Oral immunotherapy induces IgG antibodies that act through FcγRIIb to suppress IgE-mediated hypersensitivity

Abstract

Background Food anaphylaxis is triggered by specific IgE antibodies. Paradoxically, some individuals with significant IgE levels can ingest allergenic foods without incident. Similarly, subjects completing oral immunotherapy (OIT) tolerate food challenges despite persistent high-titer food-specific IgE. Objective To test whether IgG antibodies induced by food immunotherapy prevent food-induced anaphylaxis, and whether this occurs via the inhibitory receptor FcγRIIb. Methods Food allergy-susceptible Il4raF709 mice were enterally sensitized to ovalbumin (OVA). Similarly sensitized IgE-deficient Il4raF709/IgE−/− mice, which can ingest OVA without anaphylaxis, were subjected to a high-dose enteral OVA desensitization protocol (OIT). Sera from both groups were tested for the ability to activate or inhibit bone marrow mast cells (BMMC) exposed to allergen, or to passively transfer allergy to naïve hosts. In parallel experiments, sera obtained from peanut allergic patients before and after undergoing OIT were interrogated for their ability to enhance or suppress peanut-induced activation in an indirect assay using basophils from non-allergic donors. Results Il4raF709 mice exhibited strong OVA-specific IgE responses. Their sera efficiently sensitized BMMC for activation by antigen challenge. Sera from Il4raF709/IgE−/− mice subjected to OVA OIT suppressed BMMC responses. This inhibition was IgG-mediated and FcγRIIb-dependent. Similarly, pre-OIT, but not post-OIT sera from patients efficiently sensitized basophils for peanut-induced activation. IgG antibodies in post-OIT sera suppressed basophil activation by pre-OIT sera. This inhibition was blocked by antibodies against FcγRII. Conclusion Food-specific IgG antibodies, such as those induced during OIT, inhibit IgE-mediated reactions. Strategies that favor IgG responses might prove useful in the management of food allergy.

FOXP3+ Tregs require WASP to restrain Th2-mediated food allergy

“…that had been found to not be sensitized to food ( Figure 2C). The appearance of lysosomal-associated membrane protein 1 (LAMP-1) at the cell surface of mast cells is an established surrogate marker for antigen/IgE-mediated histamine release (28,29), and we found that WT mast cells loaded with serum from food-sensitized Was -/-mice degranulated in response to stimulation with an antigen extract from conventional chow, but not in response to an extract from a protein-free, amino acid-based elemental diet ( Figure 2C). In contrast, mast cells loaded with serum from nonfood-sensitized animals were not activated by either food extract, which further demonstrated that IgE-dependent degranulation was antigen specific and established that screening of antibody IgG1 was observed (Supplemental Figure 1D).…”

Current developments for improving efficacy of allergy vaccines

“…A recent systematic review and meta-analysis of research studies in OIT for food allergies, with 18 RCT and 3 controlled clinical trials, demonstrated that OIT can achieve desensitization to a range of foods with some evidence for immunomodulatory changes, including a decrease in skin prick test response to the relevant food allergen and an increase in allergen-specific IgG 4 [95]. Experimental evidence has demonstrated that IgG antibodies suppress IgE-mediated food hypersensitivity via the inhibitory receptor FcgRIIb [96].…”

Innate myeloid cells under the control of adaptive immunity: the example of mast cells and basophils

“…Similarly, and importantly, pre-immunotherapy but not post-immunotherapy sera from peanut-allergic patients efficiently sensitized normal basophils for peanut-induced activation, and IgG antibodies in post-immunotherapy serum inhibited the activation of basophils sensitized by pre-immunotherapy serum. This inhibition was blocked by anti-FcgRIIB antibodies [48 ]. Inhibition of IgE-dependent mast cell and basophil activation by food-specific IgG antibodies induced by oral immunotherapy may thus contribute to the beneficial effects of this treatment.…”