IgE-mediated food allergy affects 6-8% of the population in the United States. Type 2 immune responses are central to the pathogenesis of food allergy, but type 2 CD4+ T cell responses have been ...found to be heterogeneous in food allergy suggesting a division of labor between Tfh13 and peTH2 cells in promotion of IgE class switching, modulation of intestinal barrier function, and regulation of mast cell expansion. Oral immunotherapy for the treatment of food allergy incompletely targets subsets of type 2 immunity in a transient manner, but new therapeutics targeting different levels of type 2 immunity are in current or planned trials for food allergy. These new treatments and the basis for their use are the focus of this review.
There is increasing recognition of the non–IgE-mediated gastrointestinal food allergy known as food protein–induced enterocolitis syndrome (FPIES), with several recent publications summarizing the ...clinical experience with FPIES in the United States, the United Kingdom, Europe, and Australia. Our understanding of the mechanisms linking food exposure to typical symptoms of vomiting, hypotension, and diarrhea has lagged far behind our understanding of the immune mechanisms of IgE-mediated food allergy. The goal of this overview is to summarize and critique the current state of knowledge of the immunology of FPIES and to identify major gaps in our knowledge that need to be addressed to make significant gains in developing therapies and prevention strategies for FPIES.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The increase in food allergy prevalence in recent years suggests that environmental factors, such as diet and intestinal microbiota, play contributory roles. In this issue of the JCI, Bao et al. ...compared twins that differed with respect to food allergies. The researchers analyzed sequences from microbe ribosomal RNA and profiled microbe metabolites, identifying health-associated microbes at the species level. In addition to revealing microbes from the Clostridia class enriched in healthy twins, the authors identified two commensal species (Phascolarctobacterium faecium and Ruminococcus bromii) related to the healthy fecal metabolome. This study advances the goal for next-generation probiotic therapies that effectively treat or prevent food allergy.
Cross-linking of high-affinity immunoglobulin E (IgE) results in the life-threatening allergic reaction anaphylaxis. Yet the cellular mechanisms that induce B cells to produce IgE in response to ...allergens remain poorly understood. T follicular helper (T
) cells direct the affinity and isotype of antibodies produced by B cells. Although T
cell-derived interleukin-4 (IL-4) is necessary for IgE production, it is not sufficient. We report a rare population of IL-13-producing T
cells present in mice and humans with IgE to allergens, but not when allergen-specific IgE was absent or only low-affinity. These "T
13" cells have an unusual cytokine profile (IL-13
IL-4
IL-5
IL-21
) and coexpress the transcription factors BCL6 and GATA3. T
13 cells are required for production of high- but not low-affinity IgE and subsequent allergen-induced anaphylaxis. Blocking T
13 cells may represent an alternative therapeutic target to ameliorate anaphylaxis.
Food Protein-Induced Enterocolitis Syndrome Nowak-Wegrzyn, Anna; Berin, M Cecilia; Mehr, Sam
The journal of allergy and clinical immunology in practice (Cambridge, MA),
01/2020, Volume:
8, Issue:
1
Journal Article
Peer reviewed
Food protein-induced enterocolitis syndrome (FPIES) is a non-IgE-mediated food allergy that manifests with projectile, repetitive emesis that can be followed by diarrhea and may be accompanied by ...lethargy, hypotonia, hypothermia, hypotension, and metabolic derangements. FPIES usually starts in infancy although onset at older ages is being increasingly recognized. FPIES is not rare, with the cumulative incidence of FPIES in infants estimated to be 0.015% to 0.7%, whereas the population prevalence in the US infants was 0.51%. FPIES diagnosis is challenging and might be missed because of later (1-4 hours) onset of symptoms after food ingestion, lack of typical allergic skin and respiratory symptoms, and food triggers that are perceived to be hypoallergenic. Diagnosis is based on the recognition of symptoms because there are no biomarkers of FPIES. The pathophysiology remains obscure although activation of the innate immune compartment has been detected. Management relies of avoidance of food triggers, treatment of accidental exposures, and periodic re-evaluations with supervised oral food challenges to monitor for resolution. There are no strategies to accelerate development of tolerance in FPIES. Here we review the most important current concepts in epidemiology, pathophysiology, diagnosis, and management of FPIES.
Background Food protein–induced enterocolitis syndrome (FPIES) is a non–IgE-mediated food allergy of infancy whose pathophysiology is poorly understood. Objectives We set out to identify and ...phenotype allergen-responsive cells in peripheral blood of a cohort of subjects undergoing supervised food challenge for FPIES. Methods We profiled antigen-responsive cells in PBMCs by flow cytometry, and examined cells in whole blood obtained before and after challenge by CyTOF mass cytometry and RNAseq. Results Using a CD154-based detection approach, we observed that milk, soy, or rice-responsive T cells, and TNF-α–producing CD154+ T cells, were significantly lower in those with outgrown FPIES compared with those with active FPIES. However, levels were within the normal range and were inconsistent with a role in the pathophysiology of FPIES. Profiling of whole blood by CyTOF demonstrated profound activation of cells of the innate immune system after food challenge, including monocytes, neutrophils, natural killer cells, and eosinophils. Activation was not observed in children with outgrown FPIES. We confirmed this pattern of innate immune activation in a larger cohort by RNAseq. Furthermore, we observed pan–T-cell activation and redistribution from the circulation after a positive food challenge but not in those who had outgrown their FPIES. Conclusions Our data demonstrate a compelling role of systemic innate immune activation in adverse reactions elicited by foods in FPIES. Further investigation is needed to identify the mechanism of antigen specificity of adverse reactions to foods in FPIES.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Immune tolerance is defined as nonresponsiveness of the adaptive immune system to antigens. Immune mechanisms preventing inappropriate immune reactivity to innocuous antigens include deletion of ...reactive lymphocytes and generation of regulatory T (Treg) cells. The normal response to food antigens is the generation of antigen-specific Treg cells. In patients with food allergy, the dominant immune response is a TH 2-skewed T-cell response and the generation of food-specific IgE antibodies from B cells. It is not known whether a failure of the Treg cell response is behind this inappropriate immune response, but interventions that boost the Treg cell response, such as mucosal immunotherapy, might lead to a restoration of immune tolerance to foods. Tolerance has been notoriously difficult to restore in animal disease models, but limited data from human trials suggest that tolerance (sustained nonresponsiveness) can be re-established in a subset of patients. Furthermore, studies on the natural history of food allergy indicate that spontaneous development of tolerance to foods over time is not uncommon. The current challenge is to understand the mechanisms responsible for restoration of natural or induced tolerance so that interventions can be developed to more successfully induce tolerance in the majority of patients with food allergy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Purpose of Review
Food protein–induced enterocolitis syndrome (FPIES) is a non-IgE-mediated food allergy characterized by delayed, and potentially severe, gastrointestinal symptoms. Since the advent ...of a specific diagnostic code and establishment of diagnostic guidelines, our understanding of this condition has grown.
Recent Findings
FPIES affects patients from early infancy into adulthood. Any food can be a trigger, and common culprit foods vary geographically and by age. An understanding of the complex underlying immune mechanisms remains elusive, although studies show pan-leukocyte activation, cytokine release, and increased gastrointestinal permeability. Management involves trigger avoidance, and patients may benefit from the support of a dietitian to ensure adequate nutrient intake. Tolerance develops over time for most children, but due to the risk of severe symptoms, re-introduction of a suspected FPIES trigger is recommended only under supervision at an oral food challenge. Studies continue to evaluate the optimal challenge protocol. Caregivers of children with FPIES report high levels of anxiety and stress, which is attributed to the dramatic symptomatology, dietary restrictions, nutritional concerns, lack of confirmatory diagnostic tests, and limited tools for management of reactions.
Summary
Our understanding of the FPIES diagnosis has improved over the last few decades, but there remain opportunities, particularly regarding discerning the pathophysiology and best management practices.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background The attempt to induce oral tolerance as a treatment for food allergy has been hampered by a lack of sustained clinical protection. Immunotherapy by nonoral routes, such as the skin, may be ...more effective for the development of maintained tolerance to food allergens. Objective We sought to determine the efficacy and mechanism of tolerance induced by epicutaneous immunotherapy (EPIT) in a model of food-induced anaphylaxis. Methods C3H/HeJ mice were sensitized to ovalbumin (OVA) orally or through the skin and treated with EPIT using OVA-Viaskin patches or oral immunotherapy using OVA. Mice were orally challenged with OVA to induce anaphylaxis. Antigen-specific regulatory T (Treg)-cell induction was assessed by flow cytometry using a transgenic T-cell transfer model. Results By using an adjuvant-free model of food allergy generated by epicutaneous sensitization and reactions triggered by oral allergen challenge, we found that EPIT induced sustained protection against anaphylaxis. We show that the gastrointestinal tract is deficient in de novo generation of Treg cells in allergic mice. This defect was tissue-specific, and epicutaneous application of antigen generated a population of gastrointestinal-homing LAP+ Foxp3− Treg cells. The mechanism of protection was found to be a novel pathway of direct TGF-β–dependent Treg-cell suppression of mast cell activation, in the absence of modulation of T- or B-cell responses. Conclusions Our data highlight the immune communication between skin and gastrointestinal tract, and identifies novel mechanisms by which epicutaneous tolerance can suppress food-induced anaphylaxis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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