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.