IgE and IgG Antibodies as Regulators of Mast Cell and Basophil Functions in Food Allergy

Abstract

Food allergy is a major health issue, affecting the lives of 8% of U.S. children and their families. There is an urgent need to identify the environmental and endogenous signals that induce and sustain allergic responses to ingested allergens. Acute reactions to foods are triggered by the activation of mast cells and basophils, both of which release inflammatory mediators that lead to a range of clinical manifestations, including gastrointestinal, cutaneous, and respiratory reactions as well as systemic anaphylaxis. Both of these innate effector cell types express the high affinity IgE receptor, FcϵRI, on their surface and are armed for adaptive antigen recognition by very-tightly bound IgE antibodies which, when cross-linked by polyvalent allergen, trigger degranulation. These cells also express inhibitory receptors, including the IgG Fc receptor, FcγRIIb, that suppress their IgE-mediated activation. Recent studies have shown that natural resolution of food allergies is associated with increasing food-specific IgG levels. Furthermore, oral immunotherapy, the sequential administration of incrementally increasing doses of food allergen, is accompanied by the strong induction of allergen-specific IgG antibodies in both human subjects and murine models. These can deliver inhibitory signals via FcγRIIb that block IgE-induced immediate food reactions. In addition to their role in mediating immediate hypersensitivity reactions, mast cells and basophils serve separate but critical functions as adjuvants for type 2 immunity in food allergy. Mast cells and basophils, activated by IgE, are key sources of IL-4 that tilts the immune balance away from tolerance and towards type 2 immunity by promoting the induction of Th2 cells along with the innate effectors of type 2 immunity, ILC2s, while suppressing the development of regulatory T cells and driving their subversion to a pathogenic pro-Th2 phenotype. This adjuvant effect of mast cells and basophils is suppressed when inhibitory signals are delivered by IgG antibodies signaling via FcγRIIb. This review summarizes current understanding of the immunoregulatory effects of mast cells and basophils and how these functions are modulated by IgE and IgG antibodies. Understanding these pathways could provide important insights into innovative strategies for preventing and/or reversing food allergy in patients.

Keywords: Fc receptor; IgE; IgG; basophil activation test; food allergy; mast cells; oral immunotherapy.

Figure 1

Mechanisms of IgG mediated inhibition. Antigen encounter by neighboring FcϵRI (green)-bound IgE (blue) on the surface of mast cells or basophils induces receptor crosslinking, phosphorylation of cytosolic immunoreceptor tyrosine-based activation motif (ITAM) sequences in the tetraspanning β- and disulfide-linked γ-chain dimers, and activation of various signaling pathways involving protein tyrosine kinases, such as Syk, and inositol intermediates, including PIP₃ (left panel). These positive signals culminate in the degranulation of the cell. Allergen specific IgG antibodies (orange) counter the effects of IgE in two ways, receptor-mediated inhibition (center panel) and steric blockade (right panel). In receptor-mediated inhibition, when polyvalent allergens are simultaneously engaged by FcϵRI-bound IgE and FcγRIIb (red)-bound IgG, crosslinking of the two receptors leads to phosphorylation of FcγRIIb cytosolic immunoreceptor tyrosine-based inhibition motifs (ITIMs). These recruit protein tyrosine phosphatases and inositol phosphatases, such as SHPs and SHIPs, respectively. Phosphatases can neutralize phosphoprotein (such as Syk) and phospholipid (such as PIP₃) signaling intermediates induced by FcϵRI activation. In steric blockade, IgG antibodies bind the allergen before it reaches receptor-bound IgE. By masking IgE binding epitopes, these blocking IgG antibodies inhibit interaction with IgE and thereby prevent FcϵRI-mediated mast cell activation.

Figure 2

Structures and functions of the low-affinity IgE receptor, CD23. CD23 is expressed as a multimer of subunits consisting of coiled-coil stalks with lectin-family domain heads that bind to IgE (upper panels). Membrane-bound CD23 can be converted to a soluble form that retains IgE-binding ability following cleavage at protease sites by endogenous (ADAM) or allergen (e.g. Der p 1) proteases. Various functions have been attributed to CD23 (lower panels). It can facilitate antigen uptake for presentation by B cells and antigen presenting cells to T cells (left panel) and mediate the transport of allergens across polarized epithelium in the gut and airway (center panel). CD23 also regulates IgE production; the transmembrane form on B cells suppresses their production of IgE and the soluble form, via interactions with B cell surface CD21 and IgE, enhances IgE production (right panel).

Figure 3

The indirect basophil activation test (iBAT) as a probe for inhibitory food allergen specific IgG. In this assay, basophils from a non-allergic donor are sensitized with IgE from an allergic donor, then incubated with serum to be queried (typically pre-OIT serum, post-OIT serum, or a mix of the two) and then exposed to allergen. Conditions assayed include (proceeding clockwise starting from top center): (A) basophil incubation with allergen in the absence of serum (no activation), (B) with serum from an allergic donor (full degranulation), (C) with post-OIT serum (suppressed activation), (D) with a mix of pre- and post-OIT serum (suppressed activation if inhibitory activity is present), (E) post-OIT serum with IgG removed (to query the contribution of IgG to suppression) and (F) post-OIT serum with antibodies to FcγRIIb (to test whether inhibition is receptor-mediated).

Figure 4

Effects of mast cells on adaptive immune responses to food allergens and the regulation of these effects by IgE and IgG antibodies. Food antigens pass through damaged epithelium, specialized intraepithelial passages (8), or are sampled by antigen presenting cells (APCs). Epithelial cells subjected to stress or microbial signals secrete cytokines such as IL-25 and IL-33 that promote the activity of various cellular mediators involved in the breakdown of tolerance. Mucosal APCs present antigen to naïve T cells that mature into Th2 cells in the context of a Th2-conducive environment. Th2 cells are known to both depend on IL-4 for their differentiation and survival, and to produce IL-4 that drives IgE isotype switching by B cells and mast cell expansion, while inhibiting the production of regulatory T cells (Tregs) and subverting their function. Mast cells sensitized with allergen-specific IgE and type 2 innate lymphoid cells (ILC2s) provide a priming source of IL-4, initiating and sustaining the Th2 environment. In contrast, allergen-specific IgG antibodies induced during natural allergen resolution or during OIT can inhibit mast cell activation via signaling through FcγRIIb receptor. Inhibition of mast cell activation by IgG can break the positive feedback loop between mast cells and Th2.