Delayed Drug Hypersensitivity Reactions: Molecular Recognition, Genetic Susceptibility, and Immune Mediators

Abstract

Drug hypersensitivity reactions are classified into immediate and delayed types, according to the onset time. In contrast to the immediate type, delayed drug hypersensitivity mainly involves T lymphocyte recognition of the drug antigens and cell activation. The clinical presentations of such hypersensitivity are various and range from mild reactions (e.g., maculopapular exanthema (MPE) and fixed drug eruption (FDE)), to drug-induced liver injury (DILI) and severe cutaneous adverse reactions (SCARs) (e.g., Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), and acute generalized exanthematous pustulosis (AGEP)). The common culprits of delayed drug hypersensitivity include anti-epileptics, antibiotics, anti-gout agents, anti-viral drugs, etc. Delayed drug hypersensitivity is proposed to be initiated by different models of molecular recognition, composed of drug/metabolite antigen and endogenous peptide, HLA presentation, and T cell receptor (TCR) interaction. Increasing the genetic variants of HLA loci and drug metabolic enzymes has been identified to be responsible for delayed drug hypersensitivity. Furthermore, preferential TCR clonotypes, and the activation of cytotoxic proteins/cytokines/chemokines, are also involved in the pathogenesis of delayed drug hypersensitivity. This review provides a summary of the current understanding of the molecular recognition, genetic susceptibility, and immune mediators of delayed drug hypersensitivity.

Keywords: HLA; Stevens–Johnson syndrome; T lymphocytes; drug hypersensitivity; drug reaction with eosinophilia and systemic symptoms; severe cutaneous adverse reactions.

Figure 1

The characteristics of type IV (delayed-type) drug hypersensitivity. Delayed-type drug hypersensitivity is mostly induced by T cells. They are subdivided into four types (IVa, IVb, IVd, and IVc) according to the types of T cells, such as T_H1, T_H2, IL8 T_H cells, and cytotoxic T cells. The types IVa, IVb, and IVd are mediated by T_H cells and the activation of downstream granulocytes, such as macrophages, mast cells, eosinophils, and neutrophils. By comparison, type IVc is mainly mediated by cytotoxic T cells, which induce target cell death by releasing cytokines, such as granulysin, granzyme B, and perforin, or direct interaction of Fas/FasL. Abbreviations: FDE, fixed drug eruption; MPE, maculopapular eruption; AGEP, acute generalized exanthem pustulosis; DRESS, drug reactions with eosinophilia and systemic symptoms; DiHS, drug-induced hypersensitivity syndrome; DILI, drug-induced liver injury; SJS, Stevens–Johnson syndrome; TEN, toxic epidermal necrolysis.

Figure 2

Four hypotheses proposed for the molecular recognition of drugs by TCR in delayed type drug hypersensitivity. The hapten model hypothesizes that a drug or metabolite covalently binds to an endogenous peptide and leads to an immunogenic response. The other three hypotheses suggest non-covalent interactions between drugs, endogenous peptides, TCR, and HLA. The pharmacological interaction with the immune receptor (p-i) concept hypothesizes that the drug interacts with TCR, HLA, or both non-covalently. Altered TCR repertoire and altered peptide repertoire models propose that the drug non-covalently binds on TCR or HLA in the groove region.