Abstract
Mast cells play a key role in allergic reaction and disorders through the high affinity receptor for IgE (FcεRI) which is primarily activated by IgE and antigen complex. In humans, mast cells express two types of FcεRI on the cell surface, tetrameric αβγ2 and trimeric αγ2, whereas in mice, the tetrameric αβγ2 type is exclusively expressed. In human allergic inflammation lesions, mast cells increase in number and preferentially express the αβγ2 type FcεRI. By contrast, in the lesion of non-allergic inflammation, mast cells mainly express the αγ2type. Since the β chain amplifies the expression and signaling of FcεRI, mast cell effector functions and allergic reaction in vivo are enhanced in the presence of the β chain. In contrast, a truncated β chain-isoform (βT) inhibits FcεRI surface expression. The human FcεRIβ gene contains seven exons and a repressor element located in the forth intron, through which FcεRIβ transcription is repressed in the presence of GM-CSF. Regarding the additional signal regulatory function of the β chain, the β chain ITAM has dual (positive and negative) functions in the regulation of the mast cell activation. Namely, the FcεRIβ chain ITAM enhances the mast cell activation signal triggered by a low-intensity (weak) stimulation whereas it suppresses the signal triggered by high-intensity (strong) stimulation. In an oxazolone-induced mouse CHS model, IgE-mediated mast cell activation is required and the β chain ITAM is crucially involved. Adenosine receptor, one of the GPCRs, triggers a synergistic degranulation response with FcεRI in mast cells, for which the β chain ITAM critically plays positive role, possibly reflecting the in vivo allergic response. These regulatory functions of the FcεRIβ ITAM finely tune FcεRI-induced mast cell activation depending on the stimulation strength, enabling the FcεRIβ chain to become a potential molecular target for the development of new strategies for therapeutic interventions for allergies.
Highlights
Mast cells reside in virtually all organs, among which they are distributed in a great number in tissues at the interface between inside and outside environments, such as the skin and mucosal membrane of the airway and intestine, where they are in close contact with the outside environment and play a key role in allergic reaction and disorders
In this review we have mainly focused on recent findings regarding the roles of the FcεRIβ chain, especially the dual regulatory roles of the FcεRIβ chain immunoreceptor tyrosine-based activation motif (ITAM), both in vitro and in vivo
The N-terminal canonical tyrosine (Y219) in the FcεRIβ chain ITAM is essential for the modulation of the effects of the FcεRIβ chain because of its ability to associate with Lyn upon FcεRI engagement, whereas the other canonical tyrosine (Y229) is dispensable for the interaction of the FcεRIβ chain with Lyn
Summary
Mast cells reside in virtually all organs, among which they are distributed in a great number in tissues at the interface between inside and outside environments, such as the skin and mucosal membrane of the airway and intestine, where they are in close contact with the outside environment and play a key role in allergic reaction and disorders. The FcεRIβ chain can enhance FcεRI cell surface expression in humans by promoting the maturation (glycosylation) of the FcεRIα chain protein (Donnadieu et al, 2000b). Studies by our group recently revealed novel functions of the FcεRIβ chain ITAM and Lyn in the negative regulation of cell activation and effector functions.
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