Defective Regulatory T Cells In Patients with Severe Drug Eruptions: Timing of the Dysfunction Is Associated with the Pathological Phenotype and Outcome

Abstract

Toxic epidermal necrolysis (TEN) and drug-induced hypersensitivity syndrome (DIHS) represent two ends of a spectrum of severe drug eruptions: DIHS is unique in that severe epidermal damage seen in TEN is absent, sequential reactivations of herpesviruses occur, and autoimmunity often ensues. To investigate whether changes in regulatory T (Treg) cell function would contribute to variability in the clinical manifestations, we examined the frequency, phenotype, and function of Treg cells both during the acute stage and again long after clinical resolution of both diseases. Dramatic expansions of functional Treg cells were found in the acute stage of DIHS. In contrast, Treg function was profoundly impaired in TEN, although present in normal frequency. Skin homing addressins were more preferentially expressed on Treg cells in DIHS than in TEN. Indeed, Treg cells were more abundantly present in the skin lesions of DIHS. Surprisingly, Treg cells contracted upon resolution of DIHS became functionally deficient, whereas their functional defects in TEN were restored upon recovery. These findings indicate that a transitory impairment in their function during the acute stage of TEN may be related to severe epidermal damage, while a gradual loss of their function after resolution of DIHS may increase the risk of subsequently developing autoimmune disease.

Late onset toxic epidermal necrolysis induced by mogamulizumab, an anti‐CC chemokine receptor 4 antibody for the treatment of adult T‐cell leukaemia/lymphoma

“…Another possible mechanism for the induction of TEN by MOG is depletion by MOG of CCR4 positive regulatory T cells, which is reported previously [8]. Takahashi et al reported that a transitory impairment in the function of regulatory T cells during the acute stage of TEN may be related to severe epidermal damage [9].…”

Immediate Reactions to More Than 1 NSAID Must Not Be Considered Cross-Hypersensitivity Unless Tolerance to ASA Is Verified

“…Although multiple allergy to drugs was first reported more than 20 years ago [19,20], studies to elucidate the mechanism have been carried out only for T cell-dependent reactions, where sensitization to multiple drugs could occur both simultaneously and sequentially [19][20][21]. An imbalance of the immune system caused by effector and/or regulatory T cells may be involved [24,33].…”

Pathological Role of Regulatory T Cells in the Initiation and Maintenance of Eczema Herpeticum Lesions

“…Foxp3 + Tregs were shown to expand quickly during the course of immune reconstitution; thus, these expanded Tregs could act to prevent lymphopenia-associated autoimmunity in individuals recovering from lymphopenia in mice (29). Importantly, similar expansions of fully functional Tregs during the acute phase and the subsequent contraction upon resolution of disease as observed in EH also were reported to occur in patients with sarcoidosis or drug-induced hypersensitivity syndrome (30,31), both of which fit within the spectrum of immune reconstitution syndrome (32,33). In a recent retrospective analysis (1) of 100 cases of EH, 36% of the patients had noted a severe exacerbation of their AD that typically had started ∼2 wk before the onset of EH, and the majority of the patients had not received any corticosteroid therapy in the 4 wk before the onset of EH.…”