Diagnosing food allergy

What is oral tolerance?

Oral tolerance is the process of immune unresponsiveness to orally ingested antigens. It is initiated when antigenic material is sampled from the intestinal lumen by CX3CR1 macrophages, which is then processed by non-activated dendritic cells (Figure 1)^1,2.

These non-activated dendritic cells then present the food peptide, displayed on the major histocompatibility complex (MHC), to the T cell receptors (TCR) on naïve T cells^1,2.

This causes naïve T cell differentiation into T regulatory cells (Tregs), which then travel via α4β7 to the lamina propria. These Tregs support the maintenance of tolerance via CTLA-4 expression and the release of transforming growth factor-beta (TGF-β) and interleukin (IL)-10^1,2.

Pathogenic type 2 helper T (T_H2) cells play a central role in the pathophysiology of allergic disease³

CTLA04 then suppresses antigen-specific T_H2 cells, while TGF-β and IL-10 inhibit effector cells: eosinophils, basophils, and mast cells. In the presence of IL-10 and TGF-β, B cells produce IgA and IgG4 that are necessary for maintaining tolerance while suppressing IgE production^1,2.

An intact epithelial barrier also plays an essential role in the maintenance of tolerance and the loss of integrity of this barrier can lead to sensitisation to food allergens and the development of food allergy^1,2.

Figure 1. Overview of the tolerogenic (left) and allergic (right) response to food antigen in the gut (Adapted¹). CTLA-4, cytotoxic T lymphocyte-associated antigen-4; CX3CR1, C-X3-C Motif Chemokine Receptor 1; DC, dendritic cells; IgA, immunoglobulin A; IgE, immunoglobulin E; IL, interleukin; ILC2, type 2 innate lymphoid cells; MHC, major histocompatibility complex; TCR, T cell receptors; TGF-β, transforming growth factor-beta; T_H2, type 2 helper T cells; T_H9, type 2 helper T cells; Tregs, T regulatory cells; TSLP, thymic stromal lymphopoietin.

What is sensitisation?

Allergic sensitisation is the first step of the allergic immune response following exposure to an allergen. It is defined by the presence of detectable food-specific IgE (in blood or by skin prick test), which can lead to the development of clinical food allergy^1,2.

Sensitisation occurs when a food allergen triggers the secretion of pro-inflammatory cytokines, such as IL-33, IL-25, and thymic stromal lymphopoietin (TSLP). This promotes the expansion of type innate lymphoid cells (ILCs) and activates dendritic cells that usually defend against pathogens^1,2.

Activated dendritic cells then take up and process the antigen into short peptides in addition to upregulating the expression of the surface protein OX40L. The interaction of MHC and OX40L on dendritic cells with TCR and OX40 on naïve T cells then triggers the differentiation of naïve T cells to T_H2 cells, which are central to the pathophysiology of food allergy^1,2.

What are the effector cells of allergic reactions?

Following differentiation, T_H2 cells and ILCs secrete pro-inflammatory cytokines, such as IL-5 and IL-13, which promotes the recruitment of eosinophils and basophils. T_H2 cells also secrete IL-4, which prompts food allergen-specific B cells to class switch, leading to amplified production of food antigen-specific IgE antibodies and a state of sensitisation and allergy^1,2.

T_H9 cells are also involved in the development of the allergic response through the secretion of IL-9, which promotes the recruitment of mast cells^1,2

What is the key information to collect from a clinical history?

A comprehensive clinical history is essential for establishing the pre-test probability of food allergy and guiding further investigations⁷. A detailed clinical history, using structured questions, is recommended by various international guidelines for the diagnosis of food allergy^9,10. As part of a clinical history, there are numerous important pieces of information to collect (Table 1), including dietary history, timing and chronicity, reproducibility, known risk (co)factors, and coexisting conditions^10,11.

Table 1. Key information to collect from a clinical history (Adapted¹¹). NSAID, non-steroid anti-inflammatory drug.

Food allergy can also lead to poor growth in children, necessitating the intervention of a dietician. A physical examination should therefore assess the growth and development of children, in addition to their nutritional status, especially in children with multiple food allergies⁷.

What conditions induce a similar clinical manifestation to IgE-mediated food allergy?

It is also important to consider alternative diseases, triggers, and syndromes with similar clinical manifestations to IgE-mediated food allergy, such as^11,12:

What diagnostics are commonly used for diagnosing food allergy?

Two commonly utilised standardised tests to determine the causative food are the skin prick test (SPT) and the measurement of total and allergen-specific sIgE levels in whole extracts (Figure 2)⁷.

Figure 2. The diagnostic tests used to diagnose IgE-mediated food allergy utilise specific aspects of the underlying mechanisms of sensitisation (Adapted¹³). IgE, immunoglobulin E; IgG, immunoglobulin G.

The skin prick test entails pricking the skin with various candidate food allergens to measure the response of cutaneous mast cells to allergen. A wheal and flare response within 15 minutes suggests the presence of cutaneous mast cells with allergen specific bound IgE^13,14.

By contrast, the measurement of total IgE or sIgE utilises fluorescent enzyme immune assays to detect the presence of either total or serum IgE to allergen extracts or individual allergen components. Ratios with allergen sIgE can be calculated using total IgE and allergen-specific IgG4^13,14.