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Food allergy: immune mechanisms, diagnosis and immunotherapy

Key Points

  • There are many forms of food allergy, the most common of which are IgE mediated. Common IgE-mediated food allergies include those to peanuts, tree nuts, cow's milk, egg, soy, wheat, shellfish and fish.

  • The immune system normally develops tolerance to food proteins, at least in part due to the actions of CD4+ regulatory T cells.

  • Food allergy develops when the immune system mounts a T helper 2 (TH2) cell-mediated response against food epitopes. TH2 cell sensitization may occur initially at the skin, rather than in the gastrointestinal tract.

  • The early introduction of potentially allergenic foods may prevent the development of food allergies.

  • Patients with established food allergy may become desensitized to food allergens by oral immunotherapy, which is thought to involve a shift from allergen-specific TH2 cells to CD4+ regulatory T cells, anergic cells and apoptotic cells. Typically, patients must continue regular consumption of food allergen to maintain desensitization.

  • Some desensitized individuals proceed to develop sustained unresponsiveness and no longer require regular ingestion of food allergen to maintain immune system nonresponsiveness. The mechanism and predictors of the transition from desensitization to apparent tolerance are unknown.

Abstract

Food allergy is a pathological, potentially deadly, immune reaction triggered by normally innocuous food protein antigens. The prevalence of food allergies is rising and the standard of care is not optimal, consisting of food-allergen avoidance and treatment of allergen-induced systemic reactions with adrenaline. Thus, accurate diagnosis, prevention and treatment are pressing needs, research into which has been catalysed by technological advances that are enabling a mechanistic understanding of food allergy at the cellular and molecular levels. We discuss the diagnosis and treatment of IgE-mediated food allergy in the context of the immune mechanisms associated with healthy tolerance to common foods, the inflammatory response underlying most food allergies, and immunotherapy-induced desensitization. We highlight promising research advances, therapeutic innovations and the challenges that remain.

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Figure 1: Immune tolerance to oral antigens in the gut.
Figure 2: TH2 cell-mediated inflammatory response to oral antigen in the gut.
Figure 3: Desensitization to oral antigens in the gut.

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Acknowledgements

The authors would like to acknowledge the assistance of T. A. Chatila, S. J. Galli, M. T. Graham, V. Sampath and J. M. Spergel.

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Glossary

Atopic diseases

Disorders characterized by pathological immune responses to normally innocuous antigens.

Oral food challenge

(OFC). Used for food allergy diagnosis. Under supervision, the patient is asked to consume small but increasing amounts of the suspected food allergen until a predetermined maximum dose is reached or a food allergic reaction is observed.

IgE component testing

Purified allergen extracts or recombinant allergens are used to diagnose food allergies in a more accurate manner than is possible with crude allergen extracts.

Sustained unresponsiveness

The state in which an individual with food allergy no longer requires regular ingestion of an allergen to maintain desensitization to it; phenotypically, it resembles the normal immune tolerance of a healthy individual but may be mechanistically distinct.

Gut-associated lymphoid tissue

(GALT). The immune system of the gastrointestinal tract is collectively called the GALT; examples include the tonsils, Peyer's patches and lymphoid cells in the lamina propria.

Type 1 regulatory T cells

(Tr1 cells). A subset of regulatory T cells that are FOXP3. Tr1 cells mediate suppressive effects through IL-10 secretion.

Type 2 innate lymphoid cells

(ILC2s). Cells that produce T helper 2 cell cytokines, such as IL-4, IL-5, IL-9 and IL-13, and are implicated in the development of allergic inflammation.

Sublingual immunotherapy

(SLIT). An immunotherapeutic method in which the food allergen (in the form of a tablet or drops) is administered under the tongue.

Regulatory B cells

(Breg cells). These cells support immune tolerance through secretion of the anti-inflammatory cytokines IL-10, IL-35 and TGFβ.

H1 receptor blockers

H1 receptor antagonists that block histamine action, dampening allergic reactions.

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Yu, W., Freeland, D. & Nadeau, K. Food allergy: immune mechanisms, diagnosis and immunotherapy. Nat Rev Immunol 16, 751–765 (2016). https://doi.org/10.1038/nri.2016.111

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