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

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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HLA Associations and Clinical Implications in T-Cell Mediated Drug Hypersensitivity Reactions: An Updated Review

Journal of Immunology Research ◽

10.1155/2014/565320 ◽

2014 ◽

Vol 2014 ◽

pp. 1-8 ◽

Cited By ~ 37

Author(s):

Chi-Yuan Cheng ◽

Shih-Chi Su ◽

Chi-Hua Chen ◽

Wei-Li Chen ◽

Shin-Tarng Deng ◽

...

Keyword(s):

T Cell ◽

Drug Hypersensitivity ◽

Human Leukocyte ◽

Hypersensitivity Syndrome ◽

Stevens Johnson Syndrome ◽

Hypersensitivity Reactions ◽

Genetic Associations ◽

Drug Induced ◽

Hla Alleles ◽

Drug Hypersensitivity Reactions

T-cell mediated drug hypersensitivity reactions may range from mild rash to severe fatal reactions. Among them, drug reaction with eosinophilia and systemic symptoms (DRESS) or drug-induced hypersensitivity syndrome (DIHS), Stevens-Johnson syndrome/ toxic epidermal necrolysis (SJS/TEN), are some of the most life-threatening severe cutaneous adverse reactions (SCARs). Recent advances in pharmacogenetic studies show strong genetic associations between human leukocyte antigen (HLA) alleles and susceptibility to drug hypersensitivity. This review summarizes the literature on recent progresses in pharmacogenetic studies and clinical application of pharmacogenetic screening based on associations between SCARs and specific HLA alleles to avoid serious conditions associated with drug hypersensitivity.

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Skin Resident Memory T Cells May Play Critical Role in Delayed-Type Drug Hypersensitivity Reactions

Frontiers in Immunology ◽

10.3389/fimmu.2021.654190 ◽

2021 ◽

Vol 12 ◽

Author(s):

Elisa Maria Schunkert ◽

Pranali Nitin Shah ◽

Sherrie Jill Divito

Keyword(s):

T Cells ◽

T Cell ◽

Memory T Cells ◽

Clinical Care ◽

Drug Hypersensitivity ◽

Critical Role ◽

Hypersensitivity Reactions ◽

Disease Pathogenesis ◽

Drug Hypersensitivity Reactions ◽

Resident Memory T Cells

Delayed-type drug hypersensitivity reactions (dtDHR) are immune-mediated reactions with skin and visceral manifestations ranging from mild to severe. Clinical care is negatively impacted by a limited understanding of disease pathogenesis. Though T cells are believed to orchestrate disease, the type of T cell and the location and mechanism of T cell activation remain unknown. Resident memory T cells (TRM) are a unique T cell population potentially well situated to act as key mediators in disease pathogenesis, but significant obstacles to defining, identifying, and testing TRM in dtDHR preclude definitive conclusions at this time. Deeper mechanistic interrogation to address these unanswered questions is necessary, as involvement of TRM in disease has significant implications for prediction, diagnosis, and treatment of disease.

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Clinical Phenotypes of Severe Cutaneous Drug Hypersensitivity Reactions

Current Pharmaceutical Design ◽

10.2174/1381612825666191107162921 ◽

2019 ◽

Vol 25 (36) ◽

pp. 3840-3854 ◽

Cited By ~ 2

Author(s):

Hakan Guvenir ◽

Tugba Arikoglu ◽

Emine Vezir ◽

Emine Dibek Misirlioglu

Keyword(s):

Adverse Drug Reactions ◽

Drug Hypersensitivity ◽

Stevens Johnson Syndrome ◽

Facial Oedema ◽

Hypersensitivity Reactions ◽

Drug Reactions ◽

Cutaneous Manifestations ◽

Clinical Phenotypes ◽

Drug Eruptions ◽

Drug Hypersensitivity Reactions

Drug hypersensitivity reactions are clinically heterogenous ranging from mild to severe. Most drug hypersensitivity reactions are accompanied by cutaneous manifestations. Fever, mucous membrane involvement, large blisters, facial oedema, pustulosis and visceral involvement are clinical features that lead to suspicion of severe adverse drug reactions. Severe cutaneous adverse drug reactions (SCARs) include Stevens-Johnson syndrome, toxic epidermal necrolysis, drug rash eosinophilia and systemic symptoms, acute generalized exanthematous pustulosis. Serum sickness like reactions, drug induced vasculitis and generalized bullous fixed drug eruptions are less severe clinical entities. SCARs are uncommon but associated with significant morbidity and mortality. Physician should be aware of specific red flags and danger signs to immediately identify these reactions. Immediate drug withdrawal is mandatory. Early diagnosis and appropriate treatment significantly affect the prognosis of the disease. The purpose of our review is to discuss clinical phenotypes of severe cutaneous drug hypersensitivity reactions.

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Stevens - Johnson Syndrome and Toxic Epidermal Necrolysis; Extensive Review of Reports of Drug-Induced Etiologies, and Possible Therapeutic Modalities

Open Access Macedonian Journal of Medical Sciences ◽

10.3889/oamjms.2018.148 ◽

2018 ◽

Vol 6 (4) ◽

pp. 730-738 ◽

Cited By ~ 8

Author(s):

Adegbenro Omotuyi John Fakoya ◽

Princess Omenyi ◽

Precious Anthony ◽

Favour Anthony ◽

Precious Etti ◽

...

Keyword(s):

Adverse Drug Reaction ◽

Toxic Epidermal Necrolysis ◽

Stevens Johnson Syndrome ◽

Hypersensitivity Reactions ◽

Extensive Review ◽

Drug Induced ◽

Therapeutic Modalities ◽

Johnson Syndrome ◽

Mucous Membranes ◽

Degrees Of Severity

Stevens - Johnson Syndrome and Toxic Epidermal Necrolysis are adverse hypersensitivity reactions that affect the skin and mucous membranes. They are characterised by erythematous macules and hemorrhagic erosions of the mucous membranes. Epidermal detachments of varying degrees of severity also occur in these conditions. Various aetiologies are associated with these conditions, with adverse drug reaction being the most common. Though the worldwide incidence of these conditions is recorded as low, diverse types of medication are being observed to lead to these conditions. This review compiles information on the details of Stevens-Johnson syndrome and Toxic Epidermal Necrolysis, the pathophysiology, therapeutic management, and largely considers the drug-induced etiologies associated with these conditions.

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Meropenem-induced Stevens-Johnson syndrome/toxic epidermal necrolysis in a patient with known type IV penicillin hypersensitivity

BMJ Case Reports ◽

10.1136/bcr-2019-230144 ◽

2019 ◽

Vol 12 (8) ◽

pp. e230144 ◽

Cited By ~ 3

Author(s):

Muhammad Sameed ◽

Christine Nwaiser ◽

Prashant Bhandari ◽

Sarah A Schmalzle

Keyword(s):

Toxic Epidermal Necrolysis ◽

Cross Reactivity ◽

Delayed Hypersensitivity ◽

Stevens Johnson Syndrome ◽

Hypersensitivity Reactions ◽

Beta Lactam ◽

Type Iv ◽

Johnson Syndrome ◽

Life Threatening ◽

History Of

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are considered variants of a disease continuum that results in a life-threatening exfoliative mucocutaneous disease. These are categorised as type IV cell-mediated delayed hypersensitivity reactions, and antibiotics are often implicated as a cause. Penicillins and other beta-lactam antibiotics are known to cause both immediate and delayed hypersensitivity reactions. While immediate IgE-mediated cross-reactivity between penicillins and carbapenems is well studied, less information on the risk of type IV delayed cell-mediated cross-reactivity between the two is available. We present a case of meropenem-induced SJS in a patient with documented history of SJS from amoxicillin. There are few cases of cross-reactivity with carbapenems reported in the literature, but based on the potential for life-threatening reaction, it is likely prudent to avoid the use of any beta-lactams in a patient with a history of SJS, TEN or any other severe cutaneous adverse reactions to another beta-lactam antibiotic.

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986 Neutrophil extracellular traps induced by causative drug-specific CD8+ T cells initiate and exacerbate Stevens-Johnson syndrome and toxic epidermal necrolysis

Journal of Investigative Dermatology ◽

10.1016/j.jid.2019.03.1062 ◽

2019 ◽

Vol 139 (5) ◽

pp. S171

Author(s):

M. Kinoshita ◽

Y. Ogawa ◽

N. Hama ◽

I. Ujiie ◽

S. Shimada ◽

...

Keyword(s):

T Cells ◽

Toxic Epidermal Necrolysis ◽

Cd8 T Cells ◽

Neutrophil Extracellular Traps ◽

Stevens Johnson Syndrome ◽

Extracellular Traps ◽

Causative Drug ◽

Johnson Syndrome

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Warfarin-induced toxic epidermal necrolysis after mitral valve replacement

Asian Cardiovascular and Thoracic Annals ◽

10.1177/0218492320951024 ◽

2020 ◽

Vol 28 (9) ◽

pp. 601-603

Author(s):

Taiyo Kuroda ◽

Yukifusa Yokoyama ◽

Masao Yamada ◽

Satoshi Yuhara ◽

Hiroki Hasegawa ◽

...

Keyword(s):

Mitral Valve ◽

Toxic Epidermal Necrolysis ◽

Drug Hypersensitivity ◽

Lymphocyte Transformation ◽

Lymphocyte Transformation Test ◽

Stevens Johnson Syndrome ◽

Valve Prosthesis ◽

Mitral Valve Prosthesis ◽

Johnson Syndrome ◽

Mucous Membranes

Stevens-Johnson syndrome and toxic epidermal necrolysis are rare diseases that cause acute destruction of the epithelium of the skin and mucous membranes, almost always attributable to drugs. However, warfarin-induced Stevens-Johnson syndrome and toxic epidermal necrolysis is extremely rare. We report the case of 71-year-old woman who died due to destructive erosion all over her skin and mucous membranes. She had received a mitral valve prosthesis, and warfarin was prescribed for antithrombotic therapy. A lymphocyte transformation test for drug hypersensitivity and the clinical history confirmed this phenomenon as warfarin-induced toxic epidermal necrolysis.

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