• Hypersensitivity reactions are mediated by antibodies and T cells (if you are unfamiliar with antibodies and T cells, we recommend you review our adaptive immunity tutorials).
  — Types I, II, and II are antibody-mediated.
  — Type IV is T cell-mediated.

Type I Hypersensitivity

• Type I immediate hypersensitivity is typified by allergy.
  — Mediated by IgE antibodies and mast cell and basophil activation.
  — This reaction occurs within minutes of antigen presentation.

Mechanism

• Initial exposure to antigen
  — IgE antibodies are released from mature B cells (plasma cells).
  — These antibodies bind to mast cells (and basophils, not shown); the mast cells are now “sensitized.”
• Subsequent exposure to the same antigen
  — Antigen binding cross-links the antibodies bound to mast cells, leading to degranulation.
  — As a result, cytokines, membrane phospholipids, and granules are released form the mast cell.
• Some key mediators of type I hypersensitivity that are released upon degranulation include histamine, leukotrienes, prostaglandins, and platelet activating factor.
  — Recall that these are the mediators of acute inflammation, which, when excessive, cause damage to the tissues.

Manifestations

• Early edema and erythema are often characterized by “wheal and flare” – the “wheal” is caused by vascular leakage and swelling; the “flare” is caused by vasodilation and reddening of the skin.
• The later stage of type I hypersensitivity is characterized by eosinophilia in the effected tissues; chemokines released during degranulation and leukocyte activation attracts eosinophils, which release proteins that cause more tissue damage.
• Anaphylaxis is a systemic and potentially fatal form of type I hypersensitivity; epinephrine is administered to reverse respiratory and cardiovascular effects.

Type II Hypersensitivity

• Type II antibody-mediated hypersensitivity is characterized by cytotoxic IgG or IgM complement activation.
• Reactions occur within 1-3 hours after antigen exposure.

Mechanisms

• Example: transfusion reaction
  — Donor red blood cell with surface antigens;
  — Host IgG antibodies bind those antigens, which initiates the complement cascade.
  — As a result, a Membrane Attack Complex (MAC) forms and allows water influx into the red blood cell, causing lysis.

Manifestations

• Blood cell destruction
• Goodpasture’s syndrome: damage to renal and lung tissue by anti-basement membrane antibodies.
• Cellular dysfunction: antibodies that bind to cellular receptors, altering their activity.
  — For example, IgG antibodies can bind TSH receptors, with inhibitory OR stimulatory consequences, depending on their configuration.

Type III Hypersensitivity

• Characterized by deposition of IgG or IgM antibody-antigen complexes (also called “immune complexes”) in vessels walls and/or tissues.
• Type III reactions occur 1-3 hours after antigen exposure.

Mechanism

• When IgG-bound antigen deposits in tissues, complement and neutrophils are activated, with tissue destruction as a result.

Manifestations

• Hypersensitivity pneumonitis, aka allergic alveolitis, is a localtype III response to inhaled antigens; historically common in farmers who inhaled mold, fungi, and other environmental pathogens, it is increasingly common in office workers exposed to microorganisms in humidifiers and air conditioning systems.
  — Immune complexes activate complement in the alveoli, the site of gas exchange in the lungs. Then, local Arthus reactions thicken the lung interstitium, making gas exchange more difficult.
• Serum sickness is a systemic example of a type III reaction;
  — It is induced by antibodies from other species. It is characterized by widespread effects, including rash, edema, joint pain, and fever.

Type IV Hypersensitivity

• Also called delayed hypersensitivity, it’s mediated by helper and cytotoxic T cells.
• These responses appear 1-3 days after exposure, because it takes additional time to recruit and activate T cells and their products.

Mechanisms

• In response to antigens, helper T cells release cytokines that recruit macrophages and neutrophils, which damage host tissues.
• Cytotoxic cells directly damage host tissues via granzymes.

Manifestations

• An example of helper T cell-mediated hypersensitivity is the tuberculin reaction test: a positive result, characterized by induration and erythema, indicates that an individual has been previously infected by M. tuberculosis.
• An example of cytotoxic T cell-mediated hypersensitivity is contact dermatitis; in response to certain organic or metallic substances, such as poison ivy, cytotoxic T cells destroy host tissues and cause an itchy, red, vesicular rash.