In vivo priming of Fc alpha R functioning on eosinophils of allergic asthmatics

Inflammation in allergic asthma is characterized by an influx of eosinophil s and the presence of eosinophil products in the bronchial tissue. Orchestr ation of this inflammatory response is in part mediated by cytokines and ch emoattractants, but final activation can require additional stimuli. IgA, t he most abundant immunoglobulin at mucosal surfaces, is potentially a poten t trigger for eosinophil activation. Previously, we have shown that binding IgA-coated targets is dependent on in vitro stimulation of cells with cyto kines. Here, we demonstrate that eosinophils isolated from the blood of all ergic asthmatic patients bind IgA beads independently of prior in vitro sti mulation. Furthermore, we found that the proinflammatory cytokine, TNF-alph a, is a potent enhancer of IgA binding to eosinophils from allergic asthmat ics, and it does not activate Fc alphaR on eosinophils isolated from normal donors. The difference in IgA binding by Fc alpha Rs on normal and patient eosinophils might be explained by the activation of different signal trans duction pathways. Studying intracellular signaling, we found an enhanced ba sal activity of phosphatidylinositol 3-kinase (PI3K) in eosinophils derived from allergic asthmatics. Moreover, inhibition of PI3K in these cells bloc ked the background ant the TNF-alpha -induced IgA binding completely. In su mmary, these data demonstrate that the responsiveness of human eosinophils to TNF-alpha might be an important contribution for fine-tuning the allergi c inflammatory reaction. Furthermore, the preactivation of PI3K results in a broader sensitivity to subsequent challenge with inflammatory cytokines.