# Lecture 25: Allergy and Asthma
## Immunology
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## Learning Objectives
By the end of this lecture, students will be able to:
1. Define atopy and describe the genetic and environmental factors that predispose to allergic disease
2. Explain the immunological mechanisms of allergic sensitization and the role of Th2 immunity
3. Describe the pathophysiology of allergic asthma including early and late phase responses
4. Discuss the hygiene hypothesis and its modern refinements
5. Explain the mechanisms and clinical applications of allergy treatments including allergen immunotherapy and anti-IgE therapy
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## Lecture Content
### I. Allergy and Atopy: Overview
**Allergy** is defined as an adverse immune response to a normally harmless environmental antigen, known as an allergen. **Atopy** refers to the genetic predisposition to mount exaggerated IgE responses to common environmental allergens. Atopic individuals are at risk for the **atopic triad** of allergic rhinitis, allergic asthma, and atopic dermatitis (eczema). Many atopic children follow the **atopic march**, a typical progression from eczema to food allergy to allergic rhinitis to asthma.
Allergic diseases affect approximately 20 to 30 percent of the population in developed countries, and their prevalence has increased dramatically over the past 50 years. Common allergens include house dust mite proteins (Der p 1, Der p 2), pollen from trees, grasses, and ragweed, animal dander (such as Fel d 1 from cats), mold spores, foods (peanut, tree nuts, milk, egg, shellfish), insect venoms from bees and wasps, drugs such as penicillin, and latex. Allergens are typically proteins or glycoproteins, and many possess protease activity. For example, Der p 1 cleaves tight junctions between epithelial cells, facilitating penetration of the allergen into subepithelial tissue.
### II. Immunological Basis of Allergic Sensitization
The central immunological feature of allergic disease is a **Th2-skewed immune response**. The process of sensitization begins at epithelial surfaces, where **epithelial alarmins** initiate the allergic cascade. When allergens breach or interact with epithelial barriers in the skin, airway, or gut, damaged or activated epithelial cells release alarmins including IL-25, IL-33, and TSLP (thymic stromal lymphopoietin). These alarmins activate dendritic cells and promote Th2 differentiation, while also activating type 2 innate lymphoid cells (ILC2s) to produce early IL-5 and IL-13.
**Th2 cell differentiation** occurs when dendritic cells activated by alarmins upregulate OX40L and suppress IL-12 production, driving naive CD4+ T cells toward the Th2 fate under the control of the master transcription factor GATA3. The resulting Th2 cells produce a characteristic set of cytokines. **IL-4** drives IgE class switching in B cells and promotes further Th2 differentiation through an autocrine loop. **IL-5** is essential for eosinophil differentiation, activation, and survival. **IL-13** induces mucus hypersecretion, goblet cell metaplasia, airway hyperresponsiveness, and also contributes to IgE class switching. **IL-9** promotes mast cell proliferation.
The final step in sensitization is **IgE production and mast cell arming**. IL-4 and IL-13 drive B cell class switching to IgE, which then binds to FcepsilonRI on mast cells and basophils with very high affinity (Kd of approximately 10^-10 M). Despite its short serum half-life of about 2 days, IgE has a long functional half-life on mast cells, keeping them sensitized for weeks to months.
### III. Allergic Asthma
Allergic asthma is a chronic inflammatory airway disease characterized by reversible airflow obstruction, airway hyperresponsiveness, and airway remodeling. Its pathophysiology unfolds in three temporal phases.
**The early-phase response** occurs within minutes of allergen inhalation. The inhaled allergen cross-links IgE on mast cells residing in the airway submucosa, triggering degranulation and release of histamine, prostaglandin D2, and leukotrienes C4, D4, and E4. The effects are immediate: bronchoconstriction from smooth muscle contraction, mucus secretion, vasodilation, and mucosal edema. Patients experience wheezing, shortness of breath, cough, and chest tightness. This phase typically resolves within 1 to 2 hours.
**The late-phase response** develops 4 to 8 hours after exposure. Mast cell-derived cytokines, particularly TNF-alpha, IL-4, IL-5, and IL-13, along with chemokines such as eotaxin (CCL11), recruit inflammatory cells to the airways. **Eosinophils** are the hallmark cells of allergic asthma and are accompanied by Th2 cells, basophils, and in severe asthma, neutrophils. Eosinophils cause substantial damage through their granule proteins, including major basic protein (MBP), eosinophil cationic protein (ECP), and eosinophil peroxidase (EPO). These mediators cause epithelial damage, smooth muscle contraction, and mucus hypersecretion. Leukotrienes and platelet-activating factor released from eosinophils further amplify the inflammation, producing sustained bronchoconstriction.
**Chronic inflammation and airway remodeling** develop with persistent Th2 inflammation and lead to structural changes in the airway. These include **goblet cell metaplasia** with increased mucus-producing cells driven by IL-13, **subepithelial fibrosis** from collagen deposition beneath the basement membrane, **smooth muscle hypertrophy and hyperplasia** resulting in increased muscle mass and exaggerated bronchoconstriction, **angiogenesis** with new blood vessel formation in the airway wall, and **epithelial shedding** with loss of ciliated epithelium. These remodeling changes contribute to **fixed airflow obstruction**, representing an irreversible component in severe or long-standing asthma.
A cross-sectional diagram comparing a normal airway to an asthmatic airway during an acute attack and chronic remodeling. Left panel (Normal airway): Open lumen, thin epithelium with ciliated cells and occasional goblet cells, thin basement membrane, relaxed smooth muscle layer, no inflammatory infiltrate. Middle panel (Acute asthma -- early/late phase): The lumen is narrowed. Mast cells in the submucosa are shown degranulating (releasing histamine, leukotrienes). Smooth muscle is contracted. Mucus plugs are present in the lumen. Eosinophils, Th2 cells, and basophils infiltrate the submucosa. Edema and vasodilation are shown in the airway wall. The epithelium shows damage and shedding. Right panel (Chronic remodeling): The airway wall is thickened. Goblet cell metaplasia (increased goblet cells, decreased ciliated cells). Thickened basement membrane with subepithelial fibrosis (collagen deposition). Hypertrophied and hyperplastic smooth muscle layer. New blood vessels (angiogenesis). Persistent eosinophilic infiltrate. The lumen is permanently narrowed. Labels indicate the contributions of specific mediators: IL-13 (goblet cell metaplasia), IL-5 (eosinophilia), TGF-beta (fibrosis).
### IV. The Hygiene Hypothesis and Microbiome
The observation that allergic diseases are more prevalent in developed, urbanized countries and have increased over recent decades has prompted several explanatory hypotheses. The **original hygiene hypothesis**, proposed by Strachan in 1989, suggested that reduced childhood exposure to infections shifts immune balance toward Th2 dominance, increasing allergy susceptibility.
Modern refinements have expanded this concept considerably. The **microbiome hypothesis** proposes that reduced microbial diversity in early life, rather than simply reduced infections, impairs immune regulation. Caesarean delivery, formula feeding, and antibiotic use alter the gut microbiome and increase allergy risk, while farm exposure, pet ownership, and having older siblings provide greater microbial diversity and protection. The **regulatory T cell hypothesis** suggests that microbial exposure promotes Treg development, which suppresses inappropriate Th2 responses. Supporting this, helminth infections drive strong Treg and IL-10 responses that dampen allergy, and an inverse correlation between helminth infection and allergy prevalence has been observed across populations.
The **epithelial barrier hypothesis** proposes that modern environmental factors such as detergents, microplastics, and processed food damage epithelial barriers, increasing allergen penetration and promoting sensitization. The broader **biodiversity hypothesis** posits that loss of contact with natural biodiversity reduces the immune regulatory mechanisms that would otherwise keep allergic responses in check.
### V. Diagnosis of Allergic Disease
Several diagnostic tools are used to identify and characterize allergic disease. The **skin prick test** introduces a small amount of allergen into the dermis; a positive result manifests as a wheal-and-flare reaction within 15 to 20 minutes, indicating mast cell degranulation in sensitized individuals. **Serum-specific IgE** testing (ImmunoCAP) measures allergen-specific IgE levels in blood. **Total serum IgE** is often elevated in atopic individuals but is non-specific. **Component-resolved diagnostics** measure IgE against specific allergen protein components, enabling better risk stratification; for example, IgE against Ara h 2 in peanut allergy predicts systemic reactions. **Spirometry and bronchoprovocation** testing assess reversible airflow obstruction in asthma, while methacholine challenge evaluates airway hyperresponsiveness. **Blood eosinophil count and FeNO** (fractional exhaled nitric oxide) serve as biomarkers of type 2 airway inflammation.
### VI. Treatment of Allergic Disease
Treatment of allergic disease employs multiple strategies at different levels of the inflammatory cascade.
**Allergen avoidance** is the first-line approach where possible, including dust mite covers, pet removal, and food avoidance.
**Pharmacotherapy** provides symptomatic relief and disease control. **Antihistamines** (H1 receptor blockers such as cetirizine and loratadine) relieve pruritus, rhinorrhea, and urticaria. **Inhaled corticosteroids** are the first-line controller therapy for persistent asthma, broadly suppressing airway inflammation. **Leukotriene receptor antagonists** such as montelukast block the LTD4 receptor, reducing bronchoconstriction and inflammation. **Short-acting beta2-agonists** (salbutamol) serve as rescue bronchodilators, while **long-acting beta2-agonists** (salmeterol, formoterol) are used with inhaled corticosteroids as controller therapy. **Epinephrine** is the emergency treatment for anaphylaxis, acting through alpha1 receptors to produce vasoconstriction, beta2 receptors for bronchodilation, and beta1 receptors to support cardiac output. **Mast cell stabilizers** such as cromolyn sodium prevent degranulation when used prophylactically.
**Biologic therapies** target specific inflammatory pathways in moderate-to-severe asthma and allergy. **Omalizumab** is an anti-IgE monoclonal antibody that binds free IgE, preventing FcepsilonRI binding and reducing mast cell sensitization. **Mepolizumab and reslizumab** target IL-5 to reduce eosinophils, while **benralizumab** targets IL-5Ralpha and depletes eosinophils via ADCC. **Dupilumab** blocks the IL-4Ralpha subunit, inhibiting both IL-4 and IL-13 signaling for a broad anti-type 2 effect applicable across asthma, atopic dermatitis, and nasal polyps. **Tezepelumab** blocks TSLP, an upstream epithelial alarmin.
**Allergen immunotherapy (AIT)**, also known as desensitization, is administered via subcutaneous injection (SCIT) or sublingual tablet/drops (SLIT). Gradually increasing doses of allergen are given over months to years. The mechanisms include induction of allergen-specific Tregs producing IL-10 and TGF-beta, a shift in antibody response from IgE to IgG4 (which acts as a blocking antibody), reduced mast cell and basophil reactivity, and dampened Th2 responses. Immunotherapy can achieve long-term tolerance that persists after treatment discontinuation and is effective for allergic rhinitis, venom allergy, and some cases of asthma.
A diagram showing the mechanisms and targets of biologic therapies for allergic asthma. The allergic inflammatory cascade is shown from top to bottom: epithelial cell damage releases alarmins (TSLP, IL-25, IL-33). TSLP activates DCs (tezepelumab blocks TSLP, shown with an X). DCs activate Th2 cells, which produce IL-4, IL-5, and IL-13. IL-4 and IL-13 act on B cells to produce IgE (dupilumab blocks IL-4Ralpha, shown with an X). Free IgE binds FcεRI on mast cells (omalizumab blocks free IgE, shown with an X). IL-5 acts on eosinophils for differentiation and survival (mepolizumab and reslizumab block IL-5; benralizumab blocks IL-5Ralpha, shown with X marks). IL-13 acts on goblet cells (mucus) and smooth muscle (contraction). Each biologic is labeled at its point of action in the cascade, showing how different drugs target different levels of the pathway.
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