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.
|Authors:||Ushigome Y, Mizukawa Y, Kimishima M, Yamazaki Y, Takahashi R, Kano Y, Shiohara T.|
|Journal:||Clin Exp Allergy. 2018 Nov;48(11):1453-1463.|
|PubMed:||Find in PubMed|