Synthetic Allergen Design
Reveals the Significance
of Moderate Affinity Epitopes in Mast Cell Degranulation
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Abstract
This study describes the design of a well-defined homotetravalent
synthetic allergen (HTA) system to investigate the effect of hapten–IgE
interactions on mast cell degranulation. A library of DNP variants
with varying affinities for IgE<sup>DNP</sup> was generated (<i>K</i><sub>d</sub> from 8.1 nM to 9.2 μM), and 8 HTAs spanning
this range were synthesized via conjugation of each DNP variant to
the tetravalent scaffold. HTAs with hapten <i>K</i><sub>d</sub> < 235 nM stimulated degranulation following a bell-shaped
dose response curve with maximum response occurring near the hapten <i>K</i><sub>d</sub>. HTAs with hapten <i>K</i><sub>d</sub> ≥ 235 nM failed to stimulate degranulation. To mimic physiological
conditions, the percent of allergen specific IgE on cell surface was
varied, and maximum degranulation occurred at 25% IgE<sup>DNP</sup>. These results demonstrated that moderate hapten–IgE affinities
are sufficient to trigger mast cell degranulation. Moreover, this
study established the HTA design as a well-defined, controllable,
and physiologically relevant experimental system to elucidate the
mast cell degranulation mechanism