Multiple defects in Fc epsilon RI signaling in Syk-deficient nonreleaser basophils and IL-3-Induced recovery of Syk expression and secretion

Human basophils respond to Ag-induced cross-linking of their high affinity IgE receptor, Fc epsilon RI, by releasing histamine and other mediators Fro m granules, producing IL-4 and other cytokines and, as shown in this study, by Forming membrane ruffles and showing increased very late Ag-4 (VLA-4)-m ediated adhesion to VCAM-1-expressing target cells. We have identified five blood donors whose basophils lack detectable levels of the Fc epsilon RI-a ssociated protein tyrosine kinase, Syk. Despite showing no obvious ultrastr uctural differences from normal basophils, nonreleaser basophils fail to fo rm membrane ruffles, to show increased VLA-4-mediated adhesive activity, or to produce IL-4 in response to Fc epsilon RI cross-linking. Although Syk p rotein levels are suppressed in basophils from all five donors, Syk mRNA is consistently present. Furthermore, culturing nonreleaser basophils for 4 d ays with IL-3 restores Syk protein expression and Fc epsilon RI-mediated hi stamine release. Understanding the reversible suppression of Syk protein ex pression in nonreleaser basophils, and learning to replicate this property in patients with allergic inflammation could be a powerful and specific way to limit symptomatic disease.