How Food Allergy Works — From Tolerance to Anaphylaxis

Food allergy (FA) is a global public health concern, with a prevalence of 5% in adults and 8% in children. Rates are higher in industrialized countries, reaching as high as 10% among infants in Australia . The rise in incidence is primarily attributable to environmental factors acting on a background of genetic susceptibility. FA differs from food intolerance in that it involves specific immunologic mechanisms.

Immunologic Classification

Food allergic reactions are divided into three categories based on the effector mechanism:

• Immunoglobulin (Ig)E-mediated reactions: The most common form. Rapid onset (usually within 2 hours) due to the activation of specific IgE on mast cells and basophils. Includes oral allergy syndrome, urticaria , angioedema , bronchospasm, acute gastrointestinal symptoms, and anaphylaxis .
• Mixed IgE- and cell-mediated reactions: Characteristic of atopic dermatitis , eosinophilic esophagitis , and other eosinophilic gastrointestinal disorders. The IgE component overlaps with chronic T-cell inflammation, resulting in a more subtle clinical presentation.
• Non-IgE-mediated reactions: These include food protein-induced enterocolitis syndrome, allergic proctocolitis, protein enteropathy, and celiac disease . They are driven by T-cell responses with a delayed onset (hours to days) and predominantly gastrointestinal symptoms.

Pathogenesis

Physiologic Oral Tolerance

Under physiologic conditions, the gastrointestinal tract maintains active tolerance to food antigens. CD103+ dendritic cells convert vitamin A into retinoic acid, which induces FOXP3 and the differentiation of regulatory T cells (Tregs). Tregs produce transforming growth factor-beta and interleukin (IL)-10, inducing antigen-specific suppression and isotype switching toward secretory IgA. CX3CR1+ macrophages and hepatic sinusoidal cells help complete the tolerogenic circuit.

Breakdown of Tolerance and Sensitization

Damage to the epithelial barrier — caused by loss-of-function mutations in filaggrin (FLG), skin inflammation, or exposure to harsh detergents — releases alarm cytokines (IL-25, IL-33, and thymic stromal lymphopoietin) that activate dendritic cells and type 2 innate lymphoid cells toward a pro-T helper 2 (TH2) phenotype. Activated dendritic cells express OX40L, promoting TH2 differentiation, the production of IL-4 and IL-13, isotype switching to IgE, and mast cell expansion. A critical positive feedback loop is the reprogramming of Tregs toward a TH2 phenotype with loss of their tolerogenic function.

Dual-Allergen Exposure Hypothesis

The dual-allergen exposure hypothesis, supported by the LEAP study , a randomized controlled trial, posits that low-dose cutaneous exposure to allergens through compromised skin induces sensitization, while high-dose oral exposure promotes tolerance. FLG mutations facilitate the transepidermal penetration of allergens and are associated with the persistence of milk and egg allergies over time. Although less common, sensitization may also occur via the respiratory route.

IgE-Mediated Effector Activation

Specific IgE binds to the Fc epsilon receptor I on mast cells and basophils. Subsequent contact with the allergen leads to receptor cross-linking, activation of spleen tyrosine kinase, degranulation with the release of histamine, tryptase, and platelet-activating factor, and de novo synthesis of leukotrienes and prostaglandins. Reaction severity depends on the characteristics of IgE, mast cell density, the presence of inhibitory IgG (via Fc gamma receptor IIb), and cofactors (physical exercise, nonsteroidal anti-inflammatory drugs [NSAIDs], alcohol, and viral infections).

Classification of Allergens

Thermostability and Gastrostability

The clinical relevance of an allergen depends on its resistance to cooking and acid-peptic digestion:

• Thermolabile and gastrolabile proteins (PR-10 and profilins): denatured by cooking and digestion; they primarily trigger oral allergy syndrome and rarely cause systemic reactions.
• Thermostable and gastroresistant proteins (nonspecific lipid transfer proteins, 2S albumins, casein, ovomucoid, tropomyosin, and parvalbumin): reach the intestinal mucosa intact; they are responsible for severe systemic reactions and anaphylaxis.

The following table classifies the 12 main allergenic families based on these properties and clinical risk. Table. Classification of the 12 Main Allergen Families by Stability and Clinical Risk

• Protein family | Thermostability | Gastrostability | Main examples | Clinical risk | Diagnostic notes
• PR-10 (Bet v 1 homologs) | Thermolabile | Gastrolabile | Apple/Mal d 1; Hazelnut/Cor a 1; Soy/Gly m 4; Peach/Pru p 1; Peanut/Ara h 8 | Mild reactions, predominantly oral (oral allergy syndrome). Gly m 4 can cause systemic reactions. | Cross-reactivity with Bet v 1 (birch). CRD useful for distinguishing from systemic risk allergens.
• nsLTP | Thermostable | Gastroresistant | Peach/Pru p 3; Hazelnut/Cor a 8; Walnut/Jug r 3; Wheat/Tri a 14; Cannabis/Can s 3 | High systemic risk: urticaria, angioedema, and anaphylaxis. Leading cause of primary FA and anaphylaxis in adults in the Mediterranean region. | Cofactors (NSAIDs, alcohol, exercise) amplify reactivity. CRD on Pru p 3 for the primary sensitizer.
• 2S albumins (prolamins) | Thermostable | Gastroresistant | Peanut/Ara h 2,6; Walnut/Jug r 1; Cashew/Ana o 3; Sesame/Ses i 1; Mustard/Sin a 1 | Primary marker of severe anaphylaxis. Ara h 2 is the most potent activator of mast cells and basophils. | Diagnostic gold standard for peanut allergy. High specificity and PPV.
• Vicillins/legumins (cupin) | Thermostable | Gastroresistant | Peanut/Ara h 1,3; Walnut/Jug r 2; Hazelnut/Cor a 9,14; Cashew/Ana o 1,2 | High systemic risk, especially with cosensitization to 2S albumin. Cross-reactivity between legumes and tree nuts. | Cross-inhibition with Ara h 2 may cause false positives; recombinant allergens are preferred.
• Wheat prolamins (omega-5 gliadin and LMW-GS) | Partially stable | Gastroresistant | Wheat/Tri a 19 (omega-5 gliadin); Wheat/Tri a 36 (LMW-GS) | omega-5 gliadin: marker of WDEIA and severe wheat allergy in children. | Tri a 19 sIgE: test of choice for WDEIA. OFC with cofactor (exercise ± NSAIDs).
• Profilins | Thermolabile | Gastrolabile | Pan-allergen: Bet v 2; Phl p 12; Hev b 8; present in many fruits and vegetables | Mild-to-moderate reactions, predominantly oral. Rarely systemic. | Sensitization often secondary to pollen. A positive result does not justify elimination without OFC.
• Casein and whey proteins | Stable (casein); labile (whey) | Resistant (casein) | Milk/Bos d 8 (casein); Bos d 4 (alpha-lactalbumin); Bos d 5 (beta-lactoglobulin) | Casein: persistent allergy and reactivity to baked milk. Whey proteins: markers of tolerance to baked milk. | Casein sIgE > 2.6 kUA/L: cutoff for fresh milk allergy. Indicates need for the baked milk protocol.
• Ovomucoid/ovalbumin | Stable (ovomucoid); labile (ovalbumin) | Resistant (ovomucoid) | Egg/Gal d 1 (ovomucoid); Gal d 2 (ovalbumin); Gal d 3 (ovotransferrin) | Ovomucoid: reaction also to cooked egg. Ovalbumin: often tolerated in cooked egg. | sIgE ovomucoid > 0.8 kUA/L guides the reintroduction strategy (baked egg ladder).
• Tropomyosin (crustaceans and mollusks) | Thermostable | Gastroresistant | Shrimp/Pen a 1; Crab/Cha f 1; Squid/Tod p 1; Mite/Der p 10 | High systemic risk: urticaria, angioedema, and severe anaphylaxis. Reactions may also occur from cooking vapors. | sIgE Pen a 1: marker of systemic risk. Cross-reactivity with mites (crustacean-mite syndrome). Frequent polysensitization.
• Parvalbumin (fish) | Thermostable | Gastroresistant | Cod/Gad c 1; Salmon/Sal s 1; Tuna/Thu a 1; Carp/Cyp c 1 | High systemic risk. Extensive cross-reactivity among fish species. Reactions can also be triggered by cooking vapors. | sIgE Gad c 1: pan-fish marker. Cooking does not eliminate allergenicity. CRD to distinguish primary allergy from cross-reactions.
• Hevein and chitinase (latex-fruit syndrome) | Hev b 6 labile; chitinase stable | Variable | Latex/Hev b 6 (hevein); Avocado/Pers a 1; Banana/Mus xp 1; Kiwi/Act d 2; Chestnut/Cas s 5; Tomato/Lyc e 3 | Latex-fruit syndrome. High risk in healthcare workers and children with spina bifida or multiple surgeries. | sIgE Hev b 6: latex-fruit cross-reactivity. Hev b 5 and Hev b 13: primary sensitization to latex.
• Alpha-gal (oligosaccharide) | Heat-stable | Gastroresistant | Mammalian meats (beef, pork or lamb); medications containing gelatin | Delayed reactions (3-6 hours), often nocturnal. Urticaria, angioedema, and anaphylaxis. Associated with tick bites. | Anti-alpha-gal IgE assay. Delayed onset due to slow lipid absorption.
• CRD = component-resolved diagnostics; FA = food allergy; IgE = immunoglobulin E; LMW-GS = low molecular weight glutenin subunits; NSAIDs = nonsteroidal anti-inflammatory drugs; nsLTP = nonspecific lipid transfer protein; OFC = oral food challenge; PPV = positive predictive value; PR-10 = pathogenesis-related protein class 10; sIgE = serum-specific IgE; WDEIA = wheat-dependent exercise-induced anaphylaxis

Allergens of Clinical Significance

• Peanuts: Ara h 2 (a 2S albumin ) is the primary diagnostic marker and the most potent mast cell activator. In practice, it is more informative than whole-extract food-specific IgE testing. The use of recombinant allergens via component-resolved diagnostics is recommended to avoid false positives due to cross-reactivity.
• Crustaceans and mollusks: Tropomyosin Pen a 1 is heat-stable and gastroresistant. Severe reactions can occur even from cooking vapors. Cross-reactivity with Der p 10 from dust mites is clinically relevant, giving rise to the so-called crustacean-mite syndrome.
• Fish: Parvalbumin (Gad c 1 in cod) is heat-stable and serves as a pan-fish marker. Cooking does not eliminate its allergenicity. Extensive cross-reactivity among different species often necessitates avoiding multiple fish species.
• Latex-fruit syndrome: Sensitization to latex occurs via inhalation or contact (healthcare workers and children with spina bifida ). Cross-reactivity with avocado, banana, kiwi, chestnut, and tomato via class I chitinases. Hev b 6: marker of cross-reactivity; Hev b 5 and Hev b 13: primary sensitization.
• Alpha-gal: An emerging allergy associated with the bite of the tick Ixodes ricinus (the primary vector in Europe). The alpha-gal oligosaccharide in mammalian meats causes delayed reactions, usually 3-6 hours after ingestion, because of slow lipid absorption.

Clinical Presentations

IgE-mediated FA can affect the skin, respiratory tract, gastrointestinal tract, and cardiovascular system. Symptoms appear within 2 hours of ingestion, with variability depending on dose, food form, and other cofactors.

• Anaphylaxis: This typically involves at least two organs or systems. The World Allergy Organization criteria require an acute onset with cutaneous/mucosal involvement associated with respiratory, cardiovascular, or gastrointestinal symptoms. Cow’s milk, peanuts, tree nuts, and shellfish are the leading causes of fatal anaphylaxis. Normal tryptase levels do not rule out food-induced anaphylaxis.
• Oral allergy syndrome: The most common FA in adults, characterized by itching and mild oropharyngeal edema within minutes of eating raw fruits or vegetables that cross-react with pollens (PR-10 and profilins). Rarely systemic due to the thermal and digestive lability of the responsible proteins.
• Wheat-dependent exercise-induced anaphylaxis : The reaction is triggered only in the presence of a cofactor, typically exercise. The allergen is almost invariably omega-5 gliadin (Tri a 19).

Role of the Microbiome

The gut microbiome may alter susceptibility to FA through several mechanisms, such as modulating IgE production. Unlike other Igs, IgE levels rise in the absence of the gut microbiome (as shown in germ-free mouse models). In addition to promoting a regulatory environment in the gut, the gut microbiome influences intestinal barrier function and may promote IgA production, which can contribute to tolerance through antigen exclusion. Variations in gut microbiome composition have also been linked to differences in the natural history of FA. The gut microbiome can interact with other important environmental factors, such as diet, to suppress or modulate the development of FA. Dietary fiber is metabolized by anaerobic bacteria into short-chain fatty acids, such as butyrate, propionate, and acetate. High-fiber diets induce short-chain fatty acid production and suppress FA in a gut microbiota-dependent manner in animal models. Whether the gut microbiome can be manipulated for the prevention and treatment of FA in humans remains an open question.

Clinical Takeaways

Understanding the pathogenesis of FA, together with the biochemical classification of allergens based on thermostability and gastrostability, forms the foundation for a personalized diagnostic approach. Knowledge of the risk profile of allergen families guides molecular diagnostics and dietary recommendations. Erna Cecilia Lorenzini is a professor of general pathology and nutrition at the University of Milan, Milan, Italy, where she teaches across undergraduate programs in the Faculty of Medicine and the School of Specialization in Food Science. She holds a degree in medicine and a PhD in experimental pathology and conducted research at the Department of Molecular Biology at the University of California, San Diego. She is a specialist in food science and clinical nutrition and collaborates with Italy’s National Research Council on projects involving the microbiome and clinical decision support systems. This story was translated from Univadis Italy , part of the Medscape Professional Network.