Dataset Information

Mast cell heterogeneity underlies different manifestations of food allergy in mice.

ABSTRACT: Food can trigger a diverse array of symptoms in food allergic individuals from isolated local symptoms affecting skin or gut to multi-system severe reactions (systemic anaphylaxis). Although we know that gastrointestinal and systemic manifestations of food allergy are mediated by tissue mast cells (MCs), it is not clear why allergen exposure by the oral route can result in such distinct clinical manifestations. Our aim was to assess the contribution of mast cell subsets to different manifestations of food allergy. We used two common models of IgE-mediated food allergy, one resulting in systemic anaphylaxis and the other resulting in acute gastrointestinal symptoms, to study the immune basis of allergic reactions. We used responders and non-responders in each model system, as well as naïve controls to identify the association of mast cell activation with clinical reactivity rather than sensitization. Systemic anaphylaxis was uniquely associated with activation of connective tissue mast cells (identified by release of mouse mast cell protease (MMCP) -7 into the serum) and release of histamine, while activation of mucosal mast cells (identified by release of MMCP-1 in the serum) did not correlate with symptoms. Gastrointestinal manifestations of food allergy were associated with an increase of MMCP-1-expressing mast cells in the intestine, and evidence of both mucosal and connective tissue mast cell activation. The data presented in this paper demonstrates that mast cell heterogeneity is an important contributor to manifestations of food allergy, and identifies the connective tissue mast cell subset as key in the development of severe systemic anaphylaxis.

SUBMITTER: Benede S

PROVIDER: S-EPMC5784907 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Mast cell heterogeneity underlies different manifestations of food allergy in mice.

Benedé Sara S Berin M Cecilia MC

PloS one 20180125 1

Food can trigger a diverse array of symptoms in food allergic individuals from isolated local symptoms affecting skin or gut to multi-system severe reactions (systemic anaphylaxis). Although we know that gastrointestinal and systemic manifestations of food allergy are mediated by tissue mast cells (MCs), it is not clear why allergen exposure by the oral route can result in such distinct clinical manifestations. Our aim was to assess the contribution of mast cell subsets to different manifestatio ...[more]

PMID: 29370173

Similar Datasets

Project description: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, Fc?RI, 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, Fc?RIIb, 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 Fc?RIIb 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 Fc?RIIb. 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.

Project description:The thiol isomerase, protein disulfide isomerase (PDI), plays important intracellular roles during protein folding, maintaining cellular function and viability. Recent studies suggest novel roles for extracellular cell surface PDI in enhancing cellular activation and promoting their function. Moreover, a number of food-derived substances have been shown to regulate cellular PDI activity and alter disease progression. We hypothesized that PDI may have similar roles during mast cell-mediated allergic responses and examined its effects on IgE-induced mast cell activity during cell culture and food allergy. Mast cells were activated via IgE and antigen and the effects of PDI inhibition on mast cell activation were assessed. The effects of PDI blockade in vivo were examined by treating mice with the irreversible PDI inhibitor, PACMA-31, in an ovalbumin-induced model of food allergy. The role of dietary PDI modulators was investigated using various dietary compounds including curcumin and quercetin-3-rutinoside (rutin). PDI expression was observed on resting mast cell surfaces, intracellularly, and in the intestines of allergic mice. Furthermore, enhanced secretion of extracellular PDI was observed on mast cell membranes during IgE and antigen activation. Insulin turbidimetric assays demonstrated that curcumin is a potent PDI inhibitor and pre-treatment of mast cells with curcumin or established PDI inhibitors such as bacitracin, rutin or PACMA-31, resulted in the suppression of IgE-mediated activation and the secretion of various cytokines. This was accompanied by decreased mast cell proliferation, FcεRI expression, and mast cell degranulation. Similarly, treatment of allergic BALB/c mice with PACMA-31 attenuated the development of food allergy resulting in decreased allergic diarrhea, mast cell activation, and fewer intestinal mast cells. The production of TH2-specific cytokines was also suppressed. Our observations suggest that PDI catalytic activity is essential in the regulation of mast cell activation, and that its blockade may benefit patients with allergic inflammation.

Dataset Information

Mast cell heterogeneity underlies different manifestations of food allergy in mice.

Publications

Mast cell heterogeneity underlies different manifestations of food allergy in mice.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets