Hypersensitivity

Hypersensitivity and Autoimmunity Study Notes

Course Information

  • Title: Hypersensitivity and Autoimmunity

  • Lecturer: Dr Jennifer Dowling

  • Date: November 2025

  • Institution: RCSI Royal College of Surgeons in Ireland

Learning Outcomes

  • Understand what is meant by allergy and the types of hypersensitivity reactions.

  • Describe in detail the cells involved and the steps that occur during type I hypersensitivity reactions.

  • Describe antibody mediated (Type I-III) and cell mediated hypersensitivity (Type IV) and key characteristics of each type.

  • Understand the role of immunosuppression in the management of hypersensitivity reactions.

Overview of the Immune System

  • The immune system defends the host against infection and disease.

  • However, immune responses can cause tissue injury and disease through unwanted or over-activation.

  • Immune reactions causing injury and pathology are known as Hypersensitivity Reactions.

Definition and Classification of Hypersensitivity Reactions

  • Hypersensitivity Reactions: Arise following exposure to an antigen (a substance/molecule eliciting an immune response).

    • Antigens can be of foreign origin (microbes, environmental) or self-origin (self-antigens).

    • Responses against self-antigens are termed autoimmunity, leading to autoimmune diseases.

Types of Hypersensitivity Reactions (ABCD Classification)

  • Type I (Immediate Type):

    • Common Term: Allergic/anaphylaxis reaction

    • Time of Appearance: 2-30 minutes

    • Mediator: IgE antibodies, other mediators.

  • Type II (Cytotoxic Type):

    • Common Term: Cytotoxic reaction

    • Time of Appearance: 5-8 hours or longer

    • Mediator: Antibodies & complement (mainly IgG).

  • Type III (Immune Complex Type):

    • Common Term: Immune complex reaction

    • Time of Appearance: 2-8 hours or longer

    • Mediator: Antibody/antigen complexes.

  • Type IV (Delayed Type):

    • Common Term: Delayed-type hypersensitivity

    • Time of Appearance: 24-72 hours or longer

    • Mediator: T cell mediated response.

Allergy Overview

  • Allergy: An immune response to a typically harmless antigen, leading to a hypersensitivity reaction.

  • Individuals can become sensitized to environmental antigens, resulting in a stronger reaction upon subsequent exposure.

  • Common allergens include small, highly soluble proteins such as pollen and house dust mite antigens.

  • Allergens are typically presented at low doses at mucosal sites.

Anaphylaxis

  • Anaphylaxis: A severe allergic reaction characterized by life-threatening symptoms such as hypotension, bronchospasm, and laryngeal edema.

  • Anaphylactic shock occurs when hypotension results from an allergic reaction.

  • Treatment includes the administration of:

    • Adrenaline (epinephrine)

    • Anti-histamines

    • Steroids

    • Supportive therapy

Epidemiology of Allergy and Anaphylaxis

  • Allergy prevalence is estimated to be as high as 40%, with increasing rates possibly linked to environmental factors like urbanization.

  • Anaphylaxis has a prevalence ranging from 0.3% to 5.1% and is most common among children aged 0-4.

IgE in Allergic Responses

  • IgE is crucial in protective immunity against worms but also mediates allergic responses in industrialized countries.

  • Atopy: A genetic predisposition to develop allergies—affects an estimated 40% of individuals in industrialized areas.

  • The hygiene hypothesis proposes that reduced microbial exposure during childhood contributes to increased allergic disorders.

Mechanism of Type I Hypersensitivity Reaction

  1. Sensitization Phase:

    • Initial encounter with allergen leads to B cell processing and T cell activation (Th2 response) = production of IgE.

    • IgE binds to Fc receptors on mast cells (priming).

  2. Effector Phase (Subsequent Exposure):

    • Acute Response: Minutes after re-exposure; allergen recognized by mast cell-bound IgE leads to mast cell degranulation and histamine release.

    • Late Response: Cytokine release to recruit inflammatory cells (eosinophils).

Allergic Mediators and Symptoms

  • Immediate Effects: Release of granule contents (e.g., histamine, TNF-α) results in sneezing, nasal congestion, itchy/runny nose, watery eyes, wheezing, and bronchoconstriction shortly after exposure.

  • Late Phase: Involves lipid mediators (e.g., prostaglandins, leukotrienes) and cytokine production, recruiting inflammatory cells (specifically IL-4, IL-13).

Management of Allergic Reactions

  • Avoidance: The primary management strategy; education is vital.

  • Pharmacological Management:

    • Based on causative factors and symptoms, targeting histamine release.

    • H1-receptor antagonists: 2nd generation (e.g., cetirizine, loratadine) preferred for effectiveness without sedative effects.

    • Mast cell stabilizers: Sodium cromoglycate.

    • Glucocorticoids (steroids): Reduce inflammation at specific sites (e.g., nasal mucosa).

    • Leukotriene receptor antagonists: Montelukast.

    • Immunotherapy: Gradual desensitization to allergens (e.g., Grazax for grass pollen, Acarizax for dust mites).

Desensitization in Immunotherapy

  • Desensitization is indicated when allergen exposure is unavoidable.

  • Incremental doses of allergen aim to shift immune response from Th2 to Th1, reducing IgE levels, and allowing safe therapeutic exposure.

  • Precautionary measures include pre-administration with antihistamines and steroids due to high anaphylaxis risk.

Autoimmunity Overview

  • Autoimmunity: A breakdown in immune tolerance where immune responses are directed against self-antigens, leading to disorders characterized by the production of autoantibodies (by B cells) and the action of autoreactive T cells.

Mechanisms of Immune Tolerance

  1. Central Tolerance: Occurs in the primary lymphoid organs (bone marrow, thymus) where self-reactive lymphocytes are removed by negative selection.

  2. Peripheral Tolerance: Mechanisms protect against self-reactivity from cells that evade central tolerance, including anergy and lack of co-stimulation.

Autoimmune Diseases and Their Pathophysiology

  • Autoimmunity is triggered by genetic predisposition (mutated genes), cellular damage leading to exposure of hidden antigens, and viral mimicry, where viral proteins closely resemble self-proteins.

  • Examples include:

    • Systemic Lupus Erythematosus (SLE): Autoantibodies against nuclear components, leading to immune complex deposition.

    • Autoimmune Haemolytic Anemia: Antibodies against their own red blood cells, leading to destruction through phagocytosis.

    • Goodpasture Syndrome: Formation of antibodies against the basement membrane, primarily affecting lungs and kidneys.

    • Myasthenia Gravis: Antibodies block acetylcholine receptors, causing muscle weakness.

Summary of Antibody-Based Hypersensitivity Types

  • Type I Hypersensitivity:

    • Antibody: IgE

    • Targets: Soluble Antigen

    • Effector Mechanism: Mast cell degranulation.

  • Type II Hypersensitivity:

    • Antibody: IgG

    • Targets: Cell-bound Antigen

    • Effector Mechanism: Antibody-dependent cytotoxicity.

  • Type III Hypersensitivity:

    • Antibody: IgG

    • Targets: Soluble Antigen

    • Effector Mechanism: Immune complex deposition.

Type II Hypersensitivity Detailed Pathophysiology

  • Cells are coated by IgG, leading to antibody-dependent cell-mediated cytotoxicity (ADCC) through macrophages and NK cells.

  • Drug reactions (like penicillin) can induce hemolytic anemia by generating antibodies against coated RBCs.

Common Conditions Under Type II Hypersensitivity

  • Autoimmune Haemolytic Anemia: Antibody destruction of red blood cells; usually managed with immunosuppression (corticosteroids).

  • Goodpasture's Syndrome: Antibodies to basement membranes causing kidney dysfunction; treatment involves immunosuppression and plasma exchange.

  • Myasthenia Gravis: Associated with antibodies against acetylcholine receptors; latest therapies involve immunotherapy targeting pathogenic IgGs.

Type III Hypersensitivity Overview

  • Immune complexes formed from soluble antigens and antibodies can lead to diseases such as SLE, where tissue deposition causes inflammation and damage.