Comprehensive assessment of T cell receptor β repertoire in Stevens–Johnson syndrome/toxic epidermal necrolysis patients using high-throughput sequencing

Xiong, Hao; Wang, Lanting; Jiang, Menglin; Chen, Shengan; Yang, Feng; Zhu, Huizhong; Zhu, Qian; Tang, Chenling; Qin, Shengying; Xing, Qinghe; Luo, Xiaoqun

doi:10.1016/j.molimm.2019.01.002

Cited by 13 publications

(10 citation statements)

References 36 publications

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“…Dynamic analysis of OMDT TCR repertoires started with the repertoire diversity. As reported previously in the pilot cross-sectional study 8 , we found no significant difference in CDR3 repertoire diversity measured by 6 indices between the cases and the controls, although decreased diversity has been observed in similar diseases 10 – 12 . Remarkably, the 6 indices all showed an increasing trend with the decreasing severity from acute to recovery stage in the cases, however, the differences between the stages were not statistically significant.…”

Section: Discussionsupporting

confidence: 86%

Dynamic analysis of peripheral blood TCR β-chain CDR3 repertoire in occupational medicamentosa-like dermatitis due to trichloroethylene

Lin

Wang

et al. 2021

Sci Rep

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Previously, we had cross-sectionally explored the characteristics of T cell receptor (TCR) repertoires from occupational medicamentosa-like dermatitis due to trichloroethylene (OMDT) patients, now we further analyzed the dynamic features of OMDT TCR repertoires. Peripheral blood TCR β-chain complementarity-determining region 3 (CDR3) genes were detected with the high throughput sequencing in 24 OMDT cases in their acute, chronic and recovery stages, respectively, and in 24 trichloroethylene-exposed healthy controls. The TCR repertoire diversity, TRBV/TRBD/TRBJ gene usage and combination, frequencies of CDR3 nucleotide (nt) and amino acid (aa) sequences in the cases in different stages and in the controls were analyzed. TRBV6-4 and TRBV7-9 frequencies significantly differed between the cases and controls (both P < 6.1 × 10–4). TRBV6-4 combination with TRBJ2-1, TRBJ2-2, TRBJ2-3, and TRBJ2-6, and TRBV7-9 combination with TRBJ2-1 were associated with the stage by OMDT severity (all P < 0.001). Ten CDR3-nt and 7 CDR3-aa sequences in TRBV7-9-TRBJ2-1 combination and 1 CDR3-nt and 1 CDR3-aa sequences in TRBV6-4-TRBJ2-1 combination were identified as associated with the severity of OMDT (all P < 0.001). We revealed further how TCR repertoires vary with the severity in the development of OMDT, and severity-related TCRs may provide important therapeutic targets for OMDT in clinical practice.

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Section: Discussionsupporting

confidence: 86%

Dynamic analysis of peripheral blood TCR β-chain CDR3 repertoire in occupational medicamentosa-like dermatitis due to trichloroethylene

Lin

Wang

et al. 2021

Sci Rep

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“…For pools aligned with the RP-HPLC retention time of CBZ (pool 10), ECBZ (pool 12) and OXC (pool 13), residual sample post-peptide analysis was diluted by a factor of~2. 6 mL diluted sample was loaded onto a NanoLC Trap ChromXP C18 column (350 mm x 0.5 mm, 3 µm particle size, 120 Å pore size) in 2% ACN, 0.1% FA at a flow rate of 5 µL/min for 5 minutes, prior to separation over a ChromXP nanoLC C18 column (75 µm x 15 cm, 3 µm particle size, 120 Å pore size) at 300 nL/min using an increasing gradient of Buffer B (80% ACN, 0.1% FA): 0-1 min 2% B, 1-2 min 2-12% B, 2-30 min 12-35% B, 30 (CE 25). CE values were optimized based on injection of solubilized drug/metabolite.…”

Section: Identification Of Co-purified Drugs/metabolitesmentioning

confidence: 99%

“…These TCRs were identified using traditional Sanger sequencing and were confounded by in vitro T cell co-culture with antigen presenting cells (APCs), which has been suggested to bias the outgrown T cell repertoire (29). Another study examining the ex vivo TCRb repertoire in peripheral blood mononuclear cells (PBMCs) isolated from CBZ-induced SJS (n=5) or TEN (n=1) patients showed that diversity was directly linked to disease severity, with the TEN patient having a significantly decreased TCRb repertoire compared to SJS patients (30).…”

Section: Introductionmentioning

confidence: 99%

Carbamazepine Induces Focused T Cell Responses in Resolved Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis Cases But Does Not Perturb the Immunopeptidome for T Cell Recognition

et al. 2021

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Antiseizure medications (ASMs) are frequently implicated in T cell-mediated drug hypersensitivity reactions and cause skin tropic pathologies that range in severity from mild rashes to life-threatening systemic syndromes. During the acute stages of the more severe manifestations of these reactions, drug responsive proinflammatory CD8+ T cells display classical features of Th1 cytokine production (e.g. IFNγ) and cytolysis (e.g. granzyme B, perforin). These T cells may be found locally at the site of pathology (e.g. blister cells/fluid), as well as systemically (e.g. blood, organs). What is less understood are the long-lived immunological effects of the memory T cell pool following T cell-mediated drug hypersensitivity reactions. In this study, we examine the ASM carbamazepine (CBZ) and the CBZ-reactive memory T cell pool in patients who have a history of either Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) from 3-to-20 years following their initial adverse reaction. We show that in vitro drug restimulation of CBZ-reactive CD8+ T cells results in a proinflammatory profile and produces a mainly focused, yet private, T cell receptor (TCR) usage amongst human leukocyte antigen (HLA)-B*15:02-positive SJS or TEN patients. Additionally, we show that expression of these CBZ-reactive TCRs in a reporter cell line, lacking endogenous αβTCR, recapitulates the features of TCR activation reported for ASM-treated T cell lines/clones, providing a useful tool for further functional validations. Finally, we conduct a comprehensive evaluation of the HLA-B*15:02 immunopeptidome following ASM (or a metabolite) treatment of a HLA-B*15:02-positive B-lymphoblastoid cell line (C1R.B*15:02) and minor perturbation of the peptide repertoire. Collectively, this study shows that the CBZ-reactive T cells characterized require both the drug and HLA-B*15:02 for activation and that reactivation of memory T cells from blood results in a focused private TCR profile in patients with resolved disease.

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“…Likewise, Xiong et al found SJS/TEN patients had less TCR repertoire diversity and predominant shared usage of TRBV/ TRBJ clonotypes. The TCR repertoire diversity of these patients showed certain association with the clinical severity of disease (Xiong et al, 2019). Moreover, it was found the TCR CDR3 shared a similar motif in metronidazole-induced SCARs patients (Yang et al, 2020).…”

Section: Receptors and Sjs/tenmentioning

confidence: 88%

Current Pharmacogenetic Perspective on Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis

Cheng

2021

Front. Pharmacol.

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Adverse drug reactions are a public health issue that draws widespread attention, especially for Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) which have high mortality and lack of efficacious treatment. Though T-cell-mediated HLA-interacted immune response has been extensively studied, our understanding of the mechanism is far from satisfactory. This review summarizes infection (virus, bacterial, and mycoplasma infection), an environmental risk factor, as a trigger for SJS/TEN. The mutations or polymorphisms of drug metabolic enzymes, transporters, receptors, the immune system genes, and T-cell-mediated apoptosis signaling pathways that contribute to SJS/TEN are discussed and summarized. Epigenetics, metabolites, and mobilization of regulatory T cells and tolerogenic myeloid precursors are emerged directions to study SJS/TEN. Ex vivo lymphocyte transformation test has been exploited to aid in identifying the causative drugs. Critical questions on the pathogenesis of SJS/TEN underlying gene polymorphisms and T cell cytotoxicity remain: why some of the patients carrying the risky genes tolerate the drug and do not develop SJS/TEN? What makes the skin and mucous membrane so special to be targeted? Do they relate to skin/mucous expression of transporters? What is the common machinery underlying different HLA-B alleles associated with SJS/TEN and common metabolites?

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Comprehensive assessment of T cell receptor β repertoire in Stevens–Johnson syndrome/toxic epidermal necrolysis patients using high-throughput sequencing

Cited by 13 publications

References 36 publications

Dynamic analysis of peripheral blood TCR β-chain CDR3 repertoire in occupational medicamentosa-like dermatitis due to trichloroethylene

Dynamic analysis of peripheral blood TCR β-chain CDR3 repertoire in occupational medicamentosa-like dermatitis due to trichloroethylene

Carbamazepine Induces Focused T Cell Responses in Resolved Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis Cases But Does Not Perturb the Immunopeptidome for T Cell Recognition

Current Pharmacogenetic Perspective on Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis

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