An Updated Review of the Molecular Mechanisms in Drug Hypersensitivity

Chen, Chun‐Bing; Abe, Riichiro; Pan, Ren‐You; Wang, Chuang‐Wei; Hung, Shuen‐Iu; Tsai, Yi‐Giien; Chung, Wen Hung

doi:10.1155/2018/6431694

Cited by 120 publications

(119 citation statements)

References 280 publications

(281 reference statements)

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“…Active Wnt signaling also plays essential roles in the activation of other immune cells, including antigen presenting cells and Tregs, which are also known to be central to the pathomechansim of SJS/TEN [3,18,43]. The canonical Wnt pathway was involved in suppressing dendritic cell activation and cross-priming of CD8+ T cell response [40].…”

Section: Discussionmentioning

confidence: 99%

“…Although the underlying pathological mechanisms are not fully understood, current pharmacogenomic studies have proposed an association between drug-induced SJS/TEN and human leukocyte antigen (HLA) genes [9][10][11]. Specific HLA molecules may have higher binding affinities for drug antigens and present the drug antigens to T cell receptor (TCR), causing a cascade of T cell activations and aberrant immune responses directed at keratinocytes [3,12,13]. Though the discovery of the predisposing gene has lowered the incidence, present therapies are mostly empirical [14].…”

Section: Ivyspringmentioning

confidence: 99%

“…The affected skin specimens typically showed subepidermal blistering, extensive apoptotic keratinocytes and partial-or full-thickness epidermal necrosis and epidermal detachment with a sparse dermal T-cell lymphocyte infiltrates histopathologically [1,2]. Mucosal involvements and skin detachments are also characteristic [3]. SJS is defined by the degree of skin detachment less than 10% of body surface area (BSA), while TEN is defined as the area of denuded skin greater than 30% of BSA.…”

Section: Introductionmentioning

confidence: 99%

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Attenuation of Wnt/β-catenin signaling in patients with Stevens-Johnson syndrome and toxic epidermal necrolysis

Chen¹,

Chang²,

Wu³

et al. 2020

Int. J. Biol. Sci.

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Stevens-Johnson syndrome (SJS) and toxic epidermal necrosis (TEN) are rare but life-threatening severe cutaneous adverse reactions. Current studies have suggested that the pathobiology of drug-mediated SJS/TEN involves a dysregulation of cellular immunity with overwhelming activation of cytotoxic T lymphocytes. The canonical Wnt signaling pathway plays important roles in T cell development and activation, which may provide potential avenues for alleviating dysregulated immunity in SJS/TEN. In this study, we aimed to assess the implication of Wnt signaling in drug-reactive T cells in SJS/TEN. We showed downregulation of Wnt signaling components, including T cell factor 1 (TCF-1)/lymphoid enhancer binding factor 1 (LEF-1) transcription factors, in SJS/TEN patients, suggesting that canonical Wnt signaling is regulated during cytotoxic T cell responses in SJS/TEN. Further analyses demonstrated that engagement of the T cell receptor by antigen encounter and treatment of a prognostic marker of SJS/TEN, IL-15, in vitro led to the downregulation of LEF-1 and TCF-1 expression in CD8+ T cells. Enhancement of Wnt signaling by adding the Wnt activators attenuated ex vivo activation of drug-specific T cells from SJS/TEN patients, indicating a functional involvement of Wnt signaling in the pathomechanism of SJS/TEN. These findings provide additional insight into the immunopathogenesis and therapeutic intervention of this devastating condition.

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Section: Discussionmentioning

confidence: 99%

Section: Ivyspringmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Attenuation of Wnt/β-catenin signaling in patients with Stevens-Johnson syndrome and toxic epidermal necrolysis

Chen¹,

Chang²,

Wu³

et al. 2020

Int. J. Biol. Sci.

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“…Adverse drug reactions have been linked to Human Leukocyte Antigens (HLA) in multiple different studies, where an individual carrying a specific risk allele has a higher risk of developing a reaction to that drug, including skin conditions like Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) and drug induced liver injury (1–3). HLA proteins play a role in the adaptive immune response, presenting peptides to the T-cell receptors.…”

Section: Introductionmentioning

confidence: 99%

Informatics investigations into anti-thyroid drug induced agranulocytosis associated with multiple HLA-B alleles

Ramsbottom

Carr

Rigden

et al. 2019

Preprint

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7Adverse drug reactions have been linked with HLA alleles in different studies. These HLA proteins 8 play an essential role in the adaptive immune response for the presentation of self and non-self 9 peptides. Anti-thyroid drugs methimazole and propylthiouracil have been associated with drug 10 induced agranulocytosis (severe lower white blood cell count) in patients with B*27:05, B*38:02 and 11 DRB1*08:03 alleles in different populations: Taiwanese, Vietnamese, Han Chinese and Caucasian. 12In this study, informatics methods were used to investigate if any sequence or structural similarities 13 exist between the two associated HLA-B alleles, compared with a set of "control" alleles assumed 14 not be associated, which could help explain the molecular basis of the adverse drug reaction. We 15 demonstrated using MHC Motif Viewer and MHCcluster that the two alleles do not have a 16propensity to bind similar peptides, and thus at a gross level the structure of the antigen 17 presentation region of the two alleles are not similar. We also performed multiple sequence 18 alignment to identify polymorphisms shared by the risk but not by the control alleles and molecular 19 docking to compare the predicted binding positions of the drug-allele combinations. 20 2 Two residues, Cys67 and Thr80, were identified from the multiple sequence alignments to be unique 21 to these risk alleles alone. The molecular docking showed the poses of the risk alleles to favour the 22 F-pocket of the peptide binding groove, close to the Thr80 residue, with the control alleles generally 23 favouring a different pocket. The data are thus suggestive that Thr80 may be a critical residue in 24 HLA-mediated anti-thyroid drug induced agranulocytosis, and thus can guide future research and 25 risk assessment. 26 that of abacavir with B*57:01. For this association, the crystal structure of the drug bound in 46 complex with the risk allele is available (8, 9). Illing et al. (8) and Ostrov et al. (9) have demonstrated 47

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“…Type IVb nonimmediate drug reactions corresponds to Th2-type immune response, where Th2 T-cells secrete IL-4, IL-13 which could justify the rapid onset of skin lesions [7,8]. The activated T-cells migrate to the tissue and kill tissue cells, such as keratinocytes in a perforin/granzyme-B and/or FasL-dependent manner [9]. Part of the activated T-cells will transform into effector memory T-cells; when they are located in the skin (in our case, in the patient´s palms), as tissue-resident-memory CD8+T-cells, they can produce a faster response than the previous in the next contact with the drug (skin-homing T-cells) [2,7].…”

mentioning

confidence: 99%