Hypersensitivity

Hypersensitivity Reactions

Introduction

  • Date and Time: Monday, October 21, 2025, 9 am - 11 am

  • Instructor: DJ Evans

Definition of Hypersensitivity

  • Hypersensitivity is defined as a state of immune reactivity to antigen(s) that is greater than normal for the antigenic challenge.

  • These reactions are often harmful rather than protective.

  • Hypersensitivity reactions can be categorized into four major types.

  • Several types may manifest simultaneously in a given individual.

Learning Objectives

  1. Distinguish between the four major types of hypersensitivity reactions based on:

    • Host cell types.

    • Mediators released.

    • Mechanisms of tissue injury.

  2. Provide two clinical examples of each type of reaction.

  3. Review the principles of antigen presentation and lymphocyte activation that lead to:

    • Effector T cells.

    • Memory T cells.

    • B cells and antibodies.

Key Features of Hypersensitivity

  • Hypersensitivity reactions involve:

    • Environmental antigens (e.g. microbes).

    • Self-antigens.

  • Typically result from an imbalance between effector immune responses and the controls that regulate them.

  • The development of hypersensitivity diseases (e.g. allergic or autoimmune responses) is often associated with the inheritance of susceptibility genes.

  • The mechanisms of injury in hypersensitivity are similar to the effector mechanisms of defense against pathogens.

Type I Hypersensitivity

  • Characteristics: Immediate reaction.

  • Mechanism: Production of IgE antibodies leads to the immediate release of vasoactive amines and other mediators from mast cells. This is often followed by the recruitment of inflammatory cells.

  • Effects:

    • Vasodilation.

    • Edema.

    • Smooth muscle contraction.

    • Mucus production.

    • Tissue injury and inflammation.

  • Clinical Associations:

    • Anaphylaxis.

    • Allergies (e.g., food allergies, pollens, insect stings).

    • Bronchial asthma (atopic types).

Type II Hypersensitivity

  • Characteristics: Antibody-mediated.

  • Mechanism: Production of IgG and IgM antibodies that bind to antigens on target cells or tissues, leading to:

    • Phagocytosis or lysis of the target cell by activated complement or Fc receptors.

  • Clinical Associations:

    • Autoimmune hemolytic anemia.

    • Goodpasture syndrome.

Type III Hypersensitivity

  • Characteristics: Immune complex–mediated.

  • Mechanism: Deposition of antigen-antibody complexes activates complement, resulting in:

    • Recruitment of leukocytes through complement products and Fc receptors.

    • Release of enzymes and other toxic molecules leading to inflammation.

  • Clinical Associations:

    • Systemic lupus erythematosus.

    • Types of glomerulonephritis.

    • Serum sickness.

    • Arthus reaction.

Type IV Hypersensitivity

  • Characteristics: Cell-mediated, often referred to as delayed-type hypersensitivity (DTH).

  • Mechanism: Activated T lymphocytes (CD4+ and CD8+) release cytokines and mediate tissue injury.

  • Clinical Associations:

    • Contact dermatitis.

    • Multiple sclerosis.

    • Type 1 diabetes.

    • Poison Ivy reactions.

    • Tuberculosis (TB) + PPD reaction.

Type I Hypersensitivity: Mechanisms & Clinical Effects

  • Mediators: IgE antibody-mediated, involving mast cells and later, polymorphonuclear cells (e.g., eosinophils, basophils), and T lymphocytes.

  • Clinical Examples: Reactions to pollen, bee stings, seafood, peanuts, penicillin, and other drugs or substances.

  • Response Timeliness: Rapid (within minutes), severity can vary greatly, potentially leading to fatal outcomes.

  • Sensitization: Requires prior sensitization to produce antigen-specific IgE; repeat exposures can result in more severe reactions.

Mast Cell Mediators

  • Upon activation, mast cells release various classes of mediators leading to both immediate and late-phase reactions:

    • Immediate Response:

    • Vasodilation.

    • Vascular leakage.

    • Smooth muscle spasms.

    • Degranulation releasing histamine, proteases, arachidonic acid, and leukotrienes.

    • Late Phase Reaction: Occurs hours post-exposure, characterized by leukocyte infiltration and tissue damage.

Phases of Type I Reactions

  1. Immediate Reaction (Minutes after allergen exposure):

    • Characterized by vasodilation, congestion, and edema.

  2. Late-Phase Reaction (2-24 hours after exposure):

    • Inflammatory infiltrate (eosinophils, neutrophils, T cells).

    • Associated with tissue damage, bronchospasm.

Eosinophils in Type I Hypersensitivity

  • Frequently present in late-phase Type I reactions.

  • Recruitment: Triggered by Eotaxin chemokines and activated by IL-5 cytokines produced by CD4+ T cells (Th2).

  • Function: Release tissue-damaging proteases and cationic proteins.

Clinical Aspects of Type I Reactions

  • Atopy: Refers to the genetic predisposition to develop Type I allergies; involves increased IL-4 production by T cells and higher serum IgE levels.

    • Local Reactions: Affect approximately 10-20% of the population, manifesting as urticaria, allergic rhinitis, bronchial asthma, allergic conjunctivitis, and gastroenteritis.

    • Systemic Reactions (Anaphylaxis): Triggered by drugs or certain foods, causing shock, edema, severe bronchospasm, airway obstruction, and potentially death.

Type II Hypersensitivity: Mechanisms & Clinical Effects

  • Mediated by antigen-specific IgM or IgG; antibodies target antigens on cell membranes or tissue surfaces.

  • Tissue Injury Mechanisms:

    1. Opsonization and Phagocytosis: Antibodies opsonize cells for phagocytosis.

    2. Complement and Fc Receptor-mediated Inflammation: Inflammation induced by antibody binding and complement activation.

    3. Antibody-mediated Cellular Dysfunction: Antibodies can inhibit receptor functions, e.g., neuromuscular transmission in myasthenia gravis.

Clinical Examples of Type II Hypersensitivity

  1. Autoimmune Hemolytic Anemia: Antigen = red cell membrane proteins, leading to hemolysis and anemia.

  2. Vasculitis: Caused by anti-neutrophil cytoplasmic antibodies (ANCA), leading to inflammation.

  3. Drug-induced Hemolytic Anemia: Penicillin G complexes with RBC proteins leading to hemolysis.

  4. Goodpasture Syndrome: Antibodies against basement membrane proteins cause nephritis and lung hemorrhage.

  5. Acute Rheumatic Fever: Cross-reactivity of antibodies leads to myocarditis and arthritis.

  6. Myasthenia Gravis: Antibodies inhibit ACh receptor function, causing muscle weakness.

  7. Graves Disease: Antibodies stimulate TSH receptors leading to hyperthyroidism.

Type III Hypersensitivity: Mechanism of Tissue Injury

  • Characterized by the formation of immune complexes (ICs) that often cause systemic inflammatory diseases.

  • Mechanism of Injury:

    1. Formation of Immune Complexes (ICs) due to exogenous or endogenous antigens.

    2. Deposition of ICs in tissues leading to inflammation.

    3. Release of lytic enzymes by phagocytes, resulting in tissue damage at deposition sites (e.g., blood vessels, kidneys, joints).

Classic Example of Type III Hypersensitivity: Serum Sickness

  • Occurs due to treatment with anti-toxin antibodies derived from horse serum.

  • Symptoms develop 1-2 weeks after exposure:

    • Fever.

    • Urticaria.

    • Joint pain.

    • Lymphadenopathy.

    • Proteinuria.

Immune Complex Clearance

  • Normally, ICs are cleared by phagocytes in the reticulo-endothelial system (e.g., Kupffer cells in the liver).

  • Proper clearance results in no disease; abnormal IC clearance can lead to Type III hypersensitivity.

Size of Antibody Response

  • Production of large amounts of antibodies leads to extensive IC formation favoring clearance and fewer symptoms.

  • Conversely, lower antibody production results in smaller ICs, leading to immune complex disease (e.g., serum sickness).

Other Examples of Type III Reactions

  • Systemic Lupus Erythematosus: Autoantibodies cause nephritis and skin lesions.

  • Post-streptococcal Glomerulonephritis: Streptococcal antigens lead to nephritis.

  • Reactive Arthritis: Bacterial antigens evoke acute arthritis.

Drug-Induced Type III Hypersensitivity

  • Many drugs act as haptens, binding to proteins and eliciting antibody responses, leading to immune complex formation.

  • These reactions can mimic Type I hypersensitivity, with similar manifestations.

  • Drugs such as sulfonamides and penicillins often produce serum-sickness-like syndromes.

Stevens-Johnson Syndrome (SJS)

  • A severe form of Type III hypersensitivity reaction characterized by:

    • Erythema.

    • Arthritis.

    • Vasculitis.

    • Nephritis.

    • Myocarditis.

    • CNS abnormalities, frequently associated with sulfonamide antibiotics.

Type IV Hypersensitivity: Characteristics

  • This is a cell-mediated reaction involving T lymphocytes but not antibodies.

  • Often referred to as delayed-type hypersensitivity (DTH), which manifests 24-72 hours after the second exposure to antigen.

Mechanism of Type IV Hypersensitivity

  • Antigen presentation occurs via APCs (e.g., macrophages) in association with MHC Class II molecules.

  • Upon second exposure, memory CD4+ T lymphocytes are activated and release cytokines (e.g., IFN-γ, IL-2).

  • This leads to recruitment of inflammatory cells (monocytes, macrophages) and subsequent tissue damage.

Key Cells in Type IV Hypersensitivity

  • Include dendritic cells (APCs), CD4+ T lymphocytes (Th1 cells), macrophages, CD8+ T lymphocytes, and CD4+ Th17 lymphocytes.

  • Inflammation primarily results in granuloma formation, which is a hallmark of Type IV hypersensitivity.

Sub-division of Type IV Reactions

Type IVa

  • Classical reaction mediated by CD4+ Th1 cells that secrete IFN-γ to induce monocyte infiltration leading to granuloma formation.

Type IVb

  • Mediated by CD4+ Th2 cells, inducing eosinophil infiltration, often seen in persistent asthma.

Type IVc

  • Involves CD8+ T cell infiltration and direct cell death (e.g., in Type 1 Diabetes).

Type IVd

  • Involves CD4+ and CD8+ T cells recruiting neutrophils, causing tissue injury (e.g., skin reactions to some antibiotics).

Examples of Type IV Hypersensitivity

  1. Contact Sensitivity: Environmental chemicals (e.g., Urushiol from Poison Ivy) inducing skin rashes.

  2. Type 1 Diabetes Mellitus: T-cell-mediated destruction of pancreatic islet β cells.

  3. Rheumatoid Arthritis: Chronic inflammation in joints, mediated by self-antigens.

  4. Multiple Sclerosis: T cell-mediated destruction of myelin in the CNS leading to demyelination.

  5. Tuberculin (PPD) Reaction: Skin reaction to M. tuberculosis antigens, peaking 24-72 hours after exposure when previously sensitized.