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.

Drug-induced hypersensitivity syndrome related to piperacillin-tazobactam: a case report and review of the literature

“…The pathogenesis of this disease has not yet been fully elucidated. Recent reviews have pointed out that DiHS/DRESS caused by some anti-epileptics, anti-gout, antibiotics, and anti-viral drugs are associated with genetic polymorphisms in the HLA allele, and that mechanisms such as specific signaling pathways in T-cell activation, production of cytokines and chemokines, and viral reactivation also play a role in the pathogenesis of DiHS/DRESS ( 16 , 17 ). Rutkowski reported six patients with piperacillin-tazobactam-induced DiHS, and three patients were found to be HLA-B62-positive by testing for HLA typing ( 6 ).…”

Assessing Chemical Intolerance in Parents Predicts the Risk of Autism and ADHD in Their Children

“…An important factor affecting immunogenicity is molecular weight. If the molecular weight of a foreign chemical (xenobiotic) is less than 10,000 Daltons, the mast cell will initiate cell-mediated immunity (CMI), also known as delayed-type hypersensitivity (DTHS) [ 74 ]. The majority of xenobiotics weigh far less than 10,000 Daltons, for example, pesticides, plasticizers, dioxins, fragrances, food proteins and carbohydrates, food additives, MSG, caffeine, etc.…”

“…An important factor affecting immunogenicity is molecular weight. If the molecular weight of a foreign chemical (xenobiotic) is less than 10,000 Daltons, the mast cell will initiate cell-mediated immunity (CMI), also known as delayed-type hypersensitivity (DTHS) [74].…”

Molecular Mechanisms of Cutaneous Immune-Related Adverse Events (irAEs) Induced by Immune Checkpoint Inhibitors

“…The detailed mechanisms of ICI-induced morbilliform eruption remains unclear, but there is a hypothesis suggesting an association with type IVc hypersensitivity reactions [12,50], in which cytotoxic T cells act as effector cells. Under immunotherapy, activated cytotoxic T lymphocytes can directly harm target cells by releasing cytotoxic cytokines, including perforin, granulysin, either granzymes or granzymes B, and through physical interaction via the FasL/FasR pathway.…”