Up-Regulation of T-Cell Activation MicroRNAs in Drug-Specific CD4⁺ T-Cells from Hypersensitive Patients

Abstract

Dysregulation in the expression of microRNAs (miRNAs), single-stranded RNAs which regulate gene expression, has been associated with diseases such as Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN), although their cellular origin has not been explored. Thus, the focus of this work was to study expression patterns of reported miRNAs involved in T-cell activation following drug-specific stimulation in peripheral blood mononuclear cells (PBMCs) and drug-specific CD4 T-cell clones (TCC) from patients with different cutaneous manifestations of delayed-type drug hypersensitivity reactions. CD4 T-cells from hypersensitive patients were stimulated to proliferate, secreted cytokines (IFN-γ and IL-22), cytolytic molecules (Granzyme B) and up-regulate miRNAs 24 to 48 h after drug exposure. Carbamazepine-specific CD4 T-cells that proliferated to the greatest extent and secreted the highest levels of IFN-γ showed an up-regulation of miR-18a and miR-155. In contrast, piperacillin-specific CD4 T-cells displaying high expression of miR-9 and miR-21 showed an association with the extent of proliferation, but not IFN-γ secretion. MiR-155 up-regulation was detected in PBMCs from all hypersensitive patients 24 h after drug treatment, while miR-18a and miR-21 expression was up-regulated after 48 h. These findings demonstrate that miRNAs are expressed during drug-specific CD4 T-cell activation and shows a new regulation path for drug hypersensitivity reactions.

Recent developments and highlights in drug hypersensitivity

“…The involvement of microRNAs (miRNAs) in SJS/TEN has been explored demonstrating that their expression during drug‐specific CD4 + T‐cell activation and cytokine production depends on the drug involved. Carbamazepine was associated with an increase in IFN‐gamma secretion and miR‐18a and miR‐155 upregulation and piperacillin with high miR‐9 and miR‐21 expression in nonproliferating cells …”

“…Carbamazepine was associated with an increase in IFNgamma secretion and miR-18a and miR-155 upregulation and piperacillin with high miR-9 and miR-21 expression in nonproliferating cells. 150 In DRESS, CD4 + T cells show a TH2 pattern with production of IL-5, which is involved in eosinophil activation and recruitment to the affected tissues. 151 In this pathology, it has been also demonstrated the increased type 2 innate lymphoid (ILC2) cells, with a high expression of IL-33 and soluble suppression of tumorigenicity two peptide, important in skin inflammation.…”

Approaches to inducing antigen‐specific immune tolerance in allergy and autoimmunity: Focus on antigen‐presenting cells and extracellular vesicles

“…Antigen challenges in DTH influence the profile of miRNAs in human skin samples 133 . This may be associated with a dysregulation of the miRNA expression pattern reported in drug‐specific T cells, which contributed to the severity of the drug‐induced hypersensitivity reaction 134 . Thus, one can speculate that either direct antagonism of upregulated miRNAs by EV‐mediated delivery of anti‐miRNA (anti‐miR) sequences or a reprogramming of APCs to repress the miRNA‐induced effects in T cells would constitute promising alternatives for genetically encoded therapies of hypersensitivities (Figure 1).…”

Epigenetic Effects Mediated by Antiepileptic Drugs and their Potential Application

“…Additional experiments support the robust linkage between miRNA changes induced by PB and liver cancer in rodent models [ 26 ]. Similarly, cutaneous adverse reactions, such as Stevens-Johnson syndrome (SJS), caused by CBZ are believed to be related to the dysregulation of miRNAs in an immune cell experimental analysis [ 43 ]. This finding will be restated in subsequent chapters.…”

“…CBZ-induced hypersensitivity reactions, such as SJS, are associated with the activation of CD4 + T-cells. A recent study found that miR-18a and miR-155 may be epigenetic factors [ 43 ].…”