Hypersensitivity

Hypersensitivity Overview

Learning Outcomes

  • Explain the concept of hypersensitivity.

  • Differentiate between the four types of hypersensitivity reactions in terms of:

    • Antibody involvement

    • Complement involvement

    • Antigen triggers

    • Timing of response

  • Associate specific examples of clinical manifestations with each type of hypersensitivity.

  • Discuss the immunological mechanisms involved in each of the four types of hypersensitivity reactions.

  • Provide examples of preformed and newly synthesized mediators released from IgE-sensitized mast cells and basophils and discuss their effects.

  • Discuss the influence of genetic and environmental factors on susceptibility to type I hypersensitivity responses.

  • Discuss the types of reactions that can result from latex sensitivity and their clinical manifestations.

  • Explain the underlying mechanisms of pharmacological therapy, monoclonal anti-IgE therapy, and allergy immunotherapy in the treatment of allergies.

  • Discuss the procedure, clinical applications, and advantages and limitations of skin testing for type I hypersensitivity.

  • Discuss the principles and clinical applications of allergen-specific and total IgE testing.

  • Explain how hemolytic disease of the newborn (HDN) arises.

  • Explain the significance of a positive direct antiglobulin test.

  • Discuss the principle of cold agglutinins testing, and associate the presence of a positive result with specific disorders.

  • Discuss how skin testing for delayed hypersensitivity is performed, its clinical applications, and how to interpret the results.

Vocabulary

  • Allergen: An innocuous ("harmless") antigen.

  • Atopy: Genetically-based tendency to produce IgE antibodies against allergens.

  • Sensitization: Acute adaptive response in susceptible individuals upon first exposure to allergen.

  • Anaphylaxis: Rapid-onset, systemic allergic reaction to an antigen.

Four Types of Hypersensitivity

  1. Type I Hypersensitivity (IgE-Mediated)

    • Mechanism: Ag induces cross-linking of IgE bound to mast cells and basophils, leading to the release of vasoactive mediators.

    • Typical manifestations include systemic anaphylaxis and localized anaphylaxis (e.g., hay fever, asthma, hives, food allergies).

  2. Type II Hypersensitivity (IgG- or IgM-Mediated Cytotoxic)

    • Mechanism: Ab directed against cell surface antigens leads to cell destruction via complement activation or Antibody-Dependent Cellular Cytotoxicity (ADCC).

    • Typical manifestations include blood transfusion reactions, autoimmune hemolytic anemia.

  3. Type III Hypersensitivity (Immune Complex-Mediated)

    • Mechanism: Ag-Ab complexes deposited in tissues induce destruction by complement activation and infiltration of neutrophils.

    • Typical manifestations include serum sickness, necrotizing vasculitis, and systemic lupus erythematosus.

  4. Type IV Hypersensitivity (Cell-Mediated)

    • Mechanism: Sensitized TH1 cells release cytokines to activate macrophages or cytotoxic T cells.

    • Typical manifestations include contact dermatitis, graft rejection, and tubercular lesions.

IgE-Mediated Allergic Reactions

  • Common Stimuli: Food allergens (peanuts, tree nuts, etc.), drugs, venoms.

  • Responses:

    • Systemic: Anaphylaxis, acute urticaria (wheal-and-flare).

    • Localized: Edema, increased vascular permeability, laryngeal edema, bronchial constriction, increased mucus production.

Sensitization and Activation Process

  • Mechanism of Sensitization: Involves class switching to IgE production encoded by signals from CD4 TH2 cells, and results in the binding of IgE to high-affinity FcεRI receptors on basophils.

Allergens and Sensitization

  • Characteristics of Airborne Allergens:

    • Protein with carbohydrate side chains

    • Low dose: Favors activation of IL-4-producing CD4 T cells.

    • Low molecular weight: Diffuses into mucosal tissues.

    • Highly soluble: Readily eluted from particles.

    • Stable: Contains peptides that bind to MHC class II.

Example of an Allergen: Der p 1

  • Found in fecal pellets of house dust mites

  • Functions as a protease that cleaves occludin (important for tight junction integrity).

Mast Cells and Inflammatory Mediators

  • Mast Cells Origin: Originate from bone marrow (BM) and mature in peripheral tissues.

  • Primary (Preformed) Mediators include:

    • Histamine: Causes smooth muscle contraction, vasodilation, and increased vascular permeability.

    • Heparin.

    • Eosinophil Chemoattractant Factor (ECF-A).

    • Neutrophil Chemoattractant Factor (NCF-A).

    • Proteases (e.g., tryptase, chymase).

    • Prostaglandins (e.g., PGD2).

  • Secondary (Newly Synthesized) Mediators: Include leukotrienes and cytokines (e.g., IL-4, IL-5, TNF-α), causing further inflammation and recruitment of immune cells.

Clinical Manifestations of Type I Hypersensitivity

  • Examples include:

    • Urticaria (hives)

    • Angioedema (e.g., reactions to insect stings)

    • Various allergic responses traced to specific allergens (e.g., medications, food).

Testing for Allergies

  • IgE Testing: In-vitro methods for measuring total serum IgE and allergen-specific IgE.

  • Skin Testing: Performed to evaluate delayed hypersensitivity and to assess for immediate hypersensitivity reactions.

Genetic and Environmental Factors

  • Genetic Factors: Identified loci related to asthma and allergy predisposition include genes for chemokines and T-cell differentiation.

  • Environmental Factors: Impact of microbial exposure, hygiene hypothesis, and dietary influences on developing allergic responses.

Management of Allergic Diseases

  • Indications of pharmacological therapy and desensitization stand out in patient care to alleviate hypersensitivity responses.

  • Treatment Mechanisms: Involves antibodies aimed at blocking IgE and methods to enhance tolerance to allergens.