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Review
. 2021 Jul 5;10(7):1697.
doi: 10.3390/cells10071697.

Tuning IgE: IgE-Associating Molecules and Their Effects on IgE-Dependent Mast Cell Reactions

Tomoaki Ando  1 , Jiro Kitaura  1   2
Affiliations
Review

Tuning IgE: IgE-Associating Molecules and Their Effects on IgE-Dependent Mast Cell Reactions

Tomoaki Ando et al. Cells. .

Abstract

The recent emergence of anti-immunoglobulin E (IgE) drugs and their candidates for humans has endorsed the significance of IgE-dependent pathways in allergic disorders. IgE is distributed locally in the tissues or systemically to confer a sensory mechanism in a domain of adaptive immunity to the otherwise innate type of effector cells, namely, mast cells and basophils. Bound on the high-affinity IgE receptor FcεRI, IgE enables fast memory responses against revisiting threats of venoms, parasites, and bacteria. However, the dysregulation of IgE-dependent reactions leads to potentially life-threatening allergic diseases, such as asthma and anaphylaxis. Therefore, reactivity of the IgE sensor is fine-tuned by various IgE-associating molecules. In this review, we discuss the mechanistic basis for how IgE-dependent mast cell activation is regulated by the IgE-associating molecules, including the newly developed therapeutic candidates.

Keywords: CD23; FcεRI; IgE; basophils; glycosylation; histamine-releasing factor (HRF); mast cells; omalizumab; structure.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
FcεRI activation. Upon FcεRI aggregation, Lyn initiates downstream signaling events through phosphorylation of ITAMs on FcεRI β and γ. Syk binds phosphorylated γ ITAM, and Lyn phosphorylates tyrosine residue of FcεRIγ-bound Syk. Activated Lyn and Syk further phosphorylate many downstream signaling molecules, leading to degranulation and de-novo synthesis of chemokines, cytokines, and lipid mediators. Under strong stimuli, Lyn recruits SHIP1 and SHP-1 via the phosphorylated FcεRI β ITAM and suppresses the reaction.
Figure 2
Figure 2
Differential mast cell activation by various antigens. (A) Effects of antigen-specific IgE occupancy on mast cell surface FcεRIs. (B) Effects of antigen-binding durations. (C) Effects of affinity between IgE and its cognate antigens. The antigen concentration is adjusted so that the phosphorylation levels of FcεRIβ and γ chains are similar. Abundant low-affinity antigens induce few and large clusters, while a small amount of high-affinity antigens induce many small clusters. (D) Effects of spacing between antigen epitopes. (E) Effects of antigen valency and/or IgE clonality. (F) Effects of affinity of different clones against the same antigen.
Figure 3
Figure 3
Schematic representation of human IgG1 and IgE. (A) The extended conformations. The three-dimensional coordination (front or back) is shown. F, front; B, back. (B) The receptor bound conformations. Please note that IgE Fab is almost in the upright position, suitable for sensing its target antigens.
Figure 4
Figure 4
Schematic representation of two major conformational concepts. (A) An extended conformation of IgE-Fc. The front–back coordination is also described. (B) The bent conformation. (C) The concept of “closed” and “open” conformations.
Figure 5
Figure 5
A summary of IgE-associating molecules and their binding sites.
See this image and copyright information in PMC

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