Allergen-specific IgA and IgG antibodies as inhibitors of mast cell function in food allergy.

Food allergy, a group of adverse immune responses to normally innocuous food protein antigens, is an increasingly prevalent public health issue. The most common form is IgE-mediated food allergy in which food antigen-induced crosslinking of the high-affinity IgE-receptor, FcεRI, on the surface of mast cells triggers the release of inflammatory mediators that contribute to a wide range of clinical manifestations, including systemic anaphylaxis. Mast cells also play a critical function in adaptive immunity to foods, acting as adjuvants for food-antigen driven Th2 cell responses. While the diagnosis and treatment of food allergy has improved in recent years, no curative treatments are currently available. However, there is emerging evidence to suggest that both allergen-specific IgA and IgG antibodies can counter the activating effects of IgE antibodies on mast cells. Most notably, both antigen-specific IgA and IgG antibodies are induced in the course of oral immunotherapy. In this review, we highlight the role of mast cells in food allergy, both as inducers of immediate hypersensitivity reactions and as adjuvants for type 2 adaptive immune responses. Furthermore, we summarize current understanding of the immunomodulatory effects of antigen-specific IgA and IgG antibodies on IgE-induced mast cell activation and effector function. A more comprehensive understanding of the regulatory role of IgA and IgG in food allergy may provide insights into physiologic regulation of immune responses to ingested antigens and could seed novel strategies to treat allergic disease.

IgG:FcγRIIb signals block effector programs of IgE:FcεRI-activated mast cells but spare survival pathways.

BACKGROUND: IgE-induced mast cell (MC) degranulation can be inhibited by IgG antibodies, signaling via FcγRIIb, but the effects of IgG on IgE-induced MC transcription are unknown. OBJECTIVE: We sought to assess inhibitory IgG:FcγRIIb effects on MC responses to IgE using complementary transcriptomic and functional approaches. METHODS: RNA sequencing was performed on bone marrow-derived MCs from wild-type and FcγRIIb-deficient mice to identify genes activated following IgE receptor crosslinking that were further modulated in the presence of antigen-specific IgG in an FcγRIIb-dependent fashion. Parallel analyses of signaling pathways and allergic responses in vivo were performed to assess the impact of these changes in gene expression. RESULTS: Rapid changes in the transcription of 879 genes occurred in MCs activated by IgE, peaking at 1 hour. Surprisingly, only 12% of these were altered by IgG signaling via FcγRIIb, including numerous transcripts involved in orchestrating type 2 responses linked to spleen tyrosine kinase signaling. Consistent with this finding, IgG suppressed IgE-induced phospho-intermediates in the spleen tyrosine kinase signaling pathway. In vivo studies confirmed that the IgG-mediated suppression of both systemic anaphylaxis and MC-driven tissue recruitment of inflammatory cells following allergen challenge was dependent on FcγRIIb. In contrast, genes in the STAT5a cell survival pathway were unaltered by IgG, and STAT5a phosphorylation increased after IgE-induced MC activation but was unaffected by IgG. CONCLUSIONS: Our findings indicate that inhibitory IgG:FcγRIIb signals block an IgE-induced proallergic program but spare a prosurvival program.