Allergen-specific IgG antibody signaling through FcγRIIb promotes food tolerance.

BACKGROUND: Patients with food allergy produce high-titer IgE antibodies that bind to mast cells through FcεRI and trigger immediate hypersensitivity reactions on antigen encounter. Food-specific IgG antibodies arise in the setting of naturally resolving food allergy and accompany the acquisition of food allergen unresponsiveness in oral immunotherapy. OBJECTIVE: In this study we sought to delineate the effects of IgG and its inhibitory Fc receptor, FcγRIIb, on both de novo allergen sensitization in naive animals and on established immune responses in the setting of pre-existing food allergy. METHODS: Allergen-specific IgG was administered to mice undergoing sensitization and desensitization to the model food allergen ovalbumin. Cellular and molecular mechanisms were interrogated by using mast cell- and FcγRIIb-deficient mice. The requirement for FcγRII in IgG-mediated inhibition of human mast cells was investigated by using a neutralizing antibody. RESULTS: Administration of specific IgG to food allergy-prone IL4raF709 mice during initial food exposure prevented the development of IgE antibodies, TH2 responses, and anaphylactic responses on challenge. When given as an adjunct to oral desensitization in mice with established IgE-mediated hypersensitivity, IgG facilitated tolerance restoration, favoring expansion of forkhead box protein 3-positive regulatory T cells along with suppression of existing TH2 and IgE responses. IgG and FcγRIIb suppress adaptive allergic responses through effects on mast cell function. CONCLUSION: These findings suggest that allergen-specific IgG antibodies can act to induce and sustain immunologic tolerance to foods.

A humanized mouse model of anaphylactic peanut allergy.

BACKGROUND: Food allergy is a growing health problem with very limited treatment options. Investigation of the immunologic pathways underlying allergic sensitization to foods in humans has been greatly constrained by the limited availability of intestinal tissue and gut-resident immune cells. Although mouse models have offered insights into pathways of food sensitization, differences between rodent and human immune physiology limit the extension of these findings to our understanding of human disease. OBJECTIVE: We sought to develop a strategy for the generation of mice with humanized adaptive immune systems, complete with tissue engraftment by human mast cells that are competent to mount specific IgE-mediated responses and drive systemic anaphylaxis on ingestion challenge. METHODS: Nonobese diabetic severe combined immunodeficient mice lacking the cytokine receptor common gamma chain (γc-/-) and carrying a human stem cell factor transgene were engrafted with human hematopoietic stem cells. The impact of peanut (PN) feeding and IgE neutralization on the development of immune responses, mast cell homeostasis, and anaphylactic food allergy was assessed in these animals. RESULTS: Humanized nonobese diabetic severe combined immunodeficient common gamma chain-deficient stem cell factor (huNSG) mice exhibited robust engraftment with functional human T and B lymphocytes and human mast cells were found in significant numbers in their tissues, including the intestinal mucosa. Following gavage feeding with PN, they mounted specific antibody responses, including PN-specific IgE. When enterally challenged with PN, they exhibited mast-cell-mediated systemic anaphylaxis, as indicated by hypothermia and increases in plasma tryptase levels. Anti-IgE (omalizumab) treatment ablated this anaphylactic response. CONCLUSIONS: huNSG mice provide a novel tool for studying food allergy and IgE-mediated anaphylaxis.

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

BACKGROUND: Food-induced anaphylaxis is triggered by specific IgE antibodies. Paradoxically, some subjects 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: We sought to test whether IgG antibodies induced by food immunotherapy prevent food-induced anaphylaxis and whether this occurs through the inhibitory receptor FcγRIIb. METHODS: Food allergy-susceptible Il4raF709 mice were enterally sensitized to ovalbumin (OVA). Similarly sensitized IgE-deficient (IgE(-/-)) Il4raF709 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 (BMMCs) exposed to allergen or to passively transfer allergy to naive hosts. In parallel experiments sera obtained from patients with peanut allergy before and after undergoing OIT were interrogated for their ability to enhance or suppress peanut-induced activation in an indirect assay by using basophils from nonallergic donors. RESULTS: Il4raF709 mice exhibited strong OVA-specific IgE responses. Their sera efficiently sensitized BMMCs 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.

Immunoglobulin E signal inhibition during allergen ingestion leads to reversal of established food allergy and induction of regulatory T cells.

Immunoglobulin E (IgE) antibodies are known for triggering immediate hypersensitivity reactions such as food anaphylaxis. In this study, we tested whether they might additionally function to amplify nascent antibody and T helper 2 (Th2) cell-mediated responses to ingested proteins and whether blocking IgE would modify sensitization. By using mice harboring a disinhibited form of the IL-4 receptor, we developed an adjuvant-free model of peanut allergy. Mast cells and IgE were required for induction of antibody and Th2-cell-mediated responses to peanut ingestion and they impaired regulatory T (Treg) cell induction. Mast-cell-targeted genetic deletion of the FcεRI signaling kinase Syk or Syk blockade also prevented peanut sensitization. In mice with established allergy, Syk blockade facilitated desensitization and induction of Treg cells, which suppressed allergy when transferred to naive recipients. Our study suggests a key role for IgE in driving Th2 cell and IgE responses while suppressing Treg cells in food allergy.

IL-10 suppresses IL-17-mediated dermal inflammation and reduces the systemic burden of Vaccinia virus in a mouse model of eczema vaccinatum.

Individuals with atopic dermatitis (AD) are susceptible to a severe, potentially fatal, systemic infection and inflammatory response following exposure to Vaccinia virus (VV). IL-10 acts both as an inducer of Th2 responses and as a regulator of T cell activation. It has been shown to limit skin inflammation elicited by contact sensitizers. AD exacerbations have been associated with decreased IL-10 function. We used IL-10(-/-) mice to test the role of the cytokine in VV immunity. They exhibited larger primary lesions and increased cutaneous neutrophil infiltration compared to wild-type (WT) counterparts. This was associated with enhanced production of IL-17A, IL-17F and CXCL2. Paradoxically, despite intact adaptive immune responses, tissue viral burdens were increased in IL-10(-/-) mice. These findings suggest that IL-10 is important in limiting skin inflammation induced by VV and that abnormal IL-17-driven neutrophil recruitment at the primary infection site in the skin results in increased systemic viral dissemination.