Abstract
Release of pro-inflammatory mediators by mast cells is a key feature of allergic disease. The ‘dogma’ is that IgE molecules merely sensitise mast cells by binding FcεRI prior to cross-linking by multivalent allergen, receptor aggregation and mast cell activation. However, certain monoclonal IgE antibodies have been shown to elicit mast cell activation in an antigen-independent cytokinergic manner, and DNP-specific murine SPE-7 IgE is the most highly cytokinergic antibody known. We show that both monovalent hapten and recombinant SPE-7 IgE Fab inhibit its cytokinergic activity as measured by mast cell degranulation and TNF-α release. Using SPE-7 IgE, a non-cytokinergic human IgE and a poorly cytokinergic murine IgE, we reveal that interaction of the Fab region of ‘free’ SPE-7 IgE with the Fab of FcεRI-bound SPE-7 IgE is the basis of its cytokinergic activity. We rule out involvement of IgE Fc, Cε1 and Cλ/κ domains, and propose that ‘free’ SPE-7 IgE binds to FcεRI-bound SPE-7 IgE by an Fv-Fv interaction. Initial formation of a tri-molecular complex (one ‘free’ IgE molecule cross-linking two receptor-bound IgE molecules) leads to capture of further ‘free’ and receptor-bound IgEs to form larger clusters that trigger mast cell activation.
Highlights
Release of pro-inflammatory mediators by mast cells is a key feature of allergic disease
Using SPE-7 IgE, a non-cytokinergic human IgE and a poorly cytokinergic murine IgE, we reveal that interaction of the Fab region of ‘free’ SPE-7 IgE with the Fab of FceRI-bound SPE-7 IgE is the basis of its cytokinergic activity
In the present work we have demonstrated that human mast cells of the LAD-2 cell line can be activated by highly cytokinergic murine SPE-7 IgE (Figures 1B and C)
Summary
Release of pro-inflammatory mediators by mast cells is a key feature of allergic disease. Certain monoclonal IgE antibodies have been shown to elicit mast cell activation in an antigen-independent cytokinergic manner, and DNP-specific murine SPE-7 IgE is the most highly cytokinergic antibody known. We show that both monovalent hapten and recombinant SPE-7 IgE Fab inhibit its cytokinergic activity as measured by mast cell degranulation and TNF-a release. The ‘dogma’ of mast cell activation is that IgE bound to its high-affinity receptor, FceRI, must be cross-linked by multivalent antigen (allergen) to cause receptor aggregation, signal transduction and the release of pro-inflammatory mediators that initiate the allergic response[1,2,3]. It appears that antigen binding may interfere with a critical interaction between the ‘free’ IgE molecules in solution and a site on the mast cell surface, culminating in cytokinergic activity
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