Hypersensitivities LO1

Lecture on Hypersensitivities

Lecture Objectives

  • Define the concept of hypersensitivities.

  • Analyze the immunological mechanisms driving type one (immediate) hypersensitivity.

  • Assess immunological and environmental factors regulating type one hypersensitivity and discuss their implications for immunotherapy.

  • Discuss concepts underlying autoimmunity and immunological tolerance.

  • Analyze genetic and environmental factors contributing to the failure of tolerance in autoimmunity.

  • Differentiate antibody-mediated type two and type three hypersensitivities, with examples including myasthenia gravis, systemic lupus erythematosus (SLE), and Graves' disease.

  • Appraise cell-mediated type four hypersensitivity and explore examples like type one diabetes and rheumatoid arthritis.

Definition of Hypersensitivities

  • Hypersensitivity: An injurious or pathological immune reaction

    • Reflects an excessive or aberrant immune response.

    • Occurs in two scenarios:

    • Response to foreign antigens (pathogens or non-infectious environmental antigens, e.g., allergies).

    • Response to self-antigens (autoimmunity).

Historical Context

  • Notable events of 1963:

    • Assassination of John F. Kennedy.

    • Formation of Malaysia (Malaya, Borneo, and Singapore).

    • Release of the Beatles' first two albums.

    • Aboriginal Australians gaining voting rights

  • Classification of hypersensitivities by Gell and Coombs in 1963:

    • Types of Hypersensitivity:

    1. Type One (Immediate hypersensitivity):

      • Components: IgE, mast cells, Th2 cells, basophils, eosinophils.

    2. Type Two and Type Three:

      • Involvement of IgG (and IgM, IgA).

      • Mechanisms of antibody activations, leading to inflammation and disease.

    3. Type Four (Cell-mediated hypersensitivity):

      • T cell driven (Th1, Th17 cells, cytotoxic T lymphocytes, phagocytes).

    • Types two, three, and four can target both foreign and self-antigens; type one primarily targets foreign antigens.

Caveats of Hypersensitivity Classification

  • The classification is outdated (60 years old) and lacks recognition of distinct immune mechanisms.

  • Different immune responses might overlap or share mechanisms that do not fit neatly into a single category.

  • The immune responses discussed are normal but can be aberrant in hypersensitivity reactions.

Type One Hypersensitivity: Immediate Hypersensitivity

Overview

  • Driven by T helper 2 (Th2) immune response, promoting:

    • IgE production

    • Mast cell degranulation

    • Eosinophilic influx

  • Associated diseases include:

    • Anaphylaxis

    • Atopic diseases (asthma, allergic rhinitis, food allergies)

Sensitization Stage

  • Involves T cell priming with an allergen.

    • Allergen: Antigen recognized by IgE or Th2 cells.

    • Dendritic cells capture allergen, promoting differentiation of Th2 cells.

    • Th2 cells secrete Interleukin-4 (IL-4) stimulating B cells to produce IgE.

    • IgE coats the surface of mast cells via the Fc epsilon RI receptor.

Re-exposure Stage

  1. Mast cell degranulation occurs upon allergen re-exposure:

    • Release of vasoactive amines (histamine), lipid mediators (leukotrienes, prostaglandins), and cytokines.

    • Immediate hypersensitivity reactions occur within minutes of exposure (e.g., results in skin swelling within five minutes).

  2. Late-phase reaction occurs 6 to 24 hours later, sustained by cytokines leading to cellular inflammation.

Mast Cell Mechanism

  • Resting mast cells have granules containing inflammatory mediators.

  • Upon allergen exposure, IgE cross-links the Fc epsilon receptor, initiating signal transduction that activates degranulation:

    • Release of preformed granules leads to vascular dilation and smooth muscle contraction.

    • Cytokines drive sustained inflammation and leukocyte recruitment.

Kinetics of Reaction and Clinical Manifestations

  • Biphasic Response:

    • Immediate reaction: characterized by vasodilation, edema, and inflammation due to histamine and leukotrienes.

    • Late phase reaction: cellular infiltrate, predominantly eosinophils, mediated by cytokines.

  • Common allergic diseases:

    • Allergic rhinitis: increased mucus secretion.

    • Food allergies: increased peristalsis due to smooth muscle contraction.

    • Bronchial asthma: wheezing caused by bronchoconstriction.

    • Anaphylaxis: marked drop in blood pressure and airway obstruction.

Immunological Mechanisms

  • Th2 cells are critical to immediate hypersensitivity:

    • Cytokines produced by Th2 cells:

    • IL-4: Promotes IgE production and mast cell sensitization.

    • IL-5: Mobilizes and activates eosinophils.

    • IL-4 and IL-13: Promote tissue repair and mucus secretion.

  • Eosinophils play a critical role by targeting parasitic infections, specifically larval helminths, utilizing proteolytic granules.

  • The overall response promotes the expulsion of helminths from the body, reflected in the "weep and sweep" response that leads to increased mucus production and smooth muscle contraction.

Comparison to Allergens

  • The weep and sweep response, while effective against parasitic infections, is misguided when the immune system reacts to harmless allergens (e.g., pollen), leading to conditions like asthma.

Conclusion

  • Understanding type one hypersensitivity provides insight into mechanisms behind allergic diseases and guides potential immunotherapeutic approaches.