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.
Highlights
Global surveillance by the World Allergy Organization, shows that the prevalence of food allergies has been rising over the last decade in both developed and developing countries [1]
Stranks et al hypothesized that IgE blockade might alter the immunological changes that are induced by oral immunotherapy (OIT). The authors tested this in the PRROTECT cohort of highly peanut-allergic subjects, randomized to receive either standard OIT or OIT in combination with omalizumab [139]. While their analysis was somewhat limited by the fact that patients had the option to switch to open-label omalizumab part way through the study, which most did, the analysis revealed that those initially assigned to the omalizumab group, who received the initial peanut dose escalation in the setting of IgE blockade, exhibited a more robust induction of anti-peanut IgG antibodies, one of the key markers of successful OIT [139]
FcgRIIb-/- mice lack the receptor on all cells that would normally express the receptor, reconstitution of the mice with cultured FcgRIIb+/+ mast cells from wild type donors restores the protective effects exerted by passive administration of exogenous allergen-specific IgG, confirming the central role of mast cell FcgRIIb in regulating IgE-mediated anaphylaxis in vivo [176]
Summary
IgE and IgG Antibodies as Regulators of Mast Cell and Basophil Functions in Food Allergy. 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. 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 FcgRIIb that block IgE-induced immediate food reactions.
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