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type 2 hypersensitivity

Tuesday 10 March 2009

Type II hypersensitivity is mediated by antibodies directed toward antigens present on cell surfaces or extracellular matrix. The antigenic determinants may be intrinsic to the cell membrane or matrix, or they may take the form of an exogenous antigen, such as a drug metabolite, that is adsorbed on a cell surface or matrix.

In either case, the hypersensitivity reaction results from the binding of antibodies to normal or altered cell-surface antigens. Most of these reactions involve the effector mechanisms that are used by antibodies, namely the complement system and phagocytes.

Opsonization and Complement-and Fc Receptor-Mediated Phagocytosis

The depletion of cells targeted by antibodies is, to a large extent, because the cells are coated (opsonized) with molecules that make them attractive for phagocytes. When antibodies are deposited on the surfaces of cells, they may activate the complement system (if the antibodies are of the IgM or IgG class).

Complement activation generates byproducts, mainly C3b and C4b, which are deposited on the surfaces of the cells and recognized by phagocytes that express receptors for these proteins. In addition, cells opsonized by IgG antibodies are recognized by phagocyte Fc receptors, which are specific for the Fc portions of some IgG subclasses.

The net result is the phagocytosis of the opsonized cells and their destruction . Complement activation on cells also leads to the formation of the membrane attack complex, which disrupts membrane integrity by "drilling holes" through the lipid bilayer, thereby causing osmotic lysis of the cells.

Antibody-dependent cellular cytotoxicity (ADCC).

Antibody-mediated destruction of cells may occur by another process called antibody-dependent cellular cytotoxicity (ADCC). This form of antibody-mediated cell injury does not involve fixation of complement but instead requires the cooperation of leukocytes.

Cells that are coated with low concentrations of IgG antibody are killed by a variety of effector cells, which bind to the target by their receptors for the Fc fragment of IgG, and cell lysis proceeds without phagocytosis. ADCC may be mediated by monocytes, neutrophils, eosinophils, and NK cells.

Although, in most instances, IgG antibodies are involved in ADCC, in certain cases (e.g., eosinophil-mediated cytotoxicity against parasites), IgE antibodies are used. The role of ADCC in hypersensitivity diseases is uncertain.

Clinically, antibody-mediated cell destruction and phagocytosis occur in the following situations:

- (1) transfusion reactions, in which cells from an incompatible donor react with and are opsonized by preformed antibody in the host;

- (2) erythroblastosis fetalis, in which there is an antigenic difference between the mother and the fetus, and antibodies (of the IgG class) from the mother cross the placenta and cause destruction of fetal red cells;

- (3) autoimmune hemolytic anemia, agranulocytosis, and thrombocytopenia, in which individuals produce antibodies to their own blood cells, which are then destroyed;

- (4) certain drug reactions, in which antibodies are produced that react with the drug, which may be attached to the surface of erythrocytes or other cells.

Complement-and Fc Receptor-Mediated Inflammation

When antibodies deposit in extracellular tissues, such as basement membranes and matrix, the resultant injury is because of inflammation and not because of phagocytosis or lysis of cells.

The deposited antibodies activate complement, generating byproducts, such as C5a (and to a lesser extent C4a and C3a), that recruit neutrophils and monocytes. The same cells also bind to the deposited antibodies via their Fc receptors.

The leukocytes are activated, they release injurious substances, such as enzymes and reactive oxygen intermediates, and the result is damage to the tissues. It was once thought that complement was the major mediator of antibody-induced inflammation, but knockout mice lacking Fc receptors also show striking reduction in these reactions.

It is now believed that inflammation in antibody-mediated (and immune complex-mediated) diseases is because of both complement and Fc receptor-dependent reactions.

Antibody-mediated inflammation is the mechanism responsible for tissue injury in some forms of glomerulonephritis, vascular rejection in organ grafts, and other diseases. As we shall discuss in more detail below, the same reaction is involved in immune complex-mediated diseases.

Antibody-Mediated Cellular Dysfunction

In some cases, antibodies directed against cell-surface receptors impair or dysregulate function without causing cell injury or inflammation. For example, in myasthenia gravis, antibodies reactive with acetylcholine receptors in the motor end-plates of skeletal muscles impair neuromuscular transmission and therefore cause muscle weakness.

In pemphigus vulgaris, antibodies against desmosomes disrupt intercellular junctions in epidermis, leading to the formation of skin vesicles. The converse (i.e., antibody-mediated stimulation of cell function) is noted in Graves disease.

In this disorder, antibodies against the thyroid-stimulating hormone receptor on thyroid epithelial cells stimulate the cells, resulting in hyperthyroidism.