T-cell receptor and carbamazepine-induced Stevens–Johnson syndrome and toxic epidermal necrolysis: understanding a hypersensitivity reaction

Erythema multiforme (EM) is an acute hypersensitivity reaction characterized by distinctive skin lesions and mucous membrane involvement that has a spectrum of severity. It occurs in two forms: the more common "minor" type and the more severe "major" type, also called Stevens-Johnson syndrome (SJS). Sometimes EM includes toxic epidermal necrolysis (TEN) or Lyell disease. EM minor first was described completely by von Hebra in 1866; Stevens and Johnson described the major variant in 1922. EM occurs more often in males, and 20% to 50% of cases occur in the pediatric age group, although rarely in those younger than age 3 years.

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?? T-cell receptor-positive cells of human skin. II. Appearance in delayed-type hypersensitivity reaction

Archives of Dermatological Research ◽

10.1007/bf00372140 ◽

1993 ◽

Vol 285 (7) ◽

pp. 436-440 ◽

Cited By ~ 15

Author(s):

M. Fujita ◽

Y. Miyachi ◽

K. Nakata ◽

S. Imamura

Keyword(s):

T Cell ◽

Hypersensitivity Reaction ◽

Human Skin ◽

T Cell Receptor ◽

Cell Receptor ◽

Delayed Type Hypersensitivity

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

Frontiers in Pharmacology ◽

10.3389/fphar.2021.588063 ◽

2021 ◽

Vol 12 ◽

Author(s):

Lin Cheng

Keyword(s):

T Cell ◽

Toxic Epidermal Necrolysis ◽

Ex Vivo ◽

Lymphocyte Transformation ◽

Lymphocyte Transformation Test ◽

Stevens Johnson Syndrome ◽

Public Health Issue ◽

Johnson Syndrome ◽

Efficacious Treatment ◽

The Common

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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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

Frontiers in Immunology ◽

10.3389/fimmu.2021.653710 ◽

2021 ◽

Vol 12 ◽

Author(s):

Nicole A. Mifsud ◽

Patricia T. Illing ◽

Jeffrey W. Lai ◽

Heidi Fettke ◽

Luca Hensen ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Toxic Epidermal Necrolysis ◽

Drug Hypersensitivity ◽

Stevens Johnson Syndrome ◽

Hypersensitivity Reactions ◽

Memory T Cell ◽

Cell Pool ◽

Johnson Syndrome ◽

Drug Hypersensitivity Reactions

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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