Other Hypersensitivity States

All immunologically mediated hypersensitivity states had been classified into four types by Gell and Coombs in 1964. This classification has been a foundation for an understanding of the immunopathogenesis of clinical hypersensitivity syndromes (51). This schema depends on the location and class of antibody that interacts with antigen resulting in effector cell activation and tissue injury.

In type I, or immediate, hypersensitivity, allergen interacts with IgE antibody on the surface of mast cells and basophils, resulting in the cross-linking of IgE, FceRI receptor apposition, and mediator release from these cells. Only a few allergen molecules, interacting with cell-bound IgE, lead to the release of many mediator molecules, resulting in a major biologic amplification of the allergen-IgE antibody reaction. Clinical examples include anaphylaxis, allergic rhinitis, and allergic asthma.

In type II, or cytotoxic, injury, IgG or IgM antibody is directed against antigens on the individual's own tissue. Binding of antibody to the cell surface results in complement activation, which signals white blood cell influx and tissue injury.

In addition, cytotoxic killer lymphocytes, with Fc receptors for IgG, can bind to the tissue-bound IgG, resulting in antibody-dependent cellular cytotoxicity. Clinical examples include lung and kidney damage in Goodpasture syndrome, acute graft rejection, hemolytic disease of the newborn, and certain bullous skin diseases.

In type III, or immune complex, disease, IgG and IgM antigen-antibody complexes of a critical size are not cleared from the circulation and fix in small capillaries throughout the body. These complexes activate the complement system, which leads to the influx of inflammatory white blood cells, resulting in tissue damage. Clinical examples include serum sickness (after foreign proteins or drugs), lupus erythematosus, and glomerulonephritis after common infections.

In type IV, or delayed-type, hypersensitivity, the T-cell antigen receptor on T H1 lymphocytes binds to tissue antigens, resulting in clonal expansion of the lymphocyte population and T-cell activation with the release of inflammatory lymphokines. Clinical examples include contact dermatitis (e.g., poison ivy) and tuberculin hypersensitivity in tuberculosis and leprosy.

The classic Gell and Coombs classification has been adapted by Janeway and colleagues ( 52). Subsequently, Kay further expanded the adaptation (53). Type II reactions have been divided into two different subtypes. Type IIa are characterized by cytolytic reactions, such as are produced by antibodies causing immune mediated hemolytic anemia, whereas type IIb reactions are characterized by cell-stimulating reactions such as are produced by thyroid-stimulating antibody in patients with Graves disease or antibodies to the high-affinity mast cell receptor in chronic idiopathic urticaria. The latter antibodies cause mast cell activation.

Type IV reactions are divided into four subtypes. Type IVa1 reactions are mediated by CD4+ TH1 cells causing classic delayed-type hypersensitivity reactions, such as allergic contact dermatitis or tuberculin reactions. Type IVa2 reactions are mediated by CD4+ TH2 cells resulting in cell-mediated eosinophilic hypersensitivity as occurs in asthma. Type IVb reactions are mediated by cytotoxic CD8+ cells that mediate graft rejection and Stevens-Johnson syndrome. Type IVb2 reactions are mediated by CD8+ lymphocytes that can produce IL-5, resulting in cell-mediated eosinophilic hypersensitivity, usually in association with viral mucosal infection.

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