Activating and inhibitory signaling in mast cells: New opportunities for therapeutic intervention?
Vanessa L. Ott, PhD and John C. Cambier, PhD
Immune responses are tightly controlled by the activities of both activating and inhibitory signals. At the cellular level, these signals are generated through engagement of membrane-associated receptors and coreceptors.
The high-affinity IgE receptor FcϵRI is expressed on mast cells and basophils and, on cross-linking by multivalent antigen (allergen), stimulates the release of inflammatory mediators that induce acute allergic responses.
Activation signals mediated by a variety of immune receptors (eg, B-cell receptor, T-cell receptor, and FcϵRI) are subject to negative regulation by a growing family of structurally and functionally related inhibitory receptors.
Recent studies indicate that mast cells express multiple inhibitory receptors that may regulate FcϵRI-induced mast cell activation through similar mechanisms.
The ability of inhibitory receptors to attenuate IgE-mediated allergic responses implicates them as potential targets for therapeutic intervention in the treatment of atopic disease.
Indeed, coaggregation of activating and inhibitory receptors has been suggested as one possible mechanism to explain the beneficial effects of specific immunotherapy in the treatment of allergy.
In this review we summarize the current knowledge of inhibitory receptors expressed in mast cells and the mechanisms through which they regulate mast cell function. (J Allergy Clin Immunol 2000;106:429-40.)
Mast cells express multiple ITIM-containing inhibitory receptors that have the potential to regulate antigen-mediated FcϵRI signal transduction and cell activation.
The biologic significance of multiple inhibitory receptors is not well understood; however, identification of the li-gands for many of these receptors should provide insight into their role in the regulation of mast cell function.
Of the inhibitory receptors discussed above, only FcγRIIB is known to coaggregate with FcϵRI under physiologic conditions (ie, in the presence of allergen complexed with IgG) and may therefore be relevant to FcϵRI signaling in vivo. Coaggregation of FcγRIIB and FcϵRI suggests a possible mechanism to explain the beneficial effects of specific immunotherapy in the treatment of allergy.
As increasing doses of allergen are administered to allergic patients, an allergen-specific IgG response develops, leading to the formation of allergen-IgG complexes that are postulated to inhibit IgE-induced mast cell activation by coaggregating FcϵRI and FcγRIIB.
This mechanism of inhibition may have important implications in the treatment of atopic disease. For example, administering of allergen-IgG complexes to patients with allergic asthma significantly attenuated allergic symptoms.
Although the biologic function of many inhibitory receptors expressed in mast cells is not known, therapeutic strategies designed to coaggregate inhibitory receptors with FcϵRI may provide novel approaches for the treatment of atopic disease.