Transgenic mice expressing the human high-affinity immunoglobulin (Ig) E receptor α chain respond to human IgE in mast cell degranulation and in allergic reactions

Wai Ping Fung-Leung, Jean De Sousa-Hitzler, Armana Ishaque, Lubing Zhou, Jesse Pang, Karen Ngo, Julie A. Panakos, Erika Chourmouzis, Fu-Tong Liu, Catherine Y. Lau

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Abstract

The high-affinity receptor for immunoglobulin (Ig) E (FcεRI) on mast cells and basophils plays a key role in IgE-mediated allergies FcεRI is composed of one α, and β, and two γ chains, which are all required for cell surface expression of FcεRI, but only the α chain is involved in the binding to IgE FcεRI-IgE interaction highly species specific, and rodent FcεRI does not bind human IgE. To obtain a 'humanized' animal model that responds to human IgE in allergic reactions, transgenic mice expressing the human FcεRI α chain were generated. The human FcεRI α chain gene with a 1.3-kb promoter region as a transgenic was found to be sufficient for mast cell-specific transcription. Cell surface expression of the human FcεRI α chain was indicated by the specific binding of human IgE to mast cells from transgenic mice in flow cytometric analyses. Expression of the transgenic FcεRI on bone marrow-derived mast cells was 4.7 x 104/cell, and the human IgE-binding affinity was K(d) = 6.4 nM in receptor-binding studies using 125I-IgE. The transgenic human FcεRI α chain was complexed with the mouse β and γ chains in immunoprecipitation studies. Cross-linking of the transgenic FcεRI with human IgE and antigens led to mast cell activation as indicated by enhanced tyrosine phosphorylation of the FcεRI β and γ chains and other cellular proteins. Mast cell degranulation in transgenic mice could be triggered by human IgE and antigens, as demonstrated by β-hexosaminidase release in vitro and passive cutaneous anaphylaxis in vivo. The results demonstrate that the human FcεRI α chain alone not only confers the specificity in human IgE binding, but also can reconstitute a functional receptor by coupling with the mouse β and γ chains to trigger mast cell activation and degranulation in a whole animal system. These transgenic mice 'humanized' in IgE-mediated allergens may be valuable for development of therapeutic agents that target the binding of IgE to its receptor.

Original languageEnglish (US)
Pages (from-to)49-56
Number of pages8
JournalJournal of Experimental Medicine
Volume183
Issue number1
DOIs
StatePublished - Jan 1 1996

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IgE Receptors
Cell Degranulation
Mast Cells
Immunoglobulin E
Transgenic Mice
Hypersensitivity
Antigens
Hexosaminidases
Passive Cutaneous Anaphylaxis
Basophils
Immunoprecipitation
Genetic Promoter Regions
Allergens
Tyrosine
Rodentia

ASJC Scopus subject areas

  • Immunology

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Transgenic mice expressing the human high-affinity immunoglobulin (Ig) E receptor α chain respond to human IgE in mast cell degranulation and in allergic reactions. / Fung-Leung, Wai Ping; De Sousa-Hitzler, Jean; Ishaque, Armana; Zhou, Lubing; Pang, Jesse; Ngo, Karen; Panakos, Julie A.; Chourmouzis, Erika; Liu, Fu-Tong; Lau, Catherine Y.

In: Journal of Experimental Medicine, Vol. 183, No. 1, 01.01.1996, p. 49-56.

Research output: Contribution to journalArticle

Fung-Leung, WP, De Sousa-Hitzler, J, Ishaque, A, Zhou, L, Pang, J, Ngo, K, Panakos, JA, Chourmouzis, E, Liu, F-T & Lau, CY 1996, 'Transgenic mice expressing the human high-affinity immunoglobulin (Ig) E receptor α chain respond to human IgE in mast cell degranulation and in allergic reactions', Journal of Experimental Medicine, vol. 183, no. 1, pp. 49-56. https://doi.org/10.1084/jem.183.1.49
Fung-Leung, Wai Ping ; De Sousa-Hitzler, Jean ; Ishaque, Armana ; Zhou, Lubing ; Pang, Jesse ; Ngo, Karen ; Panakos, Julie A. ; Chourmouzis, Erika ; Liu, Fu-Tong ; Lau, Catherine Y. / Transgenic mice expressing the human high-affinity immunoglobulin (Ig) E receptor α chain respond to human IgE in mast cell degranulation and in allergic reactions. In: Journal of Experimental Medicine. 1996 ; Vol. 183, No. 1. pp. 49-56.
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abstract = "The high-affinity receptor for immunoglobulin (Ig) E (FcεRI) on mast cells and basophils plays a key role in IgE-mediated allergies FcεRI is composed of one α, and β, and two γ chains, which are all required for cell surface expression of FcεRI, but only the α chain is involved in the binding to IgE FcεRI-IgE interaction highly species specific, and rodent FcεRI does not bind human IgE. To obtain a 'humanized' animal model that responds to human IgE in allergic reactions, transgenic mice expressing the human FcεRI α chain were generated. The human FcεRI α chain gene with a 1.3-kb promoter region as a transgenic was found to be sufficient for mast cell-specific transcription. Cell surface expression of the human FcεRI α chain was indicated by the specific binding of human IgE to mast cells from transgenic mice in flow cytometric analyses. Expression of the transgenic FcεRI on bone marrow-derived mast cells was 4.7 x 104/cell, and the human IgE-binding affinity was K(d) = 6.4 nM in receptor-binding studies using 125I-IgE. The transgenic human FcεRI α chain was complexed with the mouse β and γ chains in immunoprecipitation studies. Cross-linking of the transgenic FcεRI with human IgE and antigens led to mast cell activation as indicated by enhanced tyrosine phosphorylation of the FcεRI β and γ chains and other cellular proteins. Mast cell degranulation in transgenic mice could be triggered by human IgE and antigens, as demonstrated by β-hexosaminidase release in vitro and passive cutaneous anaphylaxis in vivo. The results demonstrate that the human FcεRI α chain alone not only confers the specificity in human IgE binding, but also can reconstitute a functional receptor by coupling with the mouse β and γ chains to trigger mast cell activation and degranulation in a whole animal system. These transgenic mice 'humanized' in IgE-mediated allergens may be valuable for development of therapeutic agents that target the binding of IgE to its receptor.",
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AU - Pang, Jesse

AU - Ngo, Karen

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