A novel human immunoglobulin Fcg–Fce bifunctional fusion protein inhibits FceRI-mediated degranulation

UNCG Author/Contributor (non-UNCG co-authors, if there are any, appear on document)
Christopher Kepley, Associate Professor (Creator)
The University of North Carolina at Greensboro (UNCG )
Web Site: http://library.uncg.edu/

Abstract: Human mast cells and basophils that express the high-affinity immunoglobulin E (IgE) receptor, Fce receptor 1 (FceRI), have key roles in allergic diseases. FceRI cross-linking stimulates the release of allergic mediators1. Mast cells and basophils co-express FcgRIIb, a low affinity receptor containing an immunoreceptor tyrosine-based inhibitory motif and whose co-aggregation with FceRI can block FceRI-mediated reactivity2,3,4. Here we designed, expressed and tested the human basophil and mast-cell inhibitory function of a novel chimeric fusion protein, whose structure is gHinge-CHg2-CHg3-15aa linker-CHe2-CHe3-CHe4. This Fcg–Fce fusion protein was expressed as the predicted 140-?D dimer that reacted with anti-human e- and g-chain specific antibodies. Fcg–Fce bound to both human FceRI and FcgRII. It also showed dose- and time-dependent inhibition of antigen-driven IgE-mediated histamine release from fresh human basophils sensitized with IgE directed against NIP (4-hydroxy-3-iodo-5-nitrophenylacetyl). This was associated with altered Syk signaling. The fusion protein also showed increased inhibition of human anti-NP (4-hydroxy-3-nitrophenylacetyl) and anti-dansyl IgE-mediated passive cutaneous anaphylaxis in transgenic mice expressing human FceRIa. Our results show that this chimeric protein is able to form complexes with both FceRI and FcgRII, and inhibit mast-cell and basophil function. This approach, using a Fcg–Fce fusion protein to co-aggregate FceRI with a receptor containing an immunoreceptor tyrosine-based inhibition motif, has therapeutic potential in IgE- and FceRI-mediated diseases.

Additional Information

Nature Medicine, 2002; 8:518-21.
Language: English
Date: 2002
mast cells, human basophils, allergey, Fc receptors, histamine release

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