Activation/Inhibition of mast cells by supra-optimal antigen concentrations (1)
Mast cells (MCs) are hemopoietically derived tissue resident cells that are concentrated in tissues close to the external environment, i.e., the skin and mucosal membranes of the intestine and airway. MCs recognize multivalent allergens/antigens (Ags) via IgE immunoglobulins, which are bound to high-affinity IgE receptors (FcεRI) on the surface of the MCs. The FcεRI on murine MCs and basophils consists of an α-subunit, a β-subunit, and two disulfide-bridged γ- subunits (αβγ2).
The Ag dose-response curve of the FcεRI is a bell-shaped one showing weak responses at both low and high Ag concentrations (e.g. degranulation and proinflammatory cytokine production).
The in-solution precipitin curves, interpretation of the bell-shaped Ag/IgE-induced dose-response curve was often as sketched. Specifically, a sub- optimal dose of multivalent Ag (i. e. a high Ab/Ag ratio) was thought to cross-link only a few IgE-bound FcεRIs, resulting in a weak activation of downstream signaling pathways and effector functions. An optimal Ag concentration, reflecting the zone of equivalence, was thought to optimally cross-link all IgE-bound receptors, thus causing strong activation of Ag-triggered signaling pathways and maximal induction of effector functions. Increasing the Ag dose to the so-called supra-optimal concentration range (i. e. a low Ab/ Ag ratio) was then thought to result in the formation of monovalent complexes with every IgE binding “its own” Ag and thus Ag-mediated cross-links between different IgE-bound FcεRIs were lost.
Lyn was most activated under supra-optimal conditions, resulting in pronounced β-subunit ITAM as well as SHIP1 tyrosine phosphorylation and suppressed degranulation as well as cytokine production. Several proteins can be assigned inhibitory functions in response to supra-optimal Ag concentrations. To accomplish the bell-shaped dose-response curve of FcεRI-mediated MC activation, both positive and negative signals have to be generated and integrated to deter- mine the quantity as well as the quality of the response. Thus, altered positive signaling might result in stronger attenuation at high Ag concentrations.
