foundation
- Food Allergy Research and Education
- Mead Johnson Nutrition Company
- Austrian Science Fund (FWF) [W1248] Funding Source: Austrian Science Fund (FWF)
Background The soluble isoform of FceRI, the high-affinity IgE receptor (sFc epsilon RI), 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 sFc epsilon RI and study its in vivo functions. Methods Fc epsilon RI-transfected human cell lines (MelJuso), human monocyte-derived dendritic cells (moDCs), and murine bone marrow-derived mast cells (MC) were stimulated by Fc epsilon RI cross-linking and release of sFc epsilon RI 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 sFc epsilon RI (rsFc epsilon RI) 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 FceRI on MelJuso cells that express the trimeric or tetrameric receptor isoform induced the production of sFc epsilon RI. Using MCs and moDCs, we confirmed that IgE/FceRI activation induces sFceRI release. We demonstrated that generation of sFceRI requires Src phosphorylation and endo/lysosomal acidification. In experimental mouse models, sFceRI diminishes the severity of IgE-mediated anaphylaxis. BATs confirmed that, comparable to the anti-IgE monoclonal antibody omalizumab, sFceRI is an inhibitor of the human innate IgE effector axis, implying that sFceRI and omalizumab potentially inhibit each other in vivo. Conclusion sFceRI is produced after antigen-specific IgE/FceRI-mediated activation signals and functions as an endogenous inhibitor of IgE loading to FceRI and IgE-mediated activation. Our results imply, therefore, that sFceRI contributes to a negative regulatory feedback loop that aims at preventing overshooting responses after IgE-mediated immune activation.
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