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

Stevens-Johnson syndrome and toxic epidermal necrolysis is a very rare but lifethreatening form of cutaneous drug eruption. In recent years, several countries in Asia had succeded in preventing carbamazepine induced SJS/TEN by screening for HLA-B*15:02 before prescribing carbamazepine. This study aimed to acquire data regarding causative drugs and HLA-B allele polymorphism in SJS/TEN patient in Jakarta. We acquired data from 5 referral hospitals from March 2015 to March 2017. Subject fulfilling the inclusion and exclusion criteria was interviewed and blood sample was taken for DNA extraction. The DNA was examined with PCR SSOP and Luminex technology for high resolution HLA-B typing. We studied 22 subjects. The median age was 45,4 years old (14-74). The most common causative drug in this study is carbamazepine. HLA-B*15:02 and HLAB* 18:01 were the most common allele in all subjects. HLA-B*15:02 was found in five (72%) out of seven subjects whose condition was caused by carbamazepine. The most common causative drug of SJS/TEN in five hospitals in Jakarta is carbamazepine, with five (72%) out seven subjects had HLA-B*15:02 allele.

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Neutrophils initiate and exacerbate Stevens-Johnson syndrome and toxic epidermal necrolysis

Science Translational Medicine ◽

10.1126/scitranslmed.aax2398 ◽

2021 ◽

Vol 13 (600) ◽

pp. eaax2398

Author(s):

Manao Kinoshita ◽

Youichi Ogawa ◽

Natsumi Hama ◽

Inkin Ujiie ◽

Akito Hasegawa ◽

...

Keyword(s):

T Cells ◽

Immune Responses ◽

Toxic Epidermal Necrolysis ◽

Adverse Drug Reactions ◽

Cytotoxic T Cells ◽

Formyl Peptide Receptor ◽

Stevens Johnson Syndrome ◽

Lipocalin 2 ◽

Drug Reactions ◽

Johnson Syndrome

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening mucocutaneous adverse drug reactions characterized by massive epidermal detachment. Cytotoxic T cells and associated effector molecules are known to drive SJS/TEN pathophysiology, but the contribution of innate immune responses is not well understood. We describe a mechanism by which neutrophils triggered inflammation during early phases of SJS/TEN. Skin-infiltrating CD8+ T cells produced lipocalin-2 in a drug-specific manner, which triggered the formation of neutrophil extracellular traps (NETs) in early lesional skin. Neutrophils undergoing NETosis released LL-37, an antimicrobial peptide, which induced formyl peptide receptor 1 (FPR1) expression by keratinocytes. FPR1 expression caused keratinocytes to be vulnerable to necroptosis that caused further release of LL-37 by necroptotic keratinocytes and induced FPR1 expression on surrounding keratinocytes, which likely amplified the necroptotic response. The NETs-necroptosis axis was not observed in less severe cutaneous adverse drug reactions, autoimmune diseases, or neutrophil-associated disorders, suggesting that this was a process specific to SJS/TEN. Initiation and progression of SJS/TEN keratinocyte necroptosis appear to involve a cascade of events mediated by innate and adaptive immune responses, and understanding these responses may contribute to the identification of diagnostic markers or therapeutic targets for these adverse drug reactions.

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Galectin-7 as a potential biomarker of Stevens-Johnson syndrome/toxic epidermal necrolysis: identification by targeted proteomics using causative drug-exposed peripheral blood cells

The Journal of Allergy and Clinical Immunology In Practice ◽

10.1016/j.jaip.2019.05.002 ◽

2019 ◽

Vol 7 (8) ◽

pp. 2894-2897.e7 ◽

Cited By ~ 1

Author(s):

Natsumi Hama ◽

Keiko Nishimura ◽

Akito Hasegawa ◽

Akihiko Yuki ◽

Hideaki Kume ◽

...

Keyword(s):

Toxic Epidermal Necrolysis ◽

Peripheral Blood ◽

Blood Cells ◽

Stevens Johnson Syndrome ◽

Peripheral Blood Cells ◽

Targeted Proteomics ◽

Causative Drug ◽

Johnson Syndrome ◽

Potential Biomarker

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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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