HLA Class-II‒Restricted CD8+ T Cells Contribute to the Promiscuous Immune Response in Dapsone-Hypersensitive Patients

Zhao, Qing; Almutairi, Mubarak; Tailor, Arun; Lister, Adam; Harper, Nicholas W.; Line, James; Meng, Xiaoli; Pratoomwun, Jirawat; Jaruthamsophon, Kanoot; Sukasem, Chonlaphat; Sun, Yonghu; Sun, Lele; Ogese, Monday O.; MacEwan, David J.; Pirmohamed, Munir; Li, Jianjun; Ostrov, David A.; Liu, Hong; Zhang, Furen; Naisbitt, Dean

doi:10.1016/j.jid.2021.03.014

Cited by 15 publications

(21 citation statements)

References 53 publications

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“…DDS has also been used to treat various dermatologic and non-dermatologic diseases, including Pneumocystis jirovecii pneumonia [ 28 ], dermatitis herpetiformis [ 29 ], immune thrombocytopaenia [ 30 ] and eosinophilic fasciitis [ 31 ]. Previous studies found that DDS-specific cytotoxic T cells were significantly activated when co-cultured with HLA-B*13:01-expressing antigen presenting cells (APCs) in the presence of DDS [ 32 , 33 ]. However, HLA-B*13:01-DDS-TCR immune synapse that plays role in DDS-DIHS associated T cells activation remains uncharacterized, which makes prevention and treatment efforts more difficult.…”

Section: Introductionmentioning

confidence: 99%

Functional and structural characteristics of HLA-B*13:01-mediated specific T cells reaction in dapsone-induced drug hypersensitivity

Jiang

Wang

et al. 2022

J Biomed Sci

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Background Severe cutaneous adverse drug reactions (SCARs) are a group of serious clinical conditions caused by immune reaction to certain drugs. The allelic variance of human leukocyte antigens of HLA-B*13:01 has been strongly associated with hypersensitivities induced by dapsone (DDS). T-cell receptor mediated activation of cytotoxic T lymphocytes (CTLs) has also been suggested to play an essential role in pathogenesis of SCARs. However, HLA-B*13:01-DDS-TCR immune synapse that plays role in drug-induced hypersensitivity syndrome (DIHS) associated T cells activation remains uncharacterized. Methods To investigate the molecular mechanisms for HLA-B*13:01 in the pathogenesis of Dapsone-induced drug hypersensitivity (DDS-DIHS), we performed crystallization and expanded drug-specific CTLs to analyze the pathological role of DDS-DIHS. Results Results showed the crystal structure of HLA-B*13:01-beta-2-microglobulin (β2M) complex at 1.5 Å resolution and performed mutation assays demonstrating that I118 or I119, and R121 of HLA-B*13:01 were the key residues that mediate the binding of DDS. Subsequent single-cell TCR and RNA sequencing indicated that TCRs composed of paired TRAV12-3/TRBV28 clonotype with shared CDR3 region specifically recognize HLA-B*13:01-DDS complex to trigger inflammatory cytokines associated with DDS-DIHS. Conclusion Our study identified the novel p-i-HLA/TCR as the model of interaction between HLA-B*13:01, DDS and the clonotype-specific TCR in DDS-DIHS. Graphical Abstract

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Section: Introductionmentioning

confidence: 99%

Functional and structural characteristics of HLA-B*13:01-mediated specific T cells reaction in dapsone-induced drug hypersensitivity

Jiang

Wang

et al. 2022

J Biomed Sci

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“…The contribution of HLA class II restricted CD8+ T-cells in the pathogenesis of dapsone hypersensitivity has been studied. 16 We found the highest sensitivity, specificity, PPV, and NPV for HLA-B*38 with LTG-induced SJS/TEN. These tests could be applicable when association of certain HLA with a specific CADR is widely confirmed.…”

Section: Details Of Causative Agents and Clinical Types Of Drug React...mentioning

confidence: 58%

“…Our results showed an association of HLA class II with CIP‐induced MPE and urticaria, CTX‐induced MPE, and LTG‐induced SJS/TEN. The contribution of HLA class II restricted CD8+ T‐cells in the pathogenesis of dapsone hypersensitivity has been studied 16 …”

Section: Discussionmentioning

confidence: 99%

Association between human leukocyte antigens and cutaneous adverse drug reactions to antiepileptics and antibiotics in the Iranian population

Mortazavi

Rostami

Firooz

et al. 2022

Dermatologic Therapy

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In this case-control study, class І and ІІ human leukocyte antigen (HLA) alleles in Iranian patients with benign and severe cutaneous adverse drug reactions (CADRs) due to aromatic anticonvulsants and antibiotics were evaluated. Patients diagnosed with CADRs (based on clinical and laboratory findings) with a Naranjo score of ≥ 4 underwent blood sampling and HLA-DNA typing. The control group comprised 90 healthy Iranian adults. Alleles with a frequency of more than two were reported. Deviations from Hardy-Weinberg equilibrium were not observed. Eighty patients with CADRs including 54 females and 26 males with a mean age of 41.49 ± 16.08 years were enrolled in this study. The culprit drugs included anticonvulsants (lamotrigine, carbamazepine, and phenytoin) and antibiotics (ciprofloxacin and co-trimoxazole). The comparison of allele frequencies in the Iranian healthy control group and the group with benign CADRs revealed that HLA-Cw*04, and HLA-A*24 were significantly associated with lamotrigine-induced maculopapular CADRs. Furthermore, HLA-B*51 showed a significant correlation with carbamazepine-induced maculopapular CADRs. Significant associations were also detected between ciprofloxacin-induced urticarial CADRs with HLA-B*40, and HLA-DRB1*14. In the severe group, HLA-B*38 and HLA-DRB1*13 were significantly associated with lamotrigine-induced Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). Moreover, HLA-A*31 and HLA-Cw*04 were significantly correlated with carbamazepine-induced drug reactions with eosinophilia and systemic symptoms (DRESS). HLA-B*08 also showed a significant correlation with ciprofloxacininduced acute generalized exanthematous pustulosis (AGEP). In conclusion, Lamotrigine-induced MPE was significantly correlated with HLA-Cw*04, and HLA-A*24. Similarly, lamotrigine-induced SJS/TEN was significantly associated with HLA-B*38 and HLA-DRB1*13. Additionally, HLA-A*31 was associated with DRESS caused by carbamazepine. The most frequent CADR-inducing drugs were anticonvulsants.

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“…This drug-specific TCR shows phenotype-specificity in an HLA-B*15:02-favored manner. In addition, Zhao et al reported a promiscuous immune response associated with HLA Class-II‒-restricted T cells in patients with dapsone-induced DRESS ( Zhao et al, 2021 ), but the detailed interactions and mechanisms that underlie HLA-B*13:01/dapsone–restricted CD8 + T cell responses remain poorly understood. The recent discovery of HLA genetic predispositions and oligoclonal and clonotype-specific TCR usages ( Ko et al, 2011 ; Chung et al, 2015a ) support the concept that an immune synapse involving an HLA–drug–TCR interaction is essential for inducing type B idiosyncratic ADR.…”

Section: Genetic Factors Of Severe Adverse Drug Reactionsmentioning

confidence: 99%

An Updated Review of Genetic Associations With Severe Adverse Drug Reactions: Translation and Implementation of Pharmacogenomic Testing in Clinical Practice

et al. 2022

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Adverse drug reactions (ADR) remain the major problems in healthcare. Most severe ADR are unpredictable, dose-independent and termed as type B idiosyncratic reactions. Recent pharmacogenomic studies have demonstrated the strong associations between severe ADR and genetic markers, including specific HLA alleles (e.g., HLA-B*15:02/HLA-B*57:01/HLA-A*31:01 for carbamazepine-induced severe cutaneous adverse drug reactions [SCAR], HLA-B*58:01 for allopurinol-SCAR, HLA-B*57:01 for abacavir-hypersensitivity, HLA-B*13:01 for dapsone/co-trimoxazole-induced SCAR, and HLA-A*33:01 for terbinafine-induced liver injury), drug metabolism enzymes (such as CYP2C9*3 for phenytoin-induced SCAR and missense variant of TPMT/NUDT15 for thiopurine-induced leukopenia), drug transporters (e.g., SLCO1B1 polymorphism for statin-induced myopathy), and T cell receptors (Sulfanilamide binding into the CDR3/Vα of the TCR 1.3). This mini review article aims to summarize the current knowledge of pharmacogenomics of severe ADR, and the potentially clinical use of these genetic markers for avoidance of ADR.

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HLA Class-II‒Restricted CD8+ T Cells Contribute to the Promiscuous Immune Response in Dapsone-Hypersensitive Patients

Cited by 15 publications

References 53 publications

Functional and structural characteristics of HLA-B*13:01-mediated specific T cells reaction in dapsone-induced drug hypersensitivity

Functional and structural characteristics of HLA-B*13:01-mediated specific T cells reaction in dapsone-induced drug hypersensitivity

Association between human leukocyte antigens and cutaneous adverse drug reactions to antiepileptics and antibiotics in the Iranian population

An Updated Review of Genetic Associations With Severe Adverse Drug Reactions: Translation and Implementation of Pharmacogenomic Testing in Clinical Practice

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