Overview

• Type II Hypersensitivity reactions occur 1-3 hours after antigen exposure.
• Mediated by IgG antibodies and have cytotoxic and complement-activating effects. Recall that the complementcascade produces various proteins that promote inflammation, phagocytosis, and cell lysis.
• Three mechanisms of antibody-mediated hypersensitivity:
  — Opsonization, inflammation, and, cellular dysfunction.

Opsonization

• Coats cells in antibodies, leads to phagocytosis and/or complement activation.
  — IgG binding of cell-bound antigens initiates the complement cascade, which generates active proteins.
  — Some of these proteins, including C3b, are deposited on the cell surface.
• Thus, neutrophils can recognize the opsonized cell via two mechanisms:
  — Its high-affinity Fc receptor can bind with the Fc region of the IgG antibody.
  — Its C3b receptor can bind with the deposited complement on the cell’s surface.
• In both cases, binding promotes phagocytosis of the host cell.

Examples:

• Transfusion reactions can occur when donor cell antigens are bound by host IgG antibodies.
  — If complement protein C1 binds also those antibodies, the complement cascade ultimately produces a Membrane Attack Complex (MAC); the MAC allows massive water influx into the cell, causing its lysis.
• Hemolytic disease of the fetus and newborn: maternal anti-Rh+ antibodies attack fetal Rh+ red blood cells.
  — The maternal antibodies were produced in response to prior pregnancy with a Rh+ fetus; upon subsequent exposure to a another Rh+ fetus, the maternal antibodies readily react.
• Autoimmune blood cell destruction occurs when one’s own blood cells are targeted:
  — Anemia can result when red blood cells are destroyed.
  — Agranulocytosis, when granulocytes, such as neutrophils, are targeted.
  — Thrombocytopenia, when platelets are removed.
• Drug hapten reactions occur when haptens adhere directly to the cell surface.
  — When IgG antibodies bind the hapten, the complement system is activated and phagocytosis occurs. Penicillin is an example of a drug that can cause type II hypersensitivity reactions.

IgG-induced inflammation

• Inflammation occurs when antibodies are deposited in the tissues.
  — Neutrophil Fc receptor binding and complement activation leads to recruitment of additional leukocytes, including macrophages and additional neutrophils.
  — The released inflammatory products, including enzymes and reactive oxygen species, cause local tissue injury.
  IgG antibodies specific to host tissues can cause severe destruction.

Examples

• Vasculitis: Anti-neutrophil cytoplasmic antibodies (ANCAs) can induce vasculitis, which is inflammation of the blood vessels. This may show up as small reddish purple lesions in the skin, or larger bruise-like patterns of decay.
  — Treatments include methotrexate, prednisone, and cyclophosphamide, which suppress the immune response.
• Goodpasture’s syndrome is caused by antibodies that attack the basement membranes of renal glomeruli and/or respiratory alveoli; specifically, the antibodies attack type IV collagen in the tissues.
  — In a histological sample of an affected glomerulus, we can see the characteristic crescent-shaped area formed by excessive fibrin and cellular material.
  — In a sample of lung tissue, we highlight hemorrhaging in the inflamed alveoli.
  — Goodpasture’s syndrome may be treated with corticosteroids and cyclophosphamide, or plasmapheresis, which removes the attacking antibodies.

Cellular Dysfunction

Antibodies bind cellular receptors and cause dysfunction; two classic examples are myasthenia gravis and Graves’ disease.

• In Myasthenia gravis, IgG binds the acetylcholine receptors on the muscle tissue; thus, acetylcholine released from the nerve cell cannot bind and stimulate muscle contraction.
  — For example, eyelid drooping, called ptosis, is common in individuals with myasthenia gravis. Drooping occurs because antibodies block or destroy the acetylcholine receptors, thus inhibiting eyelid muscle contraction.
  — Immuno-suppressive steroids may reduce circulating IgG antibodies to treat muscle weakness.
• Graves Disease
  — Caused by binding of thyroid-stimulating antibody to the TSH receptor; as its name suggests, this has a stimulatory effect, and induces excessive thyroid hormone production.
  — In the histological sample, we can see the colloid-filled lumen, and, in a more magnified view, we highlight the hyperactive thyroid epithelium.
  — Indicate that excessive thyroid hormone production in periorbital tissues can produce Graves’ opthalmopathy, which is characterized by proptosis caused by swelling and adipose deposition.
  — Show that enlargement of the thyroid gland, called goiter, is caused by chronic thyroid stimulation. However, be aware that goiter can be indicative of hyper- or hypo-thyroidism; both states can involve overstimulation of the thyroid gland.
• TSH-stimulating blocking antibody can inhibit thyroid hormone production.