Hypersensitivity

CLBT 1050: SEROLOGY

HYPERSENSITIVITY

Definition

• Hypersensitivity:
  • An exaggerated immune response to a typically harmless antigen.
  • Results in injury to tissue, disease, or even death.

Malfunctions of Immune System

• Hypersensitivity types:
  • Type I
  • Type II
  • Type III
  • Type IV
• Other Related Conditions:
  • Autoimmunity
  • Immunodeficiency

Types of Hypersensitivity

• Delayed Reactions:
  • Develop 24 to 48 hours after antigen exposure (Type IV)
• Immediate Reactions:
  • Develop minutes to hours after exposure (Type I, Type II, Type III)

TYPE I HYPERSENSITIVITY

• Characteristics:
  • Also known as anaphylactic hypersensitivity.
  • Typically thought of as “allergies.”
  • Key Components:
  • IgE
  • Mast cells
  • Basophils
  • Eosinophils
  • Key Reactant: IgE antibody

Sensitization Phase

• Process:
  • Antigen-presenting cells (APCs) process allergens and present them to T-helper cells.
  • T-helper 2 cells induce production of allergen-specific IgE.
  • IgE binds to FcεRI receptors on mast cells and basophils.

Activation Phase

• Process:
  • Allergen cross-links adjacent cell-bound IgE’s.
  • Mast cells and basophils degranulate.
  • Chemical mediators are released and bind to target organs.
  • Allergy symptoms are produced.

Anaphylaxis

• Definition:
  • Most severe type of allergic response.
  • Acute response involving multiple organs.
  • Can be fatal if not treated immediately.
  • Symptoms begin within minutes and may include:
  • Bronchospasm
  • Laryngeal edema
  • Vascular congestion
  • Skin manifestations
  • Diarrhea
  • Vomiting
  • Intractable shock
  • Death may result from asphyxiation due to airway edema and congestion.
  • Example of edema: Swelling of feet and ankles, edema of airways.

Common Allergens

• Pollen
• Mold spores
• Animal dander
• Dust mites
• Insect venom
• Certain Foods (e.g., peanuts, shellfish, dairy products)
• Certain Drugs (e.g., penicillin)
• Latex

Clinical Manifestations of Type I Hypersensitivity

• Rhinitis (“hay fever”)
• Allergic asthma
• Food allergies
• Urticaria (“hives”)
• Eczema
• Systemic anaphylaxis (a potentially fatal reaction)

Treatments for Type I Hypersensitivity

• Avoidance of allergens.
• Drug therapy:
  • Antihistamines
  • Bronchodilators
  • Mast cell stabilizers
  • Corticosteroids
  • Epinephrine
• Allergy immunotherapy (AIT):
  • Monoclonal anti-IgE antibody administration, usually starting with gradual increases of allergen.

Testing for Type I Hypersensitivity

• In vivo Testing:
  • Skin prick test: Apply allergens to skin and wait 15-20 minutes to check for reaction.
• In vitro Testing:
  • RIST (RadioImmunoSorbant Test): Measures total IgE
  • RAST (Radio Allergen Specific Test): Assesses allergen-specific IgE, using radio-labeled anti-human IgE to bind with antibodies already present in serum.

TYPE II HYPERSENSITIVITY

Characteristics

• Definition:
  • Occurs against normal self-antigens due to failure of immune tolerance.
• Involves IgM & IgG antibodies directed against a cell surface antigen, also known as antibody-mediated cytotoxic hypersensitivity.

Mechanism

• Mechanisms of damage:
  • Antibody binds to antigen leading to:
  • Phagocytosis of opsonized cells by neutrophils and macrophages.
  • Activation of NK (Natural Killer) cells.
  • Induction of inflammation through interactions with WBC Fc receptors and complement pathway breakdown.
  • Complement-mediated lysis causes cell destruction.
  • Antireceptor antibodies may disturb normal cellular function (e.g., anti-TSH receptors, anti-Acetylcholine receptor antibodies).

Clinical Examples of Type II Hypersensitivity

• Transfusion reactions
• Hemolytic disease of the newborn (HDN)
• Autoimmune hemolytic anemia
• Other examples: Warm reactive antibodies, cold agglutinins, paroxysmal cold hemoglobinuria, Anti-GBM disease (Goodpasture’s syndrome), Hashimoto’s disease.

Hemolytic Disease of the Newborn (HDN)

• Occurs when a pregnant woman produces antibodies against Rh antigens on fetal RBCs (usually RhD).

Diagnostic Tests for Type II Hypersensitivity

• Direct Antiglobulin Test (DAT):
  • Detects RBCs coated with complement components or IgG antibody.
  • Method: Patient RBCs are incubated with a poly-specific anti-human Ig, directed against IgG and complement. Positive agglutination indicates a reaction.
• Indirect Antiglobulin Test (Coombs’ test):
  • Tests patient serum for antibodies to RBC antigens.
  • Process: Incubate reagent RBCs with patient serum at 37°C, wash off excess, and add anti-human globulin. Positive test = RBC agglutination.

TYPE III HYPERSENSITIVITY

Characteristics

• Definition:
  • Also known as immune complex-mediated hypersensitivity.
• Involves antigen-antibody complexes directed against soluble antigens.
• Complexes deposit in organs and tissues, causing damage.
• Cells such as macrophages and neutrophils migrate to the affected areas, releasing lysosomal enzymes resulting in tissue damage.

Mechanism of Tissue Damage

• Immune complexes (IgG and IgM) precipitate out of serum and deposit in tissues.
• Tissue damage arises from complement activation and inflammatory responses resulting from antibody binding to cellular receptors.

Clinical Examples of Type III Hypersensitivity

• Arthus Reaction:
  • Skin reaction characterized by localized inflammation (redness and edema) that peaks at 3 to 8 hours.
  • Known as Farmer’s Lung or Pigeon Breeder’s Lung.
• Serum Sickness:
  • A generalized type III hypersensitivity caused by passive immunization with animal serum, producing antibodies against foreign animal proteins.
  • Symptoms include headache, fever, nausea, joint pain, rashes, and lymphadenopathy.
• Associations with other conditions:
  • Autoimmune diseases (e.g., systemic lupus erythematosus, rheumatoid arthritis).
  • Reactions to bee stings.
  • Drug reactions (e.g., penicillin).
  • Sequelae to infections (e.g., post-streptococcal glomerulonephritis).

TYPE IV HYPERSENSITIVITY

Characteristics

• Definition:
  • Also known as delayed type hypersensitivity (DTH) and is cell-mediated.
• Key players: Th1 cells and macrophages.
  • Antigen-presenting cells (APCs) present antigens to naïve T helper cells which differentiate into Th1 cells release cytokines that attract macrophages, inducing inflammation and recruiting cytotoxic T lymphocytes to destroy target cells.
  • Hypersensitivity reaction peaks 48 to 72 hours after antigen exposure.

Clinical Examples of Type IV Hypersensitivity

• Infections with intracellular pathogens (e.g., Mycobacterium tuberculosis, Mycobacterium leprae, Pneumocystis carinii, Leishmania species, herpes simplex virus).
• Contact dermatitis caused by low-molecular-weight compounds that act as haptens (examples: poison ivy, nickel salts).
• Allergic diseases of the lungs from inhalation of bacterial and fungal spores (e.g., Farmer’s lung disease, bird breeder’s lung disease).

Skin Testing for Delayed Hypersensitivity

• Methods:
  • Inject common antigens intradermally (patch test for contact dermatitis). (+) test shows redness with papules or blisters.
• Mantoux Method:
  • Injects PPD intradermally. (+) test indicates induration suggesting TB infection.

Interferon Gamma Release Assays (IGRA)

• Measure the production of IFN-γ by T cells stimulated with MTB antigens.
  • Quantiferon TB Gold Plus assay: Incubates patient blood in tubes with MTB antigens and tests the plasma for IFN-γ by ELISA.
  • T-SPOT-TB test: Mononuclear cells incubated with MTB antigens tested for IFN-γ with ELISpot.

Summary of Hypersensitivity Reactions

• Type I: Immediate reactions involving the release of mediators from IgE-sensitized mast cells and basophils after cross-linking by allergens.
• Type II: Cell destruction is caused by antibody and complement leading to opsonization; inhibition of cell functions may also occur.
• Type III: Antigen-antibody complexes activate complement, leading to neutrophil recruitment and tissue damage.
• Type IV: Antigen-sensitized Th1 cells release cytokines that recruit macrophages and induce inflammation, activating cytotoxic T cells that cause direct cell damage.

Types of Allergy Reactions

Note: Hypersensitivity reactions may appear alongside autoimmune diseases.