Hypersensitivity reactions to drugs can cause a variety of
skin diseases like maculopapular, bullous and pustular eruptions. In recent years increasing evidence indicates the important role of T cells in these
drug-induced
skin diseases. Analysis of such
drug-specific T cell clones has revealed that drugs can be recognized by
alpha beta-T cell receptors, not only if bound covalently to
peptides, but also if the
drug binds in a rather labile way to the presenting major histocompatibility complex (MHC)-
peptide. This presentation is sufficient to stimulate T cells. In maculopapular
exanthema (MPE), histopathological analysis typically shows a dominant T cell infiltration together with a vacuolar interface
dermatitis. Immunohistochemical studies demonstrate the presence of cytotoxic CD4+ and to a lesser degree of CD8+ T cells, which contain
perforin and
granzyme B. They are close to keratinocytes that show signs of cell destruction. Expression of
Fas ligand is barely detectable, suggesting that cytotoxic granule exocytosis may be the dominant pathway leading to keratinocyte cell damage. While in MPE, the killing of cells seems to be predominantly mediated by CD4+ T cells, patients with
bullous skin disease show a strong CD8+ T cell migration to the epidermis. This is probably due to a preferential presentation of the
drug by
MHC class I molecules, and a more extensive killing of cells that present drugs on
MHC class I molecules. This might lead to
bullous skin diseases. In addition to the presence of cytotoxic T cells,
drug-specific T cells also orchestrate the inflammatory skin reaction through the release and induction of various
cytokines [i.e.
interleukin (IL)-5,
IL-6,
tumor necrosis factor-alpha and
interferon-gamma] and
chemokines (
RANTES, eotaxin or IL-8). The increased expression of these mediators seems to contribute to the generation of tissue and blood
eosinophilia, a hallmark of many
drug-induced
allergic reactions. However, in
acute generalized exanthematous pustulosis (a peculiar form of
drug allergy), neutrophils represent the predominant cell type within pustules, probably due to their recruitment by
IL-8 secreting
drug specific T cells and keratinocytes.