Dependence of Optimal Histamine Release on Cell Surface IgE Density on Human Basophils: Nature of the Stimulus

Background: The characteristics of the aggregation reaction that follows allergen binding to cell surface IgE on basophils and mast cells depend on a variety of factors that include the density of IgE and the affinity of the allergen for IgE. For simple bivalent stimuli, one prediction is that the location of the optimum for aggregation is not dependent on IgE density, only the affinity for IgE. However, this behavior does not occur for stimulation with an anti-IgE antibody (Ab) during the treatment of patients with omalizumab. Methods: This study re-examined the stability of the optimum for histamine release, relative to cell surface IgE density, using the simple bivalent penicillin hapten (BPO2) or a bivalent monoclonal anti-IgE Ab. Results: The results validated one prediction for one bivalent hapten, BPO2. Across a range of BPO-specific IgE density of 270-23,500/cell, optimal histamine release remained constant (10 nM BPO2). In contrast, across a range of approximately 6,000-110,000/cell, optimal histamine release shifted 8- to 30-fold for anti-IgE Ab. The distinguishing characteristic between the 2 bivalent stimuli was the difference in their crosslink re-equilibration. Recent modeling of histamine release suggested that the SYK-to-receptor ratio could determine the position of histamine release optimum. The study showed that there were significant shifts in the SYK-to-receptor ratio (from 1: 6 to 5: 1) but the basophil's ability to sense this ratio was restricted to transient crosslinks, as occurred with anti-IgE Ab. Conclusions: The results suggest that ligand crosslinking dynamics couple with SYK and receptor expression levels to determine qualitative characteristics of the dose response curve for secretion.