Repeated FcεRI triggering reveals modified mast cell function related to chronic allergic responses in tissue

Background Activation of mast cells through FceRI plays an important role in acute allergic reactions. However, little is known about the function of mast cells in patients with chronic allergic inflammation or the effect of repeated FceRI triggering occurring in such responses. Objective We aimed to identify changes in mast cell function after repeated FceRI triggering and to correlate these changes to chronic allergic responses in tissue. Methods Human cord blood–derived mast cells were treated for 2 weeks with anti-IgE. The function of naive or treated mast cells was analyzed by means of RNA sequencing, quantitative RT-PCR, flow cytometry, and functional assays. Protein secretion was measured with ELISAs and multiplex assays. Results We observed several changes in mast cell function after repeated anti-IgE triggering. Although the acute response was dampened, we identified 289 genes significantly upregulated after repeated anti-IgE. Most of these genes (84%) were not upregulated after a single anti-IgE stimulus, indicating a significantly different response mode characterized by increased antigen presentation, response to bacteria, and chemotaxis. Changes in mast cell function were related to changes in expression of the transcription factors RXRA and BATF and others. Importantly, we found a substantial overlap between genes upregulated after repeated anti-IgE triggering and genes upregulated in tissue from patients with chronic allergy, in particular those of patients with chronic rhinosinusitis. Conclusion Our study provides evidence for intrinsic modulation of mast cell function on repeated FceRI-mediated activation. The overlap with gene expression in tissues is suggestive of a direct link between repeated IgE-mediated activation of mast cells and chronic allergy.