Type I Hypersensitivity: Immediate Reactions

Overview of Hypersensitivity

• Hypersensitivity reactions classify into four types.
• Type I, II, and III are immediate reactions; Type IV involves delayed reactions.

Type I Hypersensitivity: Immediate Hypersensitivity

• Inhalants like pollen grains and fungal allergens trigger type 1 hypersensitivity.
• Injectants such as drugs can cause this type.
• Antiseptic sprays are an example of contact allergens for Type I hypersensitivity.
• Reactions involve the skin (urticaria and eczema), eyes (conjunctivitis), nasopharynx (rhinorrhea, rhinitis), bronchopulmonary tissues (asthma), and gastrointestinal tract (gastroenteritis).
• IgE production is part of the mechanism in response to allergens.
• IgE has a high affinity for its receptor on mast cells and basophils.
• Subsequent exposure to the same allergen cross-links cell-bound IgE, triggering the release of active substances.
• Cross-linking of IgE Fc-receptor is important for mast cell triggering and degranulation, preceded by increased Calcium influx.

Mediators of Immediate Hypersensitivity

• Histamine causes bronchoconstriction, mucus secretion, vasodilation, and vascular permeability.
• Tryptase is responsible for proteolysis.
• ECF-A attracts eosinophils and neutrophils.
• Leukotriene B4 attracts basophils.
• Leukotrienes C4 and D4 have similar effects to histamine, but are 1000x more potent.
• Prostaglandins D2 causes edema and pain.

Diagnostic Tests and Treatment

• Skin (prick and intradermal) tests are used for diagnosis.
• Total IgE and specific IgE antibodies are measured by ELISA.
• Treatment involves avoidance of exposure, symptomatic treatment, and immunotherapy.
• Covering mattresses/pillows with dust mite-resistant covers is a way of avoiding exposure.
• Removing indoor plants and drying wet carpets reduce can help minimize fungal allergens.
• Antihistamines are used to block histamine receptors.
• Chromolyn sodium inhibits mast cell degranulation by inhibiting Calcium influx.
• Leukotriene receptor blockers or cyclooxygenase inhibitors treat late-onset allergic symptoms.
• Bronchodilators (inhalants) provide short-term relief from bronchoconstriction.
• Immunotherapy involves administering gradually increasing doses of allergen extracts regularly, either by injection or sublingually.
• Immunotherapy aims to teach the immune system to tolerate the allergen and produce regulatory immune cells.
• Regulatory immune cells stop the production of IgE and increase allergen-specific IgG4 antibodies.

Type II Hypersensitivity: Cytotoxic Hypersensitivity

• Affects a variety of organs and tissues.
• Antigens are normally endogenous, though exogenous chemicals (haptens) attaching to cell membranes can lead to this type.
• Primarily mediated by IgM or IgG classes, complement-mediated lysis and phagocytes/killer cells, where ADCC plays a role.

Types of Reactions in Type II Hypersensitivity

• Incompatible blood transfusion causes ABO: intravascular hemolysis (complement) presenting with nausea, fever, rigors, and back pain, or RH: extravascular hemolysis (phagocytic cells).
• Erythroblastosis fetalis occurs when an Rh-negative mother gives birth to an Rh-positive infant. At the time of birth, antibody will cross the placenta, attach to Rh antigen on fetal RBCs, and extravascular hemolysis occur, leading to infant anemia and jaundice.
• Autoimmune hemolytic disease is another type of Type II hypersensitivity.
• WBCs lysis can cause Granulocytopenia and S.L.E.
• Platelet destruction is also attributed to Type II reactions.

Type III Hypersensitivity: Immune Complex Hypersensitivity

• Mediated by soluble immune complexes, mostly of the IgG type, with possible involvement of IgM.
• Antigens may be exogenous (chronic bacterial, viral, or parasitic infections) or endogenous (non-organ-specific autoimmunity, such as SLE).

Mechanism of Type III Hypersensitivity

• The antigen is soluble and not attached to the organ.
• Soluble antigen-antibody complexes penetrate the endothelium of vessels and deposit on the vascular basement membrane.
• Complement and chemotactic factors such as C5a are released, attracting neutrophils and releasing lysosomal enzymes that destroy the basement membrane.

Types of Reactions in Type III Hypersensitivity

• Arthus reaction.
• Serum sickness.
• Hypersensitivity pneumonitis.
• Poststreptococcal glomerulonephritis.
• Autoimmune diseases like RA and SLE.

Type IV Hypersensitivity: Cell-Mediated or Delayed-Type

• Also known as cell-mediated or delayed-type hypersensitivity
• A classical example is the tuberculin (Mantoux) reaction that peaks 48 hours post-injection of antigen (PPD or old tuberculin).
• Lesions are characterized by induration and erythema.

Mechanism of Type IV Hypersensitivity

• CD4+ helper T cells recognize antigen in complex with Class II MHC.
• Antigen-presenting cells are macrophages that secrete IL-12, stimulating CD4+ Th1 cell proliferation.
• CD4+ T cells secrete IL-2 and interferon-gamma, inducing the release of other Th1 cytokines.
• Activated CD8+ T cells destroy target cells on contact.
• Chemokines such as IL-8 and monocyte chemotactic and activating factor (MCAF) lead to macrophage activation and production of hydrolytic enzymes, leading to local tissue reactions.

Case Scenario: Clinical Correlate and points to practice

• A 74-year-old Male was transfused with 500 mL of blood during hemicolectomy, after which they experienced an episode of hypotension with an eventual acute hemolytic reaction, DIC and kidney injury
• Key questions to ask surrounding the case scenario are
  • What is the diangosis?
  • What is the underling mechanism?