TYPE II HYPERSENSITIVITY
Author: Sanketh DS, MDS
The immune system protects the human body against disease by dispatching a bunch of immune cells whenever the body encounters foreign material or antigens. These immune cells elicit an inflammatory response in order to remove or eliminate the foreign antigen without causing much damage to the host. However, under certain conditions, the host may elicit an exaggerated or an inappropriate immune response to a foreign antigen causing much damage to host tissues. This exaggerated or inappropriate immune response is termed hypersensitivity. There are four types of hypersensitivity reactions them being Type I, Type II, Type III and Type IV.
Type II hypersensitivity is an antibody mediated cytotoxic reaction, where cell damage is a result of antibodies binding to antigens on cell surfaces. The source for these antigens could either be intrinsic or extrinsic. Intrinsic antigens are the cell’s own protein antigens. For example, in certain autoimmune diseases like autoimmune haemolytic anemia or thrombocytopenic purpura, the red blood cells or platelets respectively have self-reactive autoantibodies directed specifically against their cell surface antigens. Extrinsic antigens on the other hand are antigens such as drug metabolites, for example, being attached or adsorbed on the surface of cells. Either way, antibodies specifically targeting these antigens are produced, eventually causing cell damage! Antibodies usually mediating type II hypersensitivity reactions are IgG antibodies and rarely IgM antibodies. There are several ways by which antibodies mediate cell damage.
Opsonization and phagocytosis
One of the common ways antibodies help eliminate antigens or antigen coated cells is by facilitating phagocytosis. IgG antibodies, after attaching to the antigens (on the cell surface), act as opsonins, facilitating phagocytosis of the cell. Phagocytes such as macrophages possess receptors called Fc receptors. Fc receptors of macrophages recognize the Fc portion of the IgG antibody binding the antigen, thus helping macrophages engulf the entire cell.
Another way antibodies get rid of the antigen bearing cells is by activating complement proteins. Complement proteins are a bunch of nine proteins, C1 – C9, which when activated, trigger a cascade of enzymatic reactions. Now, the resulting enzymatic reactions could get damage cells in two ways, either via inflammation or by forming a membrane attack complex.
Complement mediated cell damage
Complement enzymatic reaction is triggered when complement protein C1 attaches to the antibody on the cell. During the reactions, certain complement proteins like C3, C4 and C5 are cleaved or split. The cleaved or split proteins C3a, C4a and C5a, called anaphylatoxins, stimulate mast cells to degranulate and release histamine and other inflammatory mediators. The inflammatory mediators increase vascular permeability and help in extravasation of leukocytes like neutrophils. Complement cleaved products C3a and C5a are also chemotactic factors, which help attract neutrophils. Once recruited to the site, neutrophils are activated with their Fc receptor recognizing the Fc portion of the antibody. Activated neutrophils release a bunch of lytic enzymes and free radicals causing cell death.
The complement enzymatic reaction finally leads to a bunch of complement proteins getting together to form a “membrane attack complex” (MAC). Once formed, the MAC attaches to the cell membrane, creates channels on the cell surface and causes an osmotic imbalance. This osmotic disruption eventually leads to cell lysis!
Antibody dependent cellular cytotoxicity
Antibodies could also induce cell damage by a process called “Antibody Dependent Cellular Cytotoxicity” (ADCC). This could happen rarely and is mediated by cells like natural killer (NK) cells. NK cells also possess an Fc receptor which binds to the Fc portion of the antibody. This activates the NK cell to release enzymes called perforins and granzymes. Perforins create pores in the cell, through which granzymes enter and cause apoptosis.
Dysregulated cell function
Sometimes, rather than causing cell damage antibodies could be a bother and cause dysregulated cell function. A particular example is the disease “Myasthenia Gravis”. Antibodies specific to acetylcholine receptors in the muscles bind and inhibit the receptors from binding with neurotransmitters acetylcholine, resulting in muscle weakness. Graves’ disease is another example where antibodies bind with thyroid stimulating hormone receptor in the thyroid cells and stimulate an excess production of thyroid hormone resulting in hyperthyroidism.
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