Antigen-Induced Reduction in Mast Cell and Basophil Functional Responses due to Reduced Syk Protein Levels

Background: The high-affinity IgE receptor, FcεRI, is unresponsive on mast cells and basophils from people in several populations through an unknown mechanism. Similarly, FcεRI-positive basophils from ‘nonreleasers’ are IgE-unresponsive and are deficient in the tyrosine kinase Syk. Objective: To test the hypothesis that cross-linking FcεRI on mast cells and basophils leads to FcεRI nonresponsiveness through reduction in Syk protein levels. Methods: Human mast cells and basophils were used to determine if FcεRI hyporesponsiveness correlated with reduced Syk levels. Results: It is shown that suboptimal antigen challenge, that did not lead to significant mediator release, induced nonresponsiveness and correlated with reduced Syk. Other IgE-associated signaling molecules were unaffected by the same treatment. The ability of IgE-unresponsive mast cells to regain FcεRI responsiveness is paralleled by increased cellular Syk levels in vitro. The reduction of Syk levels with suboptimal antigen concentrations was calcium independent and mediated through a proteasome-dependent mechanism. Conclusion: These findings confirm and extend our knowledge about a novel regulatory mechanism for maintaining FcεRI in a quiescent state. This mechanism may also explain why low concentrations of allergen given to patients during allergen immunotherapy induce FcεRI nonresponsiveness and therapeutic benefit without inducing systemic anaphylaxis.