Sensitization or Tolerance?
Regulation of Mast Cell Activation by Fc Receptors
Laboratoire d'Immunologie Cellulaire & Clinique, INSERM U.255,
Institut Biomédical des Cordeliers,
Mast cell activation is regulated, positively and negatively, by membrane receptors. These include activating and inhibitory Fc Receptors (FcRs) that are coexpressed on single cells. Biological responses of mast cells result from the integration of positive and negative signals delivered by FcRs that are coengaged by immune complexes.
Activating receptors include high-affinity IgE receptors (FcεRI) and low-affinity IgG receptors (FcγRIIIA in mice, FcγRIIA/C in humans). They contain one or several Immunoreceptor Tyrosine-based Activation Motifs (ITAMs). When activating receptors are aggregated at the cell surface by multivalent ligands, their ITAMs are phosphorylated by src family protein tyrosine kinases. Phosphorylated ITAMs recruit intracellular molecules that interact with each other in an ordered fashion and generate intracellular signals. These signals activate metabolic pathways which lead to an increase in the intracellular Ca2+ concentration and to the activation of MAP kinases. Altogether, these changes induce the exocytosis of mast cell granules, the release of lipid mediators and the secretion of pro-inflammatory cytokines.
Inhibitory receptors include other low-affinity IgG receptors, FcγRIIB. These receptors contain an Immunoreceptor Tyosine-based Inhibition Motif (ITIM). When FcγRIIB are coaggregated with ITAM-containing receptors, their ITIM is phosphorylated by the same src kinases that phosphorylate ITAMs. The phosphorylated ITIM recruits the SH2 domain-containing phosphatidylinositol 5-phosphatases SHIP1 and SHIP2. These phosphatases extinguish the Ca2+ response and MAP kinase activation and, as a consequence, inhibit all mast cell secretory responses. FcγRIIB were demonstrated to be capable of inhibiting FcεRI- (both in mouse mast cells and in human basophils), FcγRIIIA-(in mouse mast cells) and FcγRIIA- (in human basophils) dependent cell activation.
Because, in addition to IgE receptors, mouse mast cells and human
basophils coexpress both activating and inhibitory IgG receptors,
all these receptors with antagonistic properties are likely to
be coaggregated when IgG immune complexes bind to IgE-sensitized
cells. We found that FcγRIIB and FcγRIIIA could behave as inhibitors
and as amplifiers of FcεRI-dependent cell responses, respectively.
Whether IgG-mediated FcγRIIB-dependent negative regulation or
FcγRIIIA-dependent positive regulation is dominant depends on
several parameters including the degree of FcεRI aggregation.
We propose that these parameters might be among those that prevent
the development of allergic symptoms in normal individuals but,
for an unknown reason, not in allergic patients. If so, IgG receptors
could be potential targets for new therapeutic approaches of allergic