Food Allergies Explained: The Immunology of Oral Tolerance

The Science Behind Why Some Foods Trigger Allergies While Others Don't

Beyond the headlines and social media posts, food allergies represent real, daily challenges for millions of families worldwide. As parents nervously introduce new foods to their infants, as school cafeterias establish "nut-free zones," and as adults scrutinize restaurant menus, the impact of food allergies extends far beyond clinical statistics.

In the past few months, food allergies have been receiving an increasing amount of attention. We've heard a call to "solve the food allergy mystery" coming from health leaders who seem to be prioritizing quick and alternative fixes over continuing research that has slowly and rigorously been unraveling the complicated science behind allergies. As public health experts, pediatricians, and immunologists, we felt it was essential to share accurate information about the underlying immunology and present genuine scientific evidence.

The reality is that the immune system and allergies are incredibly complex. Allergies arise as a complicated interplay between each individual's immune system, genetic predisposition, and environmental exposure. Understanding the immunological mechanisms behind food allergies is crucial for developing effective treatments and improving the quality of life for affected individuals. By identifying how the immune system mistakenly targets harmless food proteins, scientists can develop therapies that prevent or mitigate these adverse reactions. Let’s discuss…

The Science of Oral Tolerance

Watch a toddler for five minutes, and you’ll quickly realize: our bodies are exposed to countless things every day through our mouths. They chew on rocks, share half-eaten snacks, and occasionally lick doorknobs just for fun. Through it all, the immune system is constantly working to decide what’s dangerous and needs to be attacked and what’s harmless or helpful and should be left alone or “tolerated”.

Oral tolerance is the immune system's ability to be unresponsive to or tolerant of the food we eat. Our mucosal immune system within the gastrointestinal tract (aka ‘gut’) encounters a wide variety of dietary antigens, such as proteins and other biomolecules, from the food we eat every day. Instead of responding to these dietary antigens as a threat, the mucosal immune system learns to recognize these substances as harmless to induce tolerance to the foods that we need to grow and survive. This process involves specialized immune cells in the gut (discussed below), which help modulate the immune response toward tolerance. By building and maintaining oral tolerance, the immune system distinguishes between harmful pathogens and harmless dietary antigens from food to prevent allergic reactions. Oral tolerance is the immune system's way of ensuring that we can safely consume a wide variety of foods without adverse effects.

But sometimes oral tolerance goes awry, and food allergies arise when the immune system mistakenly identifies certain dietary antigens as harmful invaders. This can trigger an immune response, leading to symptoms such as hives, swelling, digestive issues, or even severe and life-threatening reactions like anaphylaxis. Anaphylaxis is a severe, life-threatening allergic reaction that occurs rapidly and can cause symptoms like difficulty breathing, a sudden drop in blood pressure, swelling, and death. The most common food allergens include peanuts, tree nuts, fish, shellfish, sesame, soy, egg, milk, and wheat. The immune system's inappropriate overreaction to these proteins can significantly impact a person's diet and lifestyle, requiring careful management to avoid exposure and ensure safety.

The Role of Immune Cells. Antigen-Presenting Cells (APCs) and T cells

In the gastrointestinal tract (aka ‘gut’), antigen-presenting cells (APCs), like dendritic cells (DCs), play a crucial role in our mucosal immune system. The job of the APC is just what it sounds like - they present antigen to other immune cells, specifically T cells. When we consume food, dietary antigens enter our digestive tract. APCs capture and internalize these antigens to break down the proteins into smaller pieces (chop, chop) and display them on cell surface molecules called major histocompatibility (MHC) proteins. The function of MHC molecules is to display broken-down pieces of protein to T cells. The APCs then travel to the closest lymph nodes (i.e. mesenteric) where they show off or present these antigens to T cells.

FUN FACT: APCs are the most formidable immune cells in the body - they capture the invading enemy, chop it into bits, and then display the chopped-up bits of their enemy on the surface of their own body to show their friends the enemy that needs to be vanquished.

There are many types of T cells in the body, but it is the T regulatory cells (Tregs) that play a crucial role in maintaining immune homeostasis. When broken down bits of dietary antigen are presented by APCs, Tregs help modulate the immune response by secreting anti-inflammatory cytokines like IL-10 and TGF-β. Think of cytokines as radio signals to other cells of the immune system. These cytokines inhibit the activation and proliferation of effector T cells that might otherwise mount an immune response against harmless food proteins. This suppression is essential for maintaining oral tolerance and preventing hypersensitivity reactions that result in food allergies. Tregs help maintain gut health and prevent inappropriate immune responses by ensuring that the immune system remains tolerant to dietary antigens.

However, when this process goes awry, it can lead to food allergies where the immune system mistakenly identifies harmless food proteins as threats. This misidentification can lead to an inappropriate immune response with symptoms ranging from mild hives to severe anaphylaxis.

When Oral Tolerance Fails, Food Allergies Arise

Sensitization to food allergens is the initial phase in developing a food allergy; it is essentially the body's way of accidentally "learning" to recognize and attack certain foods as threats. During this process, the immune system mistakenly identifies certain harmless food proteins as harmful. Upon first exposure to these proteins, the B cells of the immune system (cells that make antibodies) are given cytokine ‘instructions’ by T cells to produce a specific type of antibody called Immunoglobulin E (IgE). These IgE antibodies are responsible for allergies. The IgE antibodies flow through the blood and attach to immune granulocytes, called mast cells and basophils, where they act as surrogate receptors for allergens. The binding of IgE to these granulocytic cells primes the body to react to the allergen upon subsequent exposures.

When the food protein is encountered again and the IgE bound to the surface of the mast cells and basophils binds allergen, it results in immediate release of a variety of chemicals, like histamine, stored in the granules. Histamine and other chemicals lead to allergic symptoms. Some allergic responses, such as anaphylaxis, are rapid and life-threatening reactions that include symptoms like difficulty breathing, a sudden drop in blood pressure, and swelling. In some cases, they can be fatal without a lifesaving shot of epinephrine (via an Epipen) to reverse the response. This over-reactive - or hypersensitive - immune response is the body's misguided attempt to protect itself from what it mistakenly perceives as a harmful substance.

Factors that Influence the Development of Food Allergies

Genetic predisposition significantly influences the development of food allergies, with certain genes increasing the likelihood of developing allergies. Variations in genes related to the immune system's response, such as those affecting cytokine and IgE antibody production, can heighten susceptibility to allergic reactions. Environmental factors also play a crucial role. Early dietary habits, the gut microbiome, and exposure to diverse microorganisms impact oral tolerance and allergy development. As mentioned in a previous Unbiased Science Substack article, the hygiene hypothesis suggests that reduced microbial exposure in childhood may impair immune system balance, while pollution, tobacco smoke, and urban living conditions can increase allergy risk. Together, these genetic and environmental factors interact to shape the development of food allergies.

Advances in Understanding Oral Tolerance

Research over decades has revealed important discoveries in the mechanisms of oral tolerance and highlighted several key processes. Researchers have identified how dietary antigens are taken up and transported across the intestinal epithelial barrier for presentation to immune cells. The role of different antigen-presenting cells in processing and presenting dietary antigens has also been revealed. Additionally, the development of immunosuppressive T cell populations that mediate antigen-specific tolerance is better understood. Studies have also emphasized the importance of the gut microbiota in maintaining intestinal barrier function and influencing immune responses. These insights are paving the way for new therapeutic strategies to prevent and treat food allergies and autoimmune diseases.

As an example, the Learning Early About Peanut (LEAP) study investigated the impact of peanut consumption versus avoidance in preventing peanut allergy among high-risk infants. The study involved 640 infants with severe eczema or egg allergy, randomly assigned to either consume or avoid peanuts until 5 years of age. Results revealed that early peanut consumption significantly reduced the prevalence of peanut allergy compared to avoidance. The study concluded that early peanut introduction effectively decreases the risk of developing a peanut allergy and modulates immune responses toward oral tolerance. Following the data, this study revolutionized the way that pediatricians suggest parents and caregivers approach the introduction of peanuts to the diet of infants. Prior to this study, many pediatricians recommended avoiding potential food antigens. Yes, we were wrong. Be on the lookout for a ‘deep dive’ into the LEAP study and peanut allergy in an upcoming newsletter!

The Future of Therapeutic Approaches to Food Allergy

Continued research is critical to pave the way for emerging treatments for restoring oral tolerance and preventing food allergies. Oral immunotherapy (OIT) is one approach that involves gradually introducing small amounts of the allergenic food in the form of capsules or powders under medical supervision to desensitize the immune system and build oral tolerance. Sublingual immunotherapy (SLIT) is another approach that involves placing drops of the allergen under the tongue, where it is absorbed through the mucous membranes. SLIT typically uses much smaller doses of the allergen compared to OIT and is considered to have a higher safety profile. Both methods aim to desensitize the immune system to the allergen through inducing oral tolerance, but they differ in administration and dosage. Achieving sustained unresponsiveness or long-lasting oral tolerance does not indicate the food allergy has been cured. More research is needed to evaluate the true induction of oral tolerance.

Biologic therapies, such as omalizumab, a monoclonal antibody that binds and neutralizes IgE, is another therapeutic option. A recent study published in the Journal of Clinical Allergy and Immunology revealed that a 16-week course of omalizumab increased the amount of peanut, tree nuts, egg, milk, and wheat that multi-food allergic children as young as 1 year could consume without an allergic reaction. Very promising results for the NIH-sponsored phase 3 Omalizumab as Monotherapy and as Adjunct Therapy to Multi-Allergen Oral Immunotherapy in Food Allergic Children and Adults (OUtMATCH) trial were recently reported at the March 2025 American Academy of Allergy, Asthma, and Immunology meeting. This study compared omalizumab to OIT and found that tolerability outcome data suggested a superior safety profile for omalizumab compared to OIT for persons with multiple food allergies.

Treatments like these are paving the way for more effective management of food allergies and improving the quality of life for affected individuals. Recent advancements in food allergy treatments, such as oral immunotherapy (OIT), sublingual immunotherapy (SLIT) and biologic therapies like omalizumab, have shown promise in increasing tolerance and reducing allergic reactions. However, these treatments are still in the early stages and come with limitations, including varying efficacy and potential side effects.

Further studies are essential to refine these approaches, enhance their safety profiles, and develop more effective treatments to improve the quality of life for individuals with food allergies. Unfortunately, cuts to U.S. research funding jeopardize this critical research.

Key Takeaways

• Oral tolerance is the immune system's ability to accept dietary antigens without triggering adverse reactions

• This process of inducing oral tolerance involves specific antigen-presenting cells (APCs) that capture and present dietary antigens to T cells, which then differentiate into regulatory T cells (pTregs) to suppress immune responses

• When oral tolerance mechanisms fail, the immune system mistakenly identifies food proteins as threats, leading to the production of IgE antibodies and allergic reactions

• Recent research has highlighted the importance of specific cell types and interactions in maintaining oral tolerance, providing valuable insights that could lead to new treatments for food allergies

What This Means For You and Your Family

The science of oral tolerance may seem complex, but it explains phenomena you might witness in your own life - from why some children outgrow food allergies to how new treatments help retrain the immune system to recognize foods as harmless rather than threatening. Understanding these mechanisms gives us hope for better treatments and prevention strategies.

For those living with food allergies or caring for someone who does, knowledge is empowering. The research breakthroughs described above are steadily translating into clinical practices that improve quality of life. The LEAP study fundamentally changed how we introduce potentially allergenic foods to infants, and treatments like omalizumab show genuine promise for people with multiple food allergies.

We'll be diving deeper into specific food allergies in future newsletters, starting with a comprehensive look at peanut allergies next month. Science moves forward one careful step at a time, and we're committed to bringing you updates that matter to your health decisions.

Stay Curious,

Unbiased Science

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