Cutting Edge: Death of a Dogma or Enforcing the Artificial: Monomeric IgE Binding May Initiate Mast Cell Response by Inducing Its Receptor Aggregation

Abstract

Several recent reports have suggested that binding monomeric IgE (mIgE) to its type 1 receptor, FcεRI, on mast cells induces important responses. These observations contradict the notion that it is the aggregation of this receptor that is essential for initiating mast cell response. In the present study, we suggest that the most probable causes for the reported observations are the experimental protocol used combined with the high expression levels of the FcεRI by mast cells. Specifically, we suggest using the published data and physicochemical calculations that the exceptionally high number of cell surface FcεRI-bound monoclonal IgE yields, in the two-dimensions of the cells’ membranes, a situation where even a low affinity of these mIgE for epitopes on their own structure or on another cell surface component may lead to their aggregation. Hence, we hypothesize that the reported response to mIgE binding is a result of such an FcεRI-IgE induced aggregation.

Mast Cell Survival and Activation by IgE in the Absence of Antigen: A Consideration of the Biologic Mechanisms and Relevance

“…A biophysical method termed time-resolved phosphorescence anisotropy measurement (that quantifies motions of phosphorescent dye-labeled membrane proteins in the nano-to microsecond range, thus assessing the size and rigidity of the membrane structures containing the labeled proteins) suggests that IgE(-Ag) also induces receptor aggregation (24). The enhancement in the affinity of binding an Ag-combining site of an IgE molecule to an epitope on another IgE was estimated by calculating the probability of finding as nearest neighbor a distinct receptor at distances between r 0 and r 0 ϩ⌬r on a cell surface (34). This simulation (r 0 ϭ 75Å and ⌬r ϭ 30Å) predicted a significant probability (Ͼ0.4 or ϳ0.1, respectively, for cells with 3 ϫ 10 5 (RBL-2H3 rat mast cells) or 5 ϫ 10 4 (mouse bone marrowderived mast cell (BMMC)) receptors per cell), with which IgEIgE interactions (presumed Fc⑀RI aggregations) take place on the cell surface at IgE concentrations Ͼ 1 g/ml in the absence of Ag.…”

A Crystallin Fold in the Interleukin-4-inducing Principle of Schistosoma mansoni Eggs (IPSE/α-1) Mediates IgE Binding for Antigen-independent Basophil Activation

“…Moreover, different monoclonal IgEs seem to differ in their ability to activate basophils, but the structural differences that account for the functional divergence are not known (43). In contrast, Schweitzer-Stenner and Pecht consider nonphysiological experimental conditions to cause the effects of monomeric IgE (44). Recently, however, the cross-linking model for cell activation has been challenged also for the T and B cell receptors (45,46).…”

Critical Role of Protein Kinase C βII in Activation of Mast Cells by Monomeric IgE

“…Previous studies have cast some doubt on the differences in signal transduction between monomeric IgE responses and antigen responses; they speculated that monomeric IgE can induce the Fc⑀RI-aggregation and that a similar signaling pathway is activated upon both responses with different intensities (10,18). Accumulating evidence has indicated that the Fc⑀RI-mediated activation of mast cells is finely tuned.…”

“…Indeed, Kitaura et al (10) demonstrated the increase in anisotropy of the surface Fc⑀RI of a rat mast cell line stimulated with monomeric IgE. Very recently, Schweitzer-Stenner and Pecht (18) performed a simulation analysis for the distance between the surface IgE molecules bound to the Fc⑀RI and proposed a hypothesis that monomeric IgE induces the receptor aggregation via low affinity interaction between the IgEs or between the IgE and another cell surface component.…”