Food allergies and the immune response are deeply connected through a complex interplay of cellular communication, antibody activity, and inflammatory signaling. While many people are familiar with the concept of food allergies, few understand the immunological mechanisms behind them — particularly the roles of IgE antibodies and mast cells. These reactions are not simply food-related discomforts; they are manifestations of the immune system’s capacity to misidentify harmless food proteins as dangerous invaders.
In this article, we’ll explore what happens at a cellular and molecular level when someone with a food allergy consumes an allergenic food. We’ll examine the initial sensitization process, the activation of IgE-mediated pathways, and the function of mast cells and basophils in unleashing a full-blown allergic response. By understanding how the immune system interprets food proteins as threats, we gain critical insight into why symptoms occur and how therapies are designed to intervene.
This scientific deep dive is especially useful for healthcare professionals, students, and anyone who wants to move beyond surface-level definitions. By the end, you’ll have a clearer picture of the inner workings of food allergies and the immune response, and why targeting IgE and mast cells forms the cornerstone of both diagnosis and treatment.
The Immune System’s Role in Defending the Body
To understand food allergies and the immune response, we must begin with the immune system’s primary job: protecting the body from harmful invaders such as bacteria, viruses, and parasites. This defense system is incredibly complex and includes a network of cells, tissues, and signaling molecules that distinguish self from non-self and respond accordingly.
The immune system is divided into two major branches:
- Innate immunity, which offers a general defense and responds rapidly to threats
- Adaptive immunity, which learns to recognize specific threats and mounts targeted responses through T cells and B cells
In a healthy person, food proteins are recognized as harmless substances. The immune system, particularly within the gut-associated lymphoid tissue (GALT), maintains tolerance to these dietary proteins through processes like oral tolerance, involving regulatory T cells and anti-inflammatory cytokines.
However, in people with food allergies, this system malfunctions. Instead of promoting tolerance, the adaptive immune system identifies certain food proteins as threats. This error leads to sensitization, a process in which the body produces allergen-specific IgE antibodies that prepare the immune system for future attacks. Once sensitized, even trace amounts of the offending food can provoke a powerful reaction.
This inappropriate immune response sets the stage for activation of effector cells like mast cells and basophils, which are central to the symptoms of food allergy — from hives and vomiting to life-threatening anaphylaxis.
What Happens in a Food Allergy?
Food allergies and the immune response become tightly linked during a two-phase process: sensitization and reactivity. A food allergy doesn’t appear the first time a person eats an allergenic food. Instead, it develops over time through a stepwise breakdown in immune tolerance and an inappropriate escalation of immune defense.
Step 1: Sensitization — The First Mistake
Sensitization begins when a person is exposed to a food protein—often through the skin, gut, or respiratory tract—and the immune system mistakes it for a harmful pathogen. Specialized immune cells called dendritic cells capture the protein and present it to naïve T cells, which then differentiate into Th2 helper T cells. These Th2 cells secrete interleukin-4 (IL-4) and other cytokines, signaling B cells to produce IgE antibodies specific to that food protein.
This IgE doesn’t cause symptoms immediately. Instead, it binds to FcεRI receptors on the surface of mast cells and basophils, essentially priming them for future exposure.
This step of IgE production and mast cell sensitization is what makes future allergic responses possible — even to trace amounts of the food.
Step 2: Re-Exposure — The Allergic Reaction
Once a person is sensitized, re-exposure to the same food allergen can rapidly trigger a reaction. The allergen cross-links the surface-bound IgE molecules on mast cells, causing them to degranulate — a process in which they release inflammatory chemicals such as:
- Histamine: Causes blood vessels to dilate, leading to swelling, hives, and itchiness
- Leukotrienes and prostaglandins: Contribute to bronchoconstriction and mucus secretion
- Cytokines: Recruit other immune cells, prolonging the inflammatory response
This cascade can manifest in various tissues — skin, gut, lungs, or cardiovascular system — depending on where mast cells are activated.
Systemic Impact: Anaphylaxis
In some individuals, the immune reaction spreads rapidly across multiple systems, leading to anaphylaxis — a life-threatening condition marked by airway obstruction, hypotension, and collapse. This is why prompt recognition and treatment with epinephrine is critical in known food allergy cases.
IgE Antibodies — The Allergen-Specific Signal
Food allergies and the immune response are most clearly linked by a single molecular player: immunoglobulin E (IgE). These antibodies serve as the immune system’s “early warning system” in allergic individuals, tagging specific food proteins as dangerous and setting off a chain reaction that can lead to mild symptoms — or life-threatening anaphylaxis.
What Is IgE?
IgE is one of five major antibody classes (IgG, IgA, IgM, IgD, and IgE), but it is the least abundant in circulation. Despite its low concentration, it plays an outsized role in allergic disease. IgE antibodies are produced by B cells under the influence of Th2-type helper T cells during the sensitization phase. Once formed, they circulate and rapidly bind to high-affinity receptors (FcεRI) on mast cells and basophils.
How IgE Works in Allergic Reactions
On re-exposure to the food protein, the allergen cross-links multiple IgE molecules on the surface of a mast cell or basophil. This cross-linking serves as a danger signal, prompting the cell to degranulate — releasing stored inflammatory mediators such as:
- Histamine: triggers itching, swelling, and hives
- Tryptase: a protease that helps break down tissues and recruit more immune cells
- Cytokines and leukotrienes: promote broader immune system activation and inflammation
These rapid chemical releases lead to the classic symptoms of IgE-mediated food allergies: itchy skin, difficulty breathing, gastrointestinal distress, and — in severe cases — cardiovascular collapse.
Why IgE Is So Specific
The precision of IgE-allergen binding is what makes allergic reactions so selective. One person may react to peanut protein Ara h 2 but tolerate other legumes, while another may be sensitized to milk but not egg. This molecular specificity underpins current research into component-resolved diagnostics (CRD), which help determine which exact protein fractions a person reacts to.
IgE’s Role in Diagnosis
Because of its central role, IgE is a key marker in diagnostic testing:
- Skin prick tests measure localized IgE-driven reactions
- Serum-specific IgE blood tests identify circulating IgE antibodies to specific food proteins
However, a positive test alone doesn’t equal a clinical allergy. Many people have detectable IgE without symptoms, so results must be interpreted in the context of clinical history and, when needed, oral food challenges.
Mast Cells — The Body’s Rapid Responders
Food allergies and the immune response are defined not only by the presence of IgE, but by the dramatic effects of mast cell activation. These immune cells act as sentinels stationed throughout the body — particularly in tissues most likely to encounter allergens, such as the skin, lungs, and gastrointestinal tract. Once sensitized by IgE, mast cells are the front-line responders that turn immune memory into physical symptoms.
Where Mast Cells Reside
Mast cells are embedded in connective tissues near blood vessels, nerves, and mucosal surfaces. They’re found in especially high numbers in:
- Skin — causing hives or flushing when activated
- Airways — contributing to wheezing, throat tightness, or cough
- Gut lining — leading to cramping, vomiting, or diarrhea
Their strategic placement allows them to respond quickly to invading pathogens — or, in the case of food allergies, to mistakenly “invading” food proteins.
What Happens When Mast Cells Are Activated
When a sensitized individual eats an allergenic food, the food protein binds and cross-links surface-bound IgE molecules on mast cells. This triggers degranulation, releasing potent pre-formed mediators as well as newly synthesized compounds, including:
- Histamine: dilates blood vessels, increases permeability, causes itching
- Tryptase: activates surrounding immune responses and degrades extracellular matrix
- Leukotrienes & prostaglandins: contribute to bronchoconstriction, mucus secretion, and prolonged inflammation
- Cytokines: recruit additional immune cells like eosinophils and neutrophils
These effects produce the rapid, multisystem symptoms characteristic of an allergic reaction — including urticaria (hives), angioedema (swelling), nausea, and in some cases, anaphylaxis.
Mast Cells vs. Basophils
While similar in function, mast cells and basophils differ in their location and longevity:
- Mast cells reside in tissues and are long-lived
- Basophils circulate in the blood and are shorter-lived
Both are activated by IgE and contribute to allergic inflammation, but mast cells are more central to immediate hypersensitivity responses in food allergies.
Clinical Relevance
Understanding the role of mast cells helps explain:
- Why symptoms can differ by location (skin vs. gut vs. airway)
- Why antihistamines relieve some but not all symptoms (they only block histamine, not other mediators)
- Why treatments targeting mast cell stabilization (e.g., cromolyn sodium) or IgE blockade (e.g., omalizumab) are being explored in food allergy management
The Allergic Cascade — From Exposure to Reaction
Food allergies and the immune response culminate in a rapid, often dramatic cascade of events once a sensitized individual is re-exposed to their allergen. This chain reaction, known as the immediate hypersensitivity response, transforms molecular recognition into physical symptoms — often within seconds to minutes.
Step-by-Step Breakdown of the Allergic Cascade
1. Re-exposure to the Allergen
The individual ingests (or in some rare cases, inhales or touches) a food protein they’ve previously been sensitized to — for example, peanut, milk, or shellfish protein.
2. Allergen Recognition and IgE Cross-Linking
The allergen binds to and cross-links IgE antibodies already attached to the surface of mast cells and basophils via the FcεRI receptor.
3. Mast Cell and Basophil Degranulation
This cross-linking triggers the rapid release of pre-formed mediators, including:
- Histamine → swelling, hives, flushing, itching
- Tryptase → tissue remodeling and amplification of inflammation
- Heparin → anticoagulant activity and vascular effects
Within minutes, new mediators are also synthesized:
- Leukotrienes → bronchoconstriction, mucus secretion
- Prostaglandins → vasodilation, pain, fever
- Cytokines (e.g., IL-4, IL-5, TNF-α) → recruit eosinophils and other inflammatory cells
4. Tissue-Specific Symptoms Appear
Symptoms vary depending on where mast cells are activated:
- Skin: Hives, flushing, itching, angioedema
- Respiratory tract: Wheezing, coughing, throat tightness
- Gastrointestinal tract: Nausea, vomiting, cramping, diarrhea
- Cardiovascular system: Drop in blood pressure, dizziness, shock
Biphasic and Delayed Reactions
In some cases, symptoms return 4 to 8 hours after the initial reaction — a biphasic reaction. This occurs due to delayed mediator release and sustained cytokine activity. Importantly, epinephrine may control the initial phase, but patients still require observation because the second wave can be equally dangerous.
Why the Reaction Can Be So Severe
The immune system evolved to react this aggressively to threats like parasites — large invaders that require potent, multi-system defenses. In allergic individuals, however, this powerful response is misdirected at harmless food proteins, which explains the disproportionate reaction.
Basophils — Supporting Players in the Immune Response
Food allergies and the immune response involve more than just mast cells — basophils, a lesser-known type of white blood cell, also contribute to allergic inflammation. Though often overshadowed by mast cells, basophils play an important role in sustaining and amplifying allergic reactions, especially in the bloodstream and during chronic allergic states.
What Are Basophils?
Basophils are granulocytes, a class of immune cells containing granules rich in histamine and other pro-inflammatory chemicals. Unlike mast cells, which reside in tissues, basophils circulate in the blood. They represent less than 1% of white blood cells, yet their impact in allergic disease is disproportionately large.
Basophils and IgE
Like mast cells, basophils express the high-affinity IgE receptor (FcεRI) on their surface. During sensitization, IgE antibodies produced by B cells bind to these receptors, coating the basophils. Upon re-exposure to the allergen, IgE cross-linking triggers degranulation, releasing:
- Histamine
- Leukotrienes
- Interleukin-4 (IL-4) and Interleukin-13 (IL-13) — which promote further Th2 polarization, reinforcing the allergic state
These cytokines help perpetuate the type 2 immune response, a hallmark of allergic conditions.
How Basophils Differ from Mast Cells
| Feature | Mast Cells | Basophils |
|---|---|---|
| Location | In tissues (e.g., skin, gut) | Circulate in bloodstream |
| Lifespan | Long-lived | Short-lived |
| Activation | IgE + direct tissue signals | Primarily IgE cross-linking |
| Function | Immediate and local response | Amplifies systemic inflammation |
Basophils tend to play a greater role in systemic reactions and in late-phase or chronic allergic responses, helping sustain inflammation after the initial mast cell-driven phase.
Diagnostic Implications
Because basophils circulate in blood, their reactivity can be assessed using basophil activation tests (BATs). These experimental assays measure cell surface markers (e.g., CD63, CD203c) after allergen stimulation and may provide useful insights when standard IgE testing is inconclusive.
The Delayed and Biphasic Reactions
Food allergies and the immune response are most often associated with immediate reactions, but in many cases, the story doesn’t end after the first wave of symptoms. Some individuals experience delayed allergic symptoms, while others go through a biphasic reaction, in which a second round of symptoms occurs hours after the initial response has subsided. These less predictable phases are crucial for understanding the full clinical scope of food allergy reactions.
What Is a Biphasic Reaction?
A biphasic reaction refers to the reappearance of symptoms within 4 to 24 hours after the initial allergic response, without any new allergen exposure. This second phase can be:
- Milder, such as a recurrence of hives or nausea
- Or just as severe, with renewed airway tightening or hypotension
The mechanism is not completely understood, but it likely involves the late-phase recruitment of inflammatory cells, including eosinophils, neutrophils, and cytokine release that sustain or restart the inflammatory response.
What Causes the Delay?
Delayed or biphasic symptoms can result from:
- Ongoing cytokine and chemokine activity following mast cell and basophil degranulation
- Persistent allergen absorption in the gastrointestinal tract
- Secondary immune cell activation, including dendritic cells, eosinophils, and T lymphocytes
How Common Are Biphasic Reactions?
Estimates suggest that up to 20% of anaphylactic reactions may be biphasic, though this varies based on the severity of the initial reaction, co-factors (like asthma), and whether treatment (e.g., epinephrine) was delayed.
For this reason, clinical guidelines recommend that patients treated for anaphylaxis be observed for at least 4–6 hours after symptom resolution — or longer in high-risk cases.
Chronic and Delayed Symptoms in Non-IgE Food Allergies
In addition to biphasic reactions, some individuals with non-IgE–mediated food allergies (e.g., eosinophilic esophagitis or food protein-induced enterocolitis syndrome, FPIES) experience chronic inflammation or delayed GI symptoms hours after ingestion. These reactions are driven more by T cells and eosinophils than by IgE or mast cells, but they are still part of the broader immune response to food.
Diagnostic Relevance — Testing IgE and the Immune Profile
Food allergies and the immune response can only be properly understood—and safely managed—through accurate diagnosis. Since symptoms can resemble intolerances or other conditions, diagnostic testing plays a central role in identifying the presence of allergen-specific IgE antibodies and assessing a person’s true allergic risk.
Step 1: Clinical History
Diagnosis begins with a detailed clinical history, including:
- What food was consumed
- How long after symptoms occurred
- What types of symptoms developed (e.g., hives, vomiting, wheezing)
- Whether symptoms were reproducible or inconsistent
This background determines whether IgE testing is warranted and what tests are appropriate.
Step 2: Skin Prick Testing (SPT)
Skin testing is often the first-line tool for identifying IgE-mediated food allergies. In this test:
- A small amount of food protein is introduced into the skin
- If the person is sensitized, IgE on local mast cells triggers histamine release
- A wheal-and-flare reaction (like a mosquito bite) indicates sensitization
SPTs are highly sensitive but not always specific — false positives can occur, especially in people with eczema or multiple atopic conditions.
Step 3: Serum-Specific IgE Testing
Also called RAST or ImmunoCAP, this blood test measures circulating levels of IgE antibodies specific to individual food proteins. It is useful when:
- Skin testing is not possible (e.g., severe eczema, antihistamine use)
- A systemic baseline of sensitization is needed
- Component testing is desired (e.g., Ara h 2 vs. whole peanut extract)
Higher levels of specific IgE can increase the likelihood of a reaction, but they don’t reliably predict severity.
Step 4: Component-Resolved Diagnostics (CRD)
CRD breaks down foods into individual protein components to better determine risk. For example:
- Peanut Ara h 2 is more strongly associated with severe reactions than Ara h 8
- Egg ovomucoid sensitization may suggest persistence into later childhood
CRD helps distinguish between true allergy and cross-reactive sensitization (as seen in oral allergy syndrome).
Step 5: Oral Food Challenge (OFC)
The gold standard for diagnosing food allergy is a supervised oral food challenge:
- The patient consumes gradually increasing doses of the suspected allergen
- Medical professionals monitor for symptoms
- If no reaction occurs, the food may be considered safe
OFCs are critical when test results are inconclusive or outdated, or to determine whether a child has outgrown an allergy.
Step 6: Basophil Activation Test (BAT)
Used primarily in research or specialized centers, BAT measures basophil degranulation in vitro in response to allergens. It’s helpful when:
- SPT and serum IgE tests give conflicting results
- There’s a history of anaphylaxis and testing is too risky
- Precision is needed for immunotherapy planning
Therapeutic Targets — Blocking IgE and Mast Cell Activation
Food allergies and the immune response have become central to a growing field of immunotherapy research, particularly in targeting the mechanisms that trigger reactions—namely IgE production and mast cell activation. While strict avoidance remains the primary strategy for food allergy management, advances in therapeutics now offer promising alternatives aimed at modifying or suppressing the immune system’s allergic behavior.
Blocking IgE: Anti-IgE Therapy
One of the most important therapeutic advances in recent years has been the development of anti-IgE monoclonal antibodies, particularly omalizumab (Xolair). This medication binds free IgE in the bloodstream and prevents it from attaching to mast cells and basophils.
Benefits:
- Reduces allergic sensitivity over time
- Lowers the risk and severity of reactions
- Can be used alone or as an adjunct to oral immunotherapy (OIT)
Originally approved for asthma and chronic hives, omalizumab is now being studied and used off-label in peanut, milk, egg, and multiple food allergies.
Oral Immunotherapy (OIT)
OIT involves gradually exposing a patient to increasing amounts of an allergen under controlled conditions, with the goal of desensitizing the immune system.
Key facts:
- Can increase the threshold of reactivity (i.e., accidental exposure becomes less risky)
- Often combined with anti-IgE therapy to reduce reactions during escalation
- FDA-approved OIT product: Palforzia (for peanut allergy in children 4–17)
OIT does not “cure” allergies, and daily dosing is often required to maintain desensitization.
Mast Cell Stabilizers and Antihistamines
Though less targeted, medications that block or dampen mast cell activity can be useful:
- H1 antihistamines block histamine receptors on cells (e.g., cetirizine, loratadine)
- Mast cell stabilizers (e.g., cromolyn sodium) prevent degranulation but are less commonly used due to limited effectiveness in food allergy
- Epinephrine remains the first-line emergency treatment for systemic reactions
Personalized Medicine Approach
Because food allergies vary widely in severity, persistence, and immune profile, future treatments are moving toward individualized strategies:
- Combining diagnostics (e.g., CRD, BAT) with tailored immunotherapy
- Matching treatments to IgE profile, age, co-factors (e.g., asthma), and allergen type
Key Takeaways: Food Allergies and the Immune Response
- Food allergies and the immune response are rooted in a misdirected immune reaction, where harmless food proteins are treated as dangerous threats.
- The allergic process begins with sensitization, in which the body produces IgE antibodies against a food allergen. These antibodies bind to mast cells and basophils, priming them for future reactions.
- Upon re-exposure, the allergen cross-links IgE molecules, triggering the release of powerful inflammatory mediators like histamine, leukotrienes, and cytokines, leading to symptoms ranging from hives to life-threatening anaphylaxis.
- Basophils, though less well-known than mast cells, play a supporting role by amplifying systemic inflammation and sustaining chronic allergic responses.
- Some reactions are delayed or biphasic, with symptoms recurring hours after initial exposure, underscoring the need for prolonged observation after treatment.
- Diagnostic tools like skin prick tests, serum-specific IgE, component testing, and oral food challenges help accurately confirm or rule out food allergies.
- Therapies are evolving to move beyond avoidance. Options include anti-IgE therapy, oral immunotherapy, and emerging strategies like epicutaneous immunotherapy and microbiome modulation.
- Understanding the underlying immunology of food allergies enables more accurate diagnosis, personalized treatment, and safer management, especially as novel therapies aim to retrain — rather than just restrain — the immune system.