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- Title
A novel human immunoglobulin Fcγ?Fcε bifunctional fusion protein inhibits FcεRI-mediated degranulation.
- Authors
Zhu, Daocheng; Kepley, Christopher L.; Zhang, Min; Zhang, Ke; Saxon, Andrew
- Abstract
Human mast cells and basophils that express the high-affinity immunoglobulin E (IgE) receptor, Fcε receptor 1 (FcεRI), have key roles in allergic diseases. FcεRI cross-linking stimulates the release of allergic mediators. Mast cells and basophils co-express FcγRIIb, a low affinity receptor containing an immunoreceptor tyrosine-based inhibitory motif and whose co-aggregation with FcεRI can block FcεRI-mediated reactivity. Here we designed, expressed and tested the human basophil and mast-cell inhibitory function of a novel chimeric fusion protein, whose structure is γHinge-CHγ2-CHγ3-15aa linker-CHε2-CHε3-CHε4. This Fcγ?Fcε fusion protein was expressed as the predicted 140-κD dimer that reacted with anti-human ε- and γ-chain specific antibodies. Fcγ?Fcε bound to both human FcεRI and FcγRII. 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 FcεRIα. Our results show that this chimeric protein is able to form complexes with both FcεRI and FcγRII, and inhibit mast-cell and basophil function. This approach, using a Fcγ?Fcε fusion protein to co-aggregate FcεRI with a receptor containing an immunoreceptor tyrosine-based inhibition motif, has therapeutic potential in IgE- and FcεRI-mediated diseases.
- Subjects
BASOPHILS; RESPONSE inhibition; PROTEINS
- Publication
Nature Medicine, 2002, Vol 8, Issue 5, p518
- ISSN
1078-8956
- Publication type
Article
- DOI
10.1038/nm0502-518