Monocytes are involved in the balance between regulatory T cells and Th17 cells in severe drug eruptions.

BACKGROUND: Drug-induced hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms (DiHS/DRESS) is a distinct phenotype of severe drug eruptions characterized by sequential reactivations of herpesviruses. Although a progressive loss of suppressive function in regulatory T cells (Tregs) occurred during the course of DiHS/DRESS, but not in Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), no previous studies investigated the mechanism. Given the recent finding that Treg development could be differentially regulated by CD16+ patrolling monocytes (pMOs) and CD14+ classical monocytes (cMOs), we can hypothesize that a differential fine-tuned interaction between Tregs and monocytes is the driving force behind the possible shift from Tregs to Th17 cells over a prolonged period of time in DiHS/DRESS. OBJECTIVE: To investigate whether the shift from Treg to Th17 could specifically occur during the course of DiHS/DRESS and to elucidate which subsets of monocytes could be involved in the shift. METHODS: We performed a prospective longitudinal study on the frequencies of Tregs, Th17 cells and monocyte subsets after onset of DiHS/DRESS and SJS/TEN, and long after their clinical resolutions. We next examined whether pMOs and cMOs could have a strong impact on the Th17/Treg differentiation and which cytokines could be crucial for the interaction between Th17/Tregs and MO subsets, by in vitro cocultures. RESULTS: Selective depletion of pMOs occurring at the acute stage of DiHS/DRESS was associated with the relative increase in the frequencies of cMOs producing IL-10 and it did drive Treg expansions. After clinical resolution, pMOs producing IL-6 were alternatively recruited and contributed to the eventual shift from a Treg to Th17 responses. CONCLUSIONS AND CLINICAL RELEVANCE: The gradual shift from Treg to Th17 cell development observed during the clinical course of DiHS/DRESS is mediated by the predominance of cMOs at the acute stage and alternatively recruited pMOs at the resolution stage, respectively.

Two Cases of Chromomycosis Identified by Molecular Phylogenetic Analysis.

Chromomycosis is an infection caused by dematiaceous fungi. These fungi belong to several genera with varied clinical presentations and parasitic forms. The disease is roughly classified into three types: chromoblastomycosis, black-grain mycetoma, and phaeohyphomycosis. While there are many kinds of dematiaceous fungi, the major etiologic agent is Fonsecaea pedrosoi, which to date has accounted for 90% of chromoblastomycosis cases. The genus Fonsecaea has recently been assessed via rRNA ITS sequence analysis, and species have been classified into F. pedrosoi, F. monophora, and others. We encountered two cases of chromomycosis that had developed on facial and upper arm areas. Neither of the etiologic agents could be identified through morphological examination under a microscope; however, F. monophora was confirmed using molecular phylogenetic analysis. Indeed, molecular phylogenetic analysis has revealed that the etiologic agents in many reported cases of F. pedrosoi infections were actually F. monophora. This suggests that it is now necessary to reconsider the classification of genus Fonsecaea.

Sweat as an Efficient Natural Moisturizer.

Although recent research on the pathogenesis of allergic skin diseases such as atopic dermatitis has focused on defects in skin genes important for maintaining skin barrier function, the fact that excreted sweat has an overwhelmingly great capacity to increase skin surface hydration and contains moisturizing factors has long been ignored: the increase in water loss induced by these gene defects could theoretically be compensated fully by a significant increase in sweating. In this review, the dogma postulating the detrimental role of sweat in these diseases has been challenged on the basis of recent findings on the physiological functions of sweat, newly recognized sweat gland-/duct-related skin diseases, and therapeutic approaches to the management of these diseases. We are now beginning to appreciate that sweat glands/ducts are a sophisticated regulatory system. Furthermore, depending on their anatomical location and the degree of the impairment, this system might have a different function: sweating responses in sweat glands/ducts located at the folds in hairy skin such as on the trunk and extremities could function as natural regulators that maintain skin hydration under quiescent basal conditions, in addition to the better-studied thermoregulatory functions, which can be mainly mediated by those at the ridges. The normal functioning of sweat could be disturbed in various inflammatory skin diseases. Thus, we should recognize sweating disturbance as an etiologic factor in the development of these diseases.

Crucial Role of Viral Reactivation in the Development of Severe Drug Eruptions: a Comprehensive Review.

A growing number of cells, mediators, and pathways have been implicated in severe drug eruptions. Fifteen years ago, we published landmark studies that sparked the current advances in our understanding of the role of viral reactivations in severe drug eruptions. Viral reactivations then became critically important as diagnostic tools, but how precisely they participated in the pathogenesis remained less well-defined. The question of whether viral reactivations are pathogenic or are instead as epiphenomenon of severe tissue damage has plagued the field of drug allergy for some decades. Recent evidence points to a crucial role for tissue-resident memory T (TRM) cells in immune protection against viral infections. Yet immune protection against viral infections is but one side of a coin, the other side of which comprises effector cells capable of mediating severe immunopathology: Once drug antigen is cross-recognized by these T cells, they could be activated to kill surrounding epidermal cells, resulting in drug-induced tissue damage. Such TRM cells could persistently reside in the skin lesions of fixed drug eruptions (FDE) and are most likely a major cell type responsible for the development of FDE. We also discuss the role of regulatory T (Treg) cells in the setting of drug allergy, in which herpesviruses are reactivated in sequence. Although many details of the complicated interactions among viruses, anti-viral immune responses, TRM cells, and Treg cells remain to be elucidated, we review the current status of this rapidly advancing field.

Short- and long-term outcomes of 34 patients with drug-induced hypersensitivity syndrome in a single institution.

BACKGROUND: Drug-induced hypersensitivity syndrome (DIHS)/drug reaction with eosinophilia and systemic symptoms (DRESS) is a severe systemic hypersensitivity reaction caused by specific drugs, in which herpesvirus reactivations and organ dysfunction occur during the course of the disease. Although recent reports have documented the development of autoimmune disease after complete resolution of DIHS/DRESS, relatively little is known about long-term outcomes after complete resolution of the disease. OBJECTIVE: The aim of this study was to retrospectively analyze complications and sequelae in the early and late phases of DIHS/DRESS according to treatment. METHODS: In all, 34 patients were classified into 2 groups: 14 patients with oral corticosteroid treatment; and 20 with noncorticosteroid treatment. The disease time course was divided into 2 periods: the first 6 months after onset of the drug reaction (early phase); and the period thereafter (late phase). Investigations to detect the presence of viral/bacterial infectious diseases, organ dysfunction, and autoantibodies were performed in both early and late phases. RESULTS: Herpesvirus infections and pneumonia were detected in 6 and 2 patients, respectively, in the corticosteroid treatment group in the early phase. In the noncorticosteroid treatment group, 2 patients developed autoimmune diseases, namely lupus erythematosus and autoimmune thyroiditis. Autoantibodies were detected in 44.4% of patients examined in the late phase of the disease. LIMITATIONS: This study only evaluated a small number of autoantibodies. CONCLUSION: The need for anti-inflammatory effects from systemic corticosteroids should be balanced with the risk of infectious diseases and the benefits of preventing the appearance of later autoimmune conditions in patients with DIHS/DRESS.