Tissue Damage Pathways: Hypersensitivity Reactions

TISSUE DAMAGE PATHWAYS

Although the major function of the com-ponents of the immune system is to neu-tralize or destroy the invading organisms or antigen, these reactions often cause “bystander” tissue damage as well. These are called hypersensitivity reactions, and Gell and Coombs conveniently divided them into five types.

Hypersensitivity Reactions

TYPE I: IMMEDIATE

These reactions are those that involve antigens that react with IgE bound to tissue mast cells or basophils. Activation of the mast cell results in the release of large amounts of pharmacologically active sub-stances. These reactions are rapid (hence immediate) and if injected into the skin a “wheel and flare” reaction can be seen within five to ten minutes. Most anti-gens stimulating IgE are either inhaled or ingested. A perfect example of the inhaled antigen is ragweed pollen. The IgE pro-duction requires helper T cells and T-cell-derived cytokines. IL-4 and IL-13 stimulate IgE production while IFN-γ is inhibiting. Many factors regulate the balance between help and suppression, including route of administration, physical nature of the sub-stance, and the genetic background of either animals or humans. In the latter, there is a family tendency to these reactions but exact genetic factors are still ill defined.

TYPE II: CELL BOUND

These reactions are initiated by anti-body reacting with antigen on the cell mem-branes. IgM and IgG can be involved in these reactions. Clinical examples include organ-specific autoimmune diseases and immune hemolytic anemia. The role of autosensitized T cells in some diseases such as rheumatoid arthritis and multiple sclero-sis have been postulated, but the evidence for their involvement is far from clear. In Graves’ disease (hyperthyroidism), auto-antibodies have a primary pathogenic role but specific reactive T cells are also present. However, it is not clear whether the T cells exert a primary role in stimulating anti-body production or are really secondary to the tissue damage.

TYPE III: IMMUNE COMPLEX

These reactions result from the pres-ence of either circulating immune com-plexes or immune complexes in the tissues. Deposition of immune complexes depends on their size, charge, local concentration of complement, and perhaps most impor-tant the nature of the antigen. An excel-lent example of this type of reaction is the arthritis reaction in which antigen is injected into the skin of an animal previously sensi-tized to the same antigen and has produced antibody to that antigen. The preformed antibody goes to the site of the injected antigen and forms a complex, thereby inducing complement activation and neu-trophil attraction. The result is intense local inflammation, hemorrhage, and necrosis.

There are numerous examples of this type of hypersensitivity reaction, including serum sickness, glomerulonephritis, and systemic lupus erythematosus. Many of these conditions will be described in detail in later.

TYPE IV: DELAYED

T cells drive this reaction when they react with antigen and release TH1 cyto-kines. The cytokines in turn attract other cells, such as macrophages, which release their lysosomal enzymes. Histologically, the lesions consist of lymphocytes, mac-rophages, and occasionally eosinophilic polymorphonuclear leucocytes, leading to a chronic lesion of necrosis fibrosis and granulomatosus reaction. An excellent example of this reactivity is seen when PPD is injected into the skin of a person who has been previously infected with the tuberculosis organism