Lesson 10 Hypersensitivity Type I: Allergy Study Notes

Hypersensitivity Type I: Allergy

Introduction

  • Aims of the Video Series:

    • Discuss the cause and nature of allergy and allergic reactions.

    • Explain how the cause of allergy leads to specific reactions.

    • Explore how BMSs (Biomedical Scientists) and medics collaborate in identifying and diagnosing allergies.

  • Learning Objectives:

    • Explain the impact of genetic and environmental factors on allergy.

    • Describe why specific allergens cause specific reactions.

    • Detail the tests used to diagnose patients and how consultations are used to investigate symptoms.

Contents

  • Predisposition to Allergy (Atopy)

  • Mechanisms of Allergy

  • Types of Reaction

  • Testing for Allergy

Predisposition to Allergy (Atopy)

Learning Objectives

  1. Build awareness of the molecular causes of allergy.

  2. Understand genetic factors that increase the risk of allergies and their effects on the immune system.

Key Points

  • Allergy rates are rising, with approximately 40% of Western populations affected.

  • Allergy is driven by immune reactions characterized by:

    • Production of Immunoglobulin E (IgE) antibodies.

    • Activity of T-helper 2 cells (Th2 cells).

  • A requirement for class switching to IgE by B-cells involves:

    • Increased differentiation of T-cells into Th2 cells.

    • B-cells class switching to IgE.

Molecular Factors Leading to Atopy

  • Cytokines:

    • Overexpression of interleukins (IL-4, IL-5, IL-9, IL-13).

    • GATA-3 Transcription Factor is essential for the expression of these interleukins during T-cell activation.

    • IL-4 suppresses Th1 differentiation while promoting Th2 differentiation and inhibits Treg cell production.

IgE Production Mechanism

  • Process:

    • Th2 cells interact with naïve B-cells via CD40 and CD40L along with IL-13, leading to:

    • Local production of IgE in germinal centers of lymph nodes.

    • IgE binds to receptors on basophils, eosinophils, and mast cells (IgE receptors**).

Role and Implications of IgE

  • IgE functions in immune response through:

    • Positive feedback mechanisms that enhance and intensify IgE responses until the threat is neutralized.

    • Inducing degranulation of immune cells such as mast cells that release inflammatory mediators:

    • Histamine.

    • Interleukins.

    • Colony Stimulating Factors.

    • Lipid Mediators (e.g., leukotrienes, prostaglandins).

  • Aim: Attract and proliferate immune cells in response to allergens, culminating in:

    • An exponential immune response to stimuli.

Summary of Atopy

  • Allergy is a misdirected immune response to non-threatening antigens.

  • It utilizes an escalating immune response to trigger significant reactions.

  • Genetic predisposition increases the likelihood of stronger responses from Th2 cells and IgE.

Mechanisms of Allergy

Learning Objectives

  1. Comprehend the stages from sensitization to allergic reaction.

  2. Understand the cellular and molecular mechanisms involved in allergic reactions.

  3. Differentiate between antigens and allergens.

Stages of Allergy

  1. Sensitization Phase:

    • Initial exposure to allergen produces an immune response without overt misdirection.

  2. Reactive Phase:

    • Subsequent exposure induces strong immunological and physiological responses.

    • Cardinal Signs of Inflammation:

      • Rubor: Redness

      • Calor: Heat

      • Dolor: Pain

      • Tumor: Swelling (can present as a localized inflamed area, described as the "wheal and flare" reaction).

      • Loss of Function: Most prominent in digestive and respiratory systems.

Symptoms of Allergy

  • Allergic tissue reactions are mediated by IgE and activated tissue immune cells:

    • Mast Cells release inflammatory mediators leading to:

    • Histamines, interleukins, and tumor necrosis factors (TNFs) that attract eosinophils and basophils, thereby amplifying inflammation and further mast cell activation.

Common Activators of Mast Cells

  • Key mechanisms and responses include:

    • Interleukin-33 (IL-33): Activates mast cells.

    • Complement (C5a): Enhances inflammation.

    • FcE receptors (FCERI): Critical for IgE-mediated mast cell activation, resulting in degranulation and cytokine release.

Therapeutic Targets

  • Medication Examples related to allergy management:

    • Anti-IgE (e.g., Omalizumab).

    • Histamine antagonists (e.g., Diphenhydramine).

    • Anti-TNF (e.g., Infliximab).

Allergens vs. Parasitic Antigens Comparison

  • Allergen Characteristics:

    • Proteins typically present in high doses, low molecular weight (10-40 Kda), highly soluble, stable, and often enzymatically active.

  • Parasitic Characteristics:

    • Proteins in low doses with variations in activity and stability.

Severity of Allergic Response

  • The dose of allergen correlates directly with the intensity of the response. Higher allergen doses lead to heightened immune responses driven primarily by:

    • Mast cells, eosinophils, basophils.

  • Location and nature of the response dictate symptom severity.

Types of Reaction

Learning Objectives

  1. Understand the connection between allergen exposure and symptomatology.

  2. Differentiate between localized and centralized reactions.

Types of Reactions Observed

  • Anaphylaxis (centralized reaction).

  • Allergic Rhinitis: Symptoms include sneezing and coughing.

  • Gastrointestinal Reactions: Diarrhea and vomiting.

  • Allergic Dermatitis: Including hives (urticaria).

Symptoms of Anaphylaxis

  • Common symptoms include:

    • Difficulty breathing.

    • Light-headedness.

    • Fainting.

    • Pallor or hives.

Biological Responses Mediated by Mast Cells

  • Mast cells release various biologically active substances including:

    • Enzymes like tryptase and chymase.

    • Toxic mediators such as histamine which increase vascular permeability, cause smooth muscle contraction, and stimulate Th2-cell responses.

    • Cytokines that enhance eosinophil activation, such as IL-3, IL-5, and GM-CSF.

Mechanisms of Gastrointestinal Symptoms

  • Gastrointestinal symptoms like diarrhea and vomiting are often a result of:

    • Smooth muscle contraction driven by leukotrienes and prostaglandins which effectively increase digestive transit speed and lead to expulsion of stomach contents.

Diagnosis of Allergy

Learning Objectives

  1. Understand laboratory roles in diagnosing and monitoring allergies.

  2. Recognize the functionalities of diverse tests in the diagnosis and assessment of allergies.

Diagnosis Process

  • Clinicians focus on identifying:

    • Causative substances.

    • Specific epitopes related to allergens.

    • Predictive severity of allergic responses from previous reactions.

Testing Methods

  • Skin Prick Test: Assesses specific epitopes.

  • Serum IgE Testing: Measures IgE concentration to predict the likelihood of allergic reactions.

    • Higher IgE concentrations correspond to increased probabilities of allergic symptoms.

Severity Determination Factors

  • Clinicians consider many factors to assess severity, including:

    • Accounts of past reactions.

    • Stability and ubiquity of epitopes.

    • Absorption sites related to patient symptoms.

Summary of Diagnosis

  • Understanding how laboratory tests work in conjunction with clinical evaluations is critical for proper allergy diagnosis and management.