Immunology: Hypersensitivity Reactions

• Module: Foundations of Immunology BMS172
• Lecture Title: Hypersensitivity
• Contact: Professor Doctor Mohammed Mahmoud El-Naggar
• Department: Medical Microbiology and Immunology
• Email: [email protected]
• Mobile: 01126625177
• Academic hours: Sunday, 10:00-12:00 AM

Learning Outcomes

• Identify types of hypersensitivity
• Explain the mechanism of type I hypersensitivity
• Describe pharmacologically active mediators of type I hypersensitivity
• Describe diagnostic tests and treatment of type I hypersensitivity
• Explain the mechanisms of hypersensitivity
• Describe the clinical types of hypersensitivity

Lecture Outline

• Hypersensitivity types, mechanism, diagnosis and treatment
• Type I
• Type II
• Type III
• Type IV (delayed reactions)

Hypersensitivity

• Hypersensitivity reactions are classified into four types: Type I, Type II, Type III (immediate reactions), and Type IV (delayed reactions)

Type I Hypersensitivity

• Type I hypersensitivity is immediate
• It may involve: Skin (urticaria and eczema), Eyes (conjunctivitis), Nasopharynx (rhinorrhea, rhinitis), Bronchopulmonary tissues (asthma), Gastrointestinal tract (gastroenteritis)
• Allergens include: Pollen grains, Fungal allergens, Drugs, Antiseptic spray
• The mechanism involves production of IgE in response to certain antigens
• IgE has very high affinity for its receptor on mast cells and basophils
• Subsequent exposure to the same allergen cross-links the cell-bound IgE and triggers the release of various active substances
• Cross-linking of IgE Fc-receptor is important in mast cell triggering
• Mast cell degranulation is preceded by increased Ca++ influx

Mediators of Immediate Hypersensitivity

• Granule preformed mediators include: histamine, tryptase, ECF-A
• Histamine causes bronchoconstriction, mucus secretion, vasodilation, vascular permeability
• Tryptase causes proteolysis
• ECF-A attracts eosinophil and neutrophils
• Newly formed mediators include: leukotriene B4, leukotrieneC4, D4, prostaglandins D2
• Leukotriene B4 is a basophil attractant
• Leukotriene C4, D4 performs the same function as histamine (1000x more potent)
• Prostaglandins D2 cause edema and pain

Diagnostic tests for immediate hypersensitivity

• Skin (prick and intradermal) tests
• Measurment of total IgE and specific IgE antibodies by ELISA

Treatment

• Avoidance of exposure
• For dust mite allergens: cover mattresses and pillows with dust mite resistant covers
• For fungal allergens: remove indoor plants (which promote mold growth), drying or removing wet carpets
• Symptomatic treatment
  • Antihistamines block histamine receptors
  • Cromolyn sodium inhibits mast cell degranulation, by inhibiting Ca++ influx
  • Late onset allergic symptoms, particularly bronchoconstriction are treated with leukotriene receptor blockers or inhibitors of the cyclooxygenase
  • Bronchodilators provides relief from bronchoconstriction
• Immunotherapy
  • Administration of gradually increasing doses of allergen extracts at regular intervals over a period of years, given to patients by injection or drops/tablets under the tongue (sublingual)
  • It teaches the immune system to tolerate allergen, causes the production of regulatory immune cells
  • This stops the production of IgE
  • Rises in allergen-specific IgG4 antibodies with blocking activity through the inhibition of allergen-induced, IgE-mediated release of inflammatory mediators from mast cells

Type II Hypersensitivity

• Also known as cytotoxic hypersensitivity
• Affects a variety of organs and tissues
• Antigens may be endogenous or exogenous chemicals that attach to cell membranes
• Primarily mediated by IgM or IgG classes
• Complement mediated lysis is involved
• Phagocytes and Killer cells can play a role (ADCC)
• Antigens also called agglutinogens
• Antibodies called agglutinins

Types of RBC lysis

• Incompatible blood transfusion involves ABO (intravascular haemolysis (complement): nausea, fever, rigors, back pain) and RH (extravascular haemolysis (phagocytic cells)
• Erythroblastosis faetalis involves When mother (Rh negative) gives birth to Rh positive infant, at time of birth, fetal blood may enter to maternal circulation and produce antibody against Rh antigen
• At 2nd birth, the antibody will cross the placenta and become attached to Rh antigen on the surface of RBCs of the fetus and extravascular haemolysis occur and the infant show anemia and jaundice at first day then hepatosplenomegally and bilirubin encephalopathy
• Autoimmune hemolytic disease occurs
• WBCs lysis occurs. Granulocytopenia and S.L.E
• Platelet destruction occurs

Type III Hypersensitivity

• (Immune complex hypersensitivity)
• Mediated by soluble immune complexes
• Mostly of the IgG, although IgM may also be involved
• The antigen may be exogenous (chronic bacterial, viral or parasitic infections) or endogenous (non-organ specific autoimmunity: e.g. (SLE))
• The Ag is soluble and not attached to the organ involved.
• Soluble Ag-antibody complexes which penetrate the endothelium of blood vessel and deposited on the vascular basement membrane

Mechanism

• This will stimulate the complement and chemotactic factors like C5a is released that attract neutrophils which infiltrate the area and release lysosomal enzymes leading to destruction of the basement membrane

Types of Reactions

• Arthus reaction:
• Serum sickness:
• Hypersensitivity pneumonitis:
• Posstreptococcal glomerulonephritis:
• Autoimmune disease: RA, SLE

Type IV Hypersensitivity

• Also known as cell mediated or delayed type hypersensitivity
• Classical example of this hypersensitivity is tuberculin (Montoux) reaction which peaks 48 hours after the injection of antigen (PPD or old tuberculin)
• The lesion is characterized by induration and erythema
• CD4+ helper T cells recognize antigen in a complex with Class II MHC.
• The antigen-presenting cells in this case are macrophages that secrete IL-12, which stimulates the proliferation of further CD4+ Th1 cells.
• CD4+ T cells secrete IL-2 and interferon gamma, further inducing the release of other Th1 cytokines, thus mediating the immune response:
• Activated CD8+ T cells destroy target cells on contact.
• chemokines such as IL-8, monocyte chemotactic and activating factor (MCAF) that collectively lead to macrophage activation and production of hydrolytic enzymes which lead to the development of a local tissue reaction which is usually maximal in 48-72 h.

Practice Points

• A 74-year-old male was accidentally transfused with 500 mL blood during open right hemicolectomy. Immediately after the transfusion, the patient experienced a hypotension episode followed by acute hemolytic reaction, disseminated intravascular coagulation and acute kidney injury.
• Mention the diagnosis of this case?
• Clarify the underling mechanism?

Extra Information

• The following is a property of IgE is that it is involved in allergic reactions
• Erythroblastosis fetalis is considered Type II hypersensitivity
• Serum sickness is considered one of the types of Type III hypersensitivity