Immunologic mechanisms of cutaneous drug reactions

Abstract

Idiosyncratic reactions (type B) are a major complication of drug therapy, because they are related to both the drug and to individual factors in the host. In comparison with other organs, the skin is quite frequently a target of allergic reactions, which are mainly elicited by small molecular weight compounds. This is the case in allergic contact dermatitis as well as in drug allergic reactions. In contrast to allergic contact dermatitis however, drug-induced hypersensitivity reactions of the skin have enormous variability with regard to their pathophysiological pathways, clinical signs of symptoms, severity, and the drugs which can elicit these reactions. Allergic reactions are mediated either by specific antibodies or a cellular immunocompetent immune response. About 25% to 30% of type B reactions are estimated to be allergic drug reactions, which are classified by the latency period between the ingestion of the responsible allergen and the onset of clinical symptoms. Studying the mechanisms of these hypersensitivity reactions improves our understanding of these diseases in general, and shows the importance of the skin as a signaling organ in these reactions.

Multiple Cytochrome P450–Isoenzymes mRNA Are Expressed in Dendritic Cells

“…Human cytochrome P450 (CYP) isoenzymes are known to metabolize small molecular weight compounds to highly reactive species which are able to bind to proteins which is considered as a prerequisite for the sensitization by those small molecular weight compounds [1]. In our own studies we were able to show that the response of lymphocytes of sensitized patients to p–phenylenediamine is increased after adding murine liver microsomes which contain CYP–dependent isoenzymes in the lymphocyte transformation test [2]. Recently it has been shown that eugenol which is a frequent sensitizer does not sensitize CYP1A1 knockout mice whereas the wild–type mice are sensitized to eugenol suggesting that CYP1A1–dependent metabolites of eugenol are the nominative antigen [3].…”

Skin manifestations of drug allergy

“…The hapten:peptide:MHC complex is then displayed on the cell surface to be recognised by T cells with appropriate specific receptors. Many native drug molecules are not intrinsically protein-reactive, although some, including penicillins, cephalosporins and captopril, can bind directly to serum or cellular proteins [4,5]. It is thought that protein-reactive haptens are generated during the process of biodegradation and detoxification.…”

The Skin: Target Organ in Immunotoxicology of Small-Molecular-Weight Compounds

“…Morphologically, the skin lesions in the most dangerous form of bullous drug reactions -TEN -show extensive cell death in the basal and the malpighian layer, especially close to lymphocyte infiltration. Immunohistochemical analysis has identified CD8+ T cells as the predominant epidermal T cell subset in drug-induced bullous eruptions to ß-lactam antibiotics [38]. These CD8+ T lymphocytes produced a Th1-like cytokine pattern and were cytotoxic under in vitro conditions against autologous B cells upon stimulation through the T cell receptor and against epidermal keratinocytes in lectin-induced cytotoxicity assays [38].…”

“…Immunohistochemical analysis has identified CD8+ T cells as the predominant epidermal T cell subset in drug-induced bullous eruptions to ß-lactam antibiotics [38]. These CD8+ T lymphocytes produced a Th1-like cytokine pattern and were cytotoxic under in vitro conditions against autologous B cells upon stimulation through the T cell receptor and against epidermal keratinocytes in lectin-induced cytotoxicity assays [38]. Further information on recent studies suggests that the cell destruction in TEN and TEN/Stevens-Johnson syndrome may be a result of apoptosis.…”

“…We also cloned lesional T lymphocytes from a patient suffering from bullous drug reaction to sulfonamides and found an increased proliferation measured as counts per minute of incorporated 3 H-thymidine -after adding sulfonamide-modified microsomal protein [38]. Cutaneous reactions of delayedtype hypersensitivity are the most common manifestations caused by sulfamethoxazole and dapsone.…”