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.
Growing evidence points to an important role for the commensal microbiota in susceptibility to food allergy. Epidemiologic studies demonstrate associations between exposures known to modify the ...microbiome and risk of food allergy. Direct profiling of the gut microbiome in human cohort studies has demonstrated that individuals with food allergy have distinct gut microbiomes compared to healthy control subjects, and dysbiosis precedes the development of food allergy. Mechanistic studies in mouse models of food allergy have confirmed that the composition of the intestinal microbiota can imprint susceptibility or resistance to food allergy on the host and have identified a unique population of microbially responsive RORγt-positive FOXp3-positive regulatory T cells as critical for the maintenance of tolerance to foods. Armed with this new understanding of the role of the microbiota in food allergy and tolerance, therapeutics aimed at modifying the gastrointestinal microbiota are in development. In this article we review key milestones in the development of our current understanding of how the gastrointestinal microbiota contributes to food allergy and discuss our vision for the future of the field.
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.
Mechanisms of Oral Tolerance Tordesillas, Leticia; Berin, M. Cecilia
Clinical reviews in allergy & immunology,
10/2018, Volume:
55, Issue:
2
Journal Article
Peer reviewed
Open access
Oral tolerance is a state of systemic unresponsiveness that is the default response to food antigens in the gastrointestinal tract, although immune tolerance can also be induced by other routes, such ...as the skin or inhalation. Antigen can be acquired directly by intestinal phagocytes, or pass through enterocytes or goblet cell-associated passages prior to capture by dendritic cells (DCs) in the lamina propria. Mucin from goblet cells acts on DCs to render them more tolerogenic. A subset of regulatory DCs expressing CD103 is responsible for delivery of antigen to the draining lymph node and induction of Tregs. These DCs also imprint gastrointestinal homing capacity, allowing the recently primed Tregs to home back to the lamina propria where they interact with macrophages that produce IL-10 and expand. Tregs induced by dietary antigen include Foxp3
+
Tregs and Foxp3
−
Tregs. In addition to Tregs, T cell anergy can also contribute to oral tolerance. The microbiota plays a key role in the development of oral tolerance, through regulation of macrophages and innate lymphoid cells that contribute to the regulatory phenotype of gastrointestinal dendritic cells. Absence of microbiota is associated with a susceptibility to food allergy, while presence of Clostridia strains can suppress development of food allergy through enhancement of Tregs and intestinal barrier function. It is not clear if feeding of antigens can also induce true immune tolerance after a memory immune response has been generated, but mechanistic studies of oral immunotherapy trials demonstrate shared pathways in oral tolerance and oral immunotherapy, with a role for Tregs and anergy. An important role for IgA and IgG antibodies in development of immune tolerance is also supported by studies of oral tolerance in humans. The elucidation of key pathways in oral tolerance could identify new strategies to increase efficacy of immunotherapy treatments for food allergy.
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.
Immunology of Food Allergy Tordesillas, Leticia; Berin, M. Cecilia; Sampson, Hugh A.
Immunity (Cambridge, Mass.),
07/2017, Volume:
47, Issue:
1
Journal Article
Peer reviewed
Open access
Many consider food allergy as the “second wave” of the allergy epidemic following the “first wave” of respiratory allergy, i.e., asthma and allergic rhinitis, plaguing westernized countries, with up ...to 8% of young children and 2%–3% of adults in the United States now affected by hypersensitivity reactions to various foods. In the past decade, there have been great strides in our understanding of the underlying immunopathogenesis of these disorders, which have led to improved diagnostic techniques, management strategies, and therapeutic approaches. Here we will review the most recent understanding of basic mechanisms underlying IgE-mediated food allergies and novel therapeutic approaches under investigation for both the prevention and treatment of IgE-mediated food allergies.
Food allergies have increased exponentially in the last decades. Tordesillas et al. review the immune mechanisms of sensitization to foods and recent developments in the prevention of food allergies. In addidtion, they discuss efficacy of antigen-specific immunotherapies as well as other emerging therapeutic approaches.
This review provides an overview of our current understanding of the mechanisms of food protein-induced enterocolitis syndrome (FPIES).
To capture recent articles published since our previous ...comprehensive review on the pathophysiology of FPIES, we performed a literature search through PubMed database, using the search terms FPIES and food protein-induced enterocolitis syndrome from 2016 to the current year.
Studies in English containing biomarker or immune data were reviewed and summarized.
Studies of peripheral blood fail to exhibit evidence of antigen-specific humoral or cellular immunity underlying clinical reactivity to foods in FPIES. However, growing evidence suggests a robust systemic innate immune activation occurring during FPIES reactions and the activation of neuroendocrine pathways.
FPIES reactions are associated with marked activation of innate immune and neuroendocrine pathways; however, the mechanism underlying the specific recognition of foods remains elusive.
Currently, we have a poor understanding of why some food allergies are outgrown and others are not. Deciphering the immune basis of the natural resolution of food allergy will likely provide critical ...information for developing new therapies for the treatment of persistent food allergies. There are limited cohort studies that have followed children with food allergy over time, but information generated from such cohorts points to features of innate and adaptive immunity, as well as environmental differences (microbiome) that discriminate those with persistent versus transient food allergy. Studies from mouse models highlight the importance of novel subsets of memory B cells rather than plasma cells combined with antigen re-exposure and T-cell help in the maintenance of IgE. In this review we discuss these findings from human cohorts and experimental systems and discuss existing gaps in our knowledge.
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.
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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