Hypersensitivity Dr. Towne

Dr. Francina Towne - IHL Course, RVU - Class of 2029

OVERREACTIONS OF THE IMMUNE SYSTEM - HYPERSENSITIVITIES

READING ASSIGNMENT

  • Text: Basic Immunology: Functions & Disorders of the Immune System, Abbas & Lichtman

  • Chapter 11: All sections on Hypersensitivities

PURPOSE OF THIS LECTURE

  • Objective: Learn about the four different types of hypersensitivities.

  • Reminder: Utilize tutors & office hours for clarification and support.

LEARNING OBJECTIVES

  • Definitions:

    • Hypersensitivity: An exaggerated or inappropriate immune response to an antigen.

    • Allergy: A hypersensitivity reaction that is often characterized by rapid onset symptoms.

    • Allergen: A substance that causes an allergic reaction (type of antigen).

    • Wheal-and-flare: A local skin reaction indicative of hypersensitivity; characterized by a raised area (wheal) and surrounding redness (flare).

    • Immediate hypersensitivity: A rapid immune reaction often mediated by IgE antibodies.

    • Immediate reaction: Early phase response occurring typically within minutes.

    • Late-phase reaction: A secondary response occurring hours later, typically lasting longer than the immediate reaction.

    • Delayed-type hypersensitivity: A reaction that occurs 1-3 days post-exposure, typically mediated by T cells.

  • For hypersensitivity [Type I to Type IV], delineation of:

    • Immune reactant (effector cell)

    • Antigen

    • Effector mechanisms

    • Mechanism of tissue injury, if applicable.

  • Explain at least one example for each type of hypersensitivity in depth.

  • Elaborate on all steps in the development and processes of Type I hypersensitivity reactions, including:

    • Generation of IgE

    • Cells involved in the immune response

    • Signal initiating the response

    • Cytokines involved in the reaction

    • Primary mediators and their biological effects

  • Contrast the immunoglobulins acting as receptors on mast cells vs. B cells and discuss the differences in the cellular responses upon antigen binding.

  • Describe systemic anaphylaxis including mediators, location, and tissue effects.

  • Explain how food allergies can often lead to skin rashes following consumption.

  • Discuss the hygiene hypothesis and its implications regarding allergy predisposition.

  • Compare Arthus reaction and serum sickness, detailing their immune complex contributions.

  • Discuss the purpose and workings of the tuberculin test and the complications associated with BCG vaccination rendering it invalid.

  • Define contact sensitivity and its relationship to haptens, using relevant examples.

  • Outline current treatments available for hypersensitivities.

HYPERSENSITIVITY REACTIONS

Overview

  • Hypersensitivity reactions, also known as allergic reactions, occur when the immune system reacts excessively to harmless substances, leading to inflammation and tissue damage.

  • Allergens: Substances that induce hypersensitivity reactions.

FOUR TYPES OF HYPERSENSITIVITY REACTIONS

  • Combs and Gell Classification (1963) identifies four types based on different effector mechanisms and antigens.

Type I Hypersensitivity

  • Mechanism:

    • Antigen binds to specific antibodies (IgE) on mast cells.

    • Results in mast cell degranulation, releasing inflammatory mediators.

  • Characteristics:

    • Also referred to as allergy or atopy.

    • Immediate reaction can present mild to severe symptoms.

Type II Hypersensitivity

  • Mechanism:

    • Small molecules covalently bond to cell surface proteins, marking them as foreign.

    • B cells activate, producing IgG antibodies that bind modified proteins, activating complement and phagocytosis, leading to tissue damage.

Type III Hypersensitivity

  • Mechanism:

    • Involves small soluble immune complexes that deposit in blood vessels, activating complement and recruiting phagocytes, leading to inflammation.

Type IV Hypersensitivity

  • Mechanism:

    • Mediated by antigen-specific T cells, primarily CD4 Th1 cells, with some involvement from CD8 T cells.

    • It manifests as delayed-type hypersensitivity (DTH), developing over 1-3 days.

Predisposition to Allergic Disease

  • Genetic vs. Environmental Risk Factors:

    • 50% genetic factors, 50% environmental influences.

  • Asthma and other allergic diseases often result from an imbalance between Th1 and Th2 responses.

TYPE I HYPERSENSITIVITY

General Mechanism

  • Primary exposure to allergen activates B cells to produce IgE.

  • IgE binds to Fc receptors on mast cells and basophils, inducing degranulation upon subsequent exposure.

  • **Mediators Released:

    • Vasoactive substances leading to smooth muscle contraction, increased vascular permeability, and vasodilation.**

IgE Production and Class Switching

  • Class switching from IgM to IgE is T cell-dependent:

    • CD4+ Th2 cells produce IL-4, facilitating IgE production.

    • Low antigen doses favor Th2 activation.

Cross-linking and Mast Cell Activation

  • High-affinity IgE binding to FcεRI on mast cells.

  • Activates rapidly without requiring proliferation or differentiation, allowing prompt immune response against parasites and allergens.

Mediators Released from Mast Cells

  • Inflammatory Mediators Include:

    • Histamines, leukotrienes, TNF-alpha, IL-4, and IL-5, leading to various biological effects including vascular permeability and smooth muscle contraction.

Primary Routes of Exposure to Allergens

  • Inhaled, ingested, or dermal exposure leads to activation of respective tissue mast cells.

Responses to Allergens

  • Local and systemic responses vary based on antigen route and dose.

    • E.g., anaphylaxis following bloodstream exposure vs. localized hay fever from inhalation.

Eosinophils in Allergic Response

  • Eosinophils are recruited to tissues during Th2 responded and can damage tissues when responding to benign allergens.

Implications of Type I Reactions

  • Immediate and delayed phases of reactions must be addressed to reduce severity of allergic symptoms.

  • Systemic anaphylaxis is a serious, life-threatening reaction characterized by

    • Rapid drop in blood pressure (anaphylactic shock)

    • Potential need for epinephrine administration to counteract effects.

  • Common food allergies include grains, nuts, milk, and seafood.

Hygiene Hypothesis

  • Suggests that reduced exposure to infectious agents leads to elevated susceptibility to allergic diseases due to a miseducated immune system.

  • Children with higher exposures to infections in early life show reduced allergic responses.

Clinical Cases and Examples

  • Case of John Mason: Development of severe allergic reactions to peanut butter highlighting the shift in immune response from harmless to life-threatening.

Food Protein-Induced Enterocolitis Syndrome (FPIES)

  • Description of FPIES as a non-IgE mediated condition presenting with gastrointestinal symptoms within hours of exposure to allergens.

  • Common Triggers: Cow's milk, soy, oats, etc.

  • Symptoms include dehydration, vomiting and potential hospitalization risk.

Types II, III, and IV Hypersensitivity Reactions

  • Detailed mechanisms and clinical manifestations including occurrences in drug-based hypersensitivity and transfusion reactions.

  • The importance of understanding the underlying mechanisms leads to proper diagnostics and treatment strategies.

Treatments for Hypersensitivities

  • Various treatment modalities to address symptoms based on the type of hypersensitivity:

    • Anaphylaxis: Epinephrine (auto-injectors)

    • Bronchial asthma: Corticosteroids and leukotriene antagonists

    • General allergic diseases: Antihistamines, desensitization protocols, and alternative medications targeting IgE and inflammation.

Knowledge Check Examples

  • A scenario involving anaphylaxis leads to the necessity for immediate epinephrine administration as first-line response.

  • Practice Charts for Hypersensitivity Types: Guidelines for differentiating each type based on immune reactants, antigens, and mechanisms.

SUMMARY CHART OF HYPERSENSITIVITY TYPES

  • A comparative overview of Type I, II, III, and IV hypersensitivities focusing on immune mechanisms, clinical presentations, and treatment modalities.