Recent progress of elucidating the mechanisms of drug hypersensitivity

Abstract

Recent technical approaches to investigating drug hypersensitivity have provided a great deal of information to solve the mechanisms that remain poorly understood. First, immunological investigations and in silico analysis have revealed that a novel interaction between T cells and antigen-presenting cells, namely the pharmacological interaction concept, is involved in drug recognition and the hapten theory. Second, progress in immunology has provided a new concept of CD4+ T cell subsets. Th17 cells have proven to be a critical player in acute generalized exanthematous pustulosis. Our recent findings suggest that this subset might contribute to the pathogenesis of Stevens-Johnson syndrome/toxic epidermal necrolysis. Third, alarmins, molecules associated with innate immunity, are also associated with exaggeration and the persistence of severe drug hypersensitivity. The latest innovative techniques are providing a new landscape to examine drug hypersensitivity.

Keywords: Allergy; Drug hypersensitivity; Human herpesvirus-6; Innate immunity; T cell; T cell receptor.

Fig. 1

Interaction of T cells and antigen-presenting cells (APCs) in drug antigen recognition. A new epitope is presented by covalent binding of drugs with self-proteins, which is recognized by T cells as a haptenic antigen (A). On the other hand, a high affinity of the drug for T cell receptors (TCRs) expressed on T cells (B), or major histocompatibility complex (MHC) expressed on APCs (C), increases the possibility of activating T cells (p-i concept, modified in the Fig. of ref. [9]).

Fig. 2

Functional subsets of effector CD4+ T cells [15]. APC, antigen-presenting cell; GATA3, the transcription factor GATA-binding protein-3; IFN, interferon; TGF, transforming growth factor; AHR, aryl hydrocarbon receptor; RORγt, retinoic acid-related orphan receptor γt; T-bet, T-box expressed in T cells; DTH, delayed type hypersensitivity; EAE, experimental autoimmune encephalomyelitis; EAU, experimental autoimmune uveitis; CIA, collagen-induced arthritis; PIA, peptoglycan-induced arthritis.

Fig. 3

Phenotypic analysis of peripheral blood mononuclear cells (PBMCs) and mononuclear cells in blisters (Blisters) in a toxic epidermal necrolysis patient. Numbers indicate percentages of total cells.

Fig. 4

IFN-γ and IL-17 productions of drug-specific T cell clones (TCCs) after stimulation with anti-CD3 antibody for 3 days. TCCs were established from patients with gold and nickel allergies (Metal), SJS/TEN and DIHS. Y-axis, cytokine concentrations (pg/mL). ^*p < 0.05, Dunn's Multiple Comparison Test. SJS, Stevens-Johnson syndrome; TEN, toxic epidermal necrolysis; DIHS, drug-induced hypersensitivity syndrome.

Fig. 5

Circulating monocytes in drug-induced hypersensitivity syndrome (DIHS) patients. (A) Representative data of total blood cell counts (closed squares), numbers of eosinophils (closed triangles) and monocytes (open circles). Numbers indicate cell counts (/mm³). An arrow indicates human herpes virus (HHV)-6 reactivation. (B) Flowcytometric analysis of peripheral blood mononuclear cells in normal individuals and patients with DIHS and Stevens-Johnson syndrome (SJS). Monocytes from DIHS patients show higher side scatter counts (SCC). FSC, forward scatter counts. (C) Percentage of monocytes at early (≤21 days after the onset) and late (>21 days after the onset) phase.