Mast cell desensitization inhibits calcium flux and aberrantly remodels actin

Abstract

Rush desensitization (DS) is a widely used and effective clinical strategy for the rapid inhibition of IgE-mediated anaphylactic responses. However, the cellular targets and underlying mechanisms behind this process remain unclear. Recent studies have implicated mast cells (MCs) as the primary target cells for DS. Here, we developed a murine model of passive anaphylaxis with demonstrated MC involvement and an in vitro assay to evaluate the effect of DS on MCs. In contrast with previous reports, we determined that functional IgE remains on the cell surface of desensitized MCs following DS. Despite notable reductions in MC degranulation following DS, the high-affinity IgE receptor FcεRI was still capable of transducing signals in desensitized MCs. Additionally, we found that displacement of the actin cytoskeleton and its continued association with FcεRI impede the capacity of desensitized MCs to evoke the calcium response that is essential for MC degranulation. Together, these findings suggest that reduced degranulation responses in desensitized MCs arise from aberrant actin remodeling, providing insights that may lead to improvement of DS treatments for anaphylactic responses.

Blocking antibodies induced by peanut oral and sublingual immunotherapy suppress basophil activation and are associated with sustained unresponsiveness

“…Future experiments are needed to determine intrinsic cellular changes in subjects actively undergoing immunotherapy in addition to the plasma changes observed in these studies. For example, we have previously demonstrated impaired calcium flux due to actin rearrangement following desensitization in model systems . The findings also assist in the understanding of the changes that distinguish subjects that develop SU.…”

Drug Hypersensitivity and Desensitizations: Mechanisms and New Approaches

“…This in vitro model of rapid MCs/IgE DS protocol has been reproduced in many studies and has consistently shown the inhibition of all of the MC activation hallmarks (Figure 3 and Figure 4) [45,53,54]. As shown in Figure 3 and Figure 4, compared to activated cells, desensitized cells had a diminished immediate release of β-hexosaminidase (Figure 3a), early and late TNF-α (Figure 3b), IL-6 production (Figure 3c), de novo synthesis of lipid mediators (Figure 3d), and calcium flux (Figure 3e) [53].…”

“…This demonstrates that the mechanism of DS is an antigen-specific process and does not disable the IgE bounded FcεRI receptor for other antigens [45]. …”

Recovery from desensitization of IgE‐dependent responses in human lung mast cells

“…At the cellular level, there have been a number of studies of desensitization using both basophil and mast cell models . Emphasis has been placed on determining whether subthreshold dosing of the cells in vitro mimics the process observed in vivo.…”