By Aria Afsharian

Graphic design by Emily Huang

Food allergies are a global health problem affecting 1-10% of the world population.¹ In Canada, 7.45% of children aged six months to 11 years old are impacted by food allergy, with the most common allergens found in milk, peanuts, and eggs.² One major allergic pathway involves immunoglobulin E (IgE).³ Normally, food antigens are processed by immune cells and recognized as harmless, releasing signals that suppress IgE production.³ However, in allergic individuals, the immune system mistakes food as pathogenic, increasing pro-inflammatory signals and allergen-specific IgE.³ The most severe form of this response is anaphylaxis, with symptoms like hives and airway constriction.³ Rarely, anaphylaxis can be fatal. The best treatment is prompt epinephrine injection. Together, these factors necessitate precise predictors of anaphylaxis and a more holistic approach to the diagnosis, prevention, and treatment of food allergies beyond just symptom treatment.

Dr. Julia Upton is a staff immunologist and allergist in the Department of Paediatrics at The Hospital for Sick Children (SickKids). As part of the Division of Immunology and Allergy at SickKids, Dr. Upton’s research is diverse, spanning from oral immunotherapies to predictive immune markers. During our conversation, Dr. Upton explained how approaching the immune system in a simplified manner helps in understanding its role in pathology: “It’s all the immune system making decisions. What does it fight or not fight? How does it turn on or off its attack?” It is this decision-making process, according to Dr. Upton, that makes the immune system a central target for many diseases and an important area of interest for therapeutic research.

Currently, Dr. Upton is investigating how we can change the immune system’s response to food allergens. “The most obvious way is to eat the food itself,” Dr. Upton says. This thought coincides with studies that show that repeated ingestion of a food allergen can increase the threshold amount that can be tolerated without a reaction. For example, studies have shown that medically managed ingestion of around 300-4000 mg peanut protein can increase the threshold of reaction.⁵ This strategy is called Oral Immunotherapy (OIT), and it can help train the body to limit reaction in cases of accidental exposures or other instances of micro-exposures.^4,5 

However, there are challenges to OIT, as a balance is needed between inducing desensitization while minimizing allergic responses.⁴ Interestingly, exposure to small amounts of food can increase threshold tolerances at magnitudes far greater than the initial dose, as evident in one study where dosages of 500 mg lead to threshold tolerances of 4 g in peanuts in some individuals.^4,5 Dr. Upton is exploring even lower OIT doses to try to balance safety and efficacy. She is also studying different routes of administration, such as skin patches and under-the-tongue absorption, which can induce desensitization at very low doses.^6,7

Aside from dose and routes of entry, the processing of foods also affects their allergenicity due to changes in their chemical structure. For example, how foods change after being cooked can have a substantial effect on allergenicity. Studies have shown that allergic individuals can better tolerate milk and eggs after baking.^8,9 Conversely, some foods exhibit greater harm when processed, as seen with peanuts after roasting.⁸ In addition to external food processing, there are biological factors within the body that can also play a role in allergenicity. Emerging evidence indicates that the bacteria residing in our mouths and intestinal tract may modify the allergenicity of food allergens and reduce anaphylaxis severity.¹⁰ Dr. Upton stresses the importance of all these factors in advancing treatment methods, highlighting that, “Understanding how the immune system responds to food after processing helps us minimize the part that triggers the reaction.” This aligns with Dr. Upton’s recent work surveying allergists in North America in their implementation of baked food diets, pushing for more structured guidance on procedures and patient education.⁹ 

Current methods of allergy diagnosis are not ideal, relying on giving a suspect food to the patient and tracking reaction progression. This can pose a risk to the patient if anaphylaxis ensues post-test. Dr. Upton is interested in improving allergy diagnosis through predictive markers that can be assessed on a patient-to-patient basis. Differences in predictive immune markers can help identify patients at high risk of anaphylaxis, allowing physicians to direct personalized care. 

One of these predictive biomarkers, a marker of anaphylaxis, is Platelet Activating Factor (PAF). PAF is a lipid-based compound released by mast cells and macrophages. The factor mediates several pro-inflammatory processes such as vasodilation.¹¹ PAF is broken down by the enzyme PAF-acetylhydrolase (PAF-AH) in the liver.¹¹ Since PAF-AH levels correlate inversely with PAF, it may be possible to use PAF-AH as a marker for anaphylactic severity. To test this, Dr. Upton conducted a trial at SickKids, in which the reaction severity of pediatric patients admitted to the emergency department with acute anaphylaxis was compared to the measured PAF-AH levels in their blood.¹² It was found that children with severe anaphylaxis had lower levels of PAF-AH.¹² To determine if this pattern was consistent in the absence of an allergic reaction, follow-up tests were performed on the same patients four weeks later, revealing the same result: children who were severely anaphylactic had lower PAF-AH levels even at baseline.¹² This was a breakthrough in furthering the understanding of the intrinsic, individual markers that predict one’s vulnerability to allergies.

 Our discussions with Dr. Upton converged on a common theme: the need for individualized and personalized care in food allergy treatment discovery. When asked about the future of allergy treatment, Dr. Upton emphasized that a multifaceted, holistic approach is essential: “It is not just about the food or dose, but also these personal and individual factors that we must consider.” By breaking free from the view that strict avoidance is the only way to treat allergies, we can take steps to “teach” our immune system to make the right decisions.

References

1.Gupta R, Marvel J, Tassinari P, T. Mnif, M. Hleyhel, Vincent B, et al. Global Prevalence of Pediatric and Adult IgE-mediated Food Allergies: Results: FROM THE ASSESS FA STUDY. Annals of Allergy, Asthma & Immunology.2023 Nov 1;131(5): S7–8.

2.Health Canada. Common food allergens-Canada.ca [Internet]. Canada.ca.2019. Available from: https://www.canada.ca/en/health-canada/services/food-nutrition/food-safety/food-allergies-intolerances/food-allergies.html

3.Anvari S, Miller J, Yeh CY, Davis CM. IgE-Mediated Food Allergy. Clinical Reviews in Allergy & Immunology[Internet].2018 Oct 29;57(2):244–60. Available from: https://pubmed.ncbi.nlm.nih.gov/30370459/

4.Upton J, Eiwegger T. How Low Should We Go? International Archives of Allergy and Immunology.2015;168(3):147–9.

5.Upton J, Arnon Elizur. Target maintenance dose for peanut OIT is 300 mg protein (or less): Pros and cons. Allergy.2024 Jun 6;79(8):2305–6.

6.Anagnostou A, Upton J, Chinthrajah R. The promise of sublingual and other immunotherapy options for infants and toddlers with food allergy. The Journal of Allergy and Clinical Immunology.2024Jan1;153(1):95–7.

7.Greenhawt M, Sindher SB, Wang J, O’Sullivan M, George du Toit, Kim EH, et al. Phase 3 Trial of Epicutaneous Immunotherapy in Toddlers with Peanut Allergy. The New England Journal of Medicine.2023May11;388(19):1755–66.

8.Gonzalez PM, Cassin AM, Durban R, Upton J. Effects of Food Processing on Allergenicity. Current Allergy and Asthma Reports.2025Jan13;25(1).

9.Upton JEM, Lanser BJ, Bird JA, Nowak-Węgrzyn A. Baked Milk and Baked Egg Survey: A Work Group Report of the AAAAI Adverse Reactions to Foods Committee. The Journal of Allergy and Clinical Immunology: In Practice.2023Aug;11(8):2335-2344.e4.

10.Rondeau LE, Sanchez-Martinez E, Garrido-Romero M, Barbosa B, Haas DA, Yuen G, et al. Microbial metabolism of food allergens determines the severity of IgE-mediated anaphylaxis. bioRxiv (Cold Spring Harbor Laboratory).2025Feb19.

11.Upton J, Grunebaum E, Sussman G, Vadas P.Platelet Activating Factor (PAF): A Mediator of Inflammation. BioFactors. 2022Aug27;6(48).

12.Upton J, Hoang JA, Leon‐Ponte M, Finkelstein Y, Du YJ, Khosrow Adeli, et al.Platelet‐activating factor acetylhydrolase is a biomarker of severe anaphylaxis in children. Allergy. 2022Apr9;77(9):2665–76.