Phenotypic diversity in delayed drug hypersensitivity: an immunologic explanation.

Drug hypersensitivity reactions are a significant cause of iatrogenic-induced illness. (They were originally classified as type IV hypersensitivity, to describe the tuberculin skin reaction.) It now appears that the T-cell directs the entire inflammatory cascade induced by delayed drug allergy. Delayed drug hypersensitivity, usually manifested in the skin, is triggered when drug-specific CD4+ and CD8+ T cells recognize drugs through their T-cell receptors in a process that is dependent on a major histocompatibility complex. Drugs stimulate T-cell receptors by either covalently binding to peptides or using their structural features to interact via a more direct approach. Immunohistochemical and functional analysis of drug-reactive T-cell clones has shown that the phenotypic pattern of delayed drug hypersensitivity depends on the cytokine pattern induced. For example, maculo-papular exanthema may be either TH-1 or TH-2 in nature, depending on whether they are interferon- g /tumor necrosis factor- a or interleukin-4, 5 and 13 driven. Bullous reactions to drugs (i.e., Stevens-Johnson syndrome or toxic epidermal necrolysis) are characterized by widespread keratinocyte apoptosis, a consequence of high CD8+ T-cell involvement and the molecular cytotoxicity of Fas, perforin and granzyme B. Pustular exanthema reactions to medications are stimulated via the T-cell release of IL-8 and granulocyte-monocyte colony-stimulating factor (GM-CSF). With better understanding of these unique inflammatory cascades, delayed type IV hypersensitivity reactions have been re-classified into four main subtypes: IVa (TH-1/monocyte directed), IVb (TH-2/eosinophil directed), IVc (CD8+/ Fas/perforin/Granzyme B directed) and IVd (IL-8/GM-CSF/neutrophil directed). Clinically, delayed hypersensitivity eruptions are often an overlap of cytokine pathways, with one preferential reaction dominating the final picture.