Drug Hypersensitivity Reactions: Pathomechanism and Clinical Symptoms

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Hapten and Prohapten Concepts

Small chemical compounds, usually less than 1000 Da, are not immunogenic per se. These compounds are normally degraded, metabolized, and eliminated without stimulating an immune response. However, if the chemical is reactive and able to bind covalently to proteins, DNA, and so forth, a new antigenic determinant arises that can produce a new immune response. This modification can, theoretically, affect any kind of autologous protein, such as soluble extracellular proteins (eg, albumin), membrane

Classification of drug hypersensitivity reactions

Coombs and Gell28 classified drug hypersensitivity, as well as other immune reactions, into 4 categories termed type I-IV reactions: This classification relies on the formation of IgE antibodies that bind to high-affinity IgE receptors on mast cells and basophilic leukocytes, on complement-fixing antibodies, and in T-cell reactions. Because recent immunologic data reveal that T cells orchestrate different forms of inflammation, which may result in different symptoms, the classification of

Pseudoallergy (non–immune-mediated hypersensitivity)

So-called pseudoallergic reactions (non–immune-mediated hypersensitivities) to drugs, which are as frequent as true IgE-mediated reactions, are a pathogenetically poorly defined problem.

Most of these reactions resemble the clinical features of milder forms of immediate, IgE-mediated reactions (erythema, urticaria), but some reactions cause anaphylaxis and can be lethal. Detection of specific immune mechanism is negative. NSAID-induced pseudoallergic reactions seem to arise less rapidly (often

IgG-mediated reactions (cytotoxic mechanism and immune complex deposition, types II and III)

Type II and type III reactions rely on the formation of complement-fixing IgG antibodies (IgG1, IgG3). IgM is occasionally involved. They are similar, in that both depend on the formation of immune complexes and interaction with complement and Fc-IgG receptor (Fc-IgGI, IIa, and IIIa)–bearing cells (on macrophages, natural killer [NK] cells, granulocytes, and platelets), but the target structures and physiologic consequences are different.

In type II reactions, the drug-specific antibodies formed

Subclassification of Type IV Reactions

The detailed analysis of T-cell subsets and functions in the last 30 years has revealed that T cells play a major role in most immune reactions: as helper T cells, which regulate B-cell maturation to antibody-producing cells; as drug-specific T cells, which orchestrate different forms of inflammation; or as effector T cells mediating cytotoxicity. Based on these findings, as well as studies of immune reactions to drugs in vitro and in vivo, a refined subclassification of T-cell–meditated type

Summary

Small chemical compounds can interact with the immune system in 2 ways: by forming hapten-carrier complexes, which can stimulate innate and adaptive immunity (T and B cells) and cause localized or systemic reactions due to an immune response against the hapten-carrier complex; alternatively, chemicals that are unable to form covalent bonds can directly interact with proteins by van der Waals and other forces. Some of these labile interactions occur with immune receptors (pharmacologic

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