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

ABSTRACT: 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.

SUBMITTER: Kinoshita M

PROVIDER: S-EPMC9392155 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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

Kinoshita Manao M Ogawa Youichi Y Hama Natsumi N Ujiie Inkin I Hasegawa Akito A Nakajima Saeko S Nomura Takashi T Adachi Jun J Sato Takuya T Koizumi Schuichi S Shimada Shinji S Fujita Yasuyuki Y Takahashi Hayato H Mizukawa Yoshiko Y Tomonaga Takeshi T Nagao Keisuke K Abe Riichiro R Kawamura Tatsuyoshi T

Science translational medicine 20210601 600

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<sup>+</sup> T cells produced lipocali ...[more]

PMID: 34193610

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Project description:BackgroundStevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are two of the most severe dermatologic emergencies. Although pregnant women comprise a subset of individuals at risk for SJS and TEN development, little is known with regard to outcomes and treatment.ObjectiveThis study aimed to conduct a systematic review to characterize the risk factors, outcomes, and treatment of SJS and TEN in pregnant patients and newborns.MethodsA primary literature search was conducted using PubMed in September 2019, using the following search terms entered in separate pairs: pregnant or pregnancy and stevens-johnson or SJS or toxic epidermal necrolysis. Reviews, studies in a language other than English, and articles not including pregnant patients were excluded.ResultsTwenty-six articles were included for review, including a total of 177 patients. The average maternal age for a reaction was 29.9 years, gestational age was 24.9 weeks, and time to reaction after drug initiation was 27.5 days. Approximately 85% of pregnant women in this review were infected with HIV. The most common causative medications were antiretroviral therapy (90% of all cases), antibiotics (3%), and gestational drugs (2%). Of the 94 cases in which outcome data were available, the survival rates of pregnant women and newborns after delivery were 98% and 96%, respectively. Withdrawal of the offending agent and supportive care was often sufficient for treatment, but antibiotics, steroids, and intravenous immunoglobulin were implemented in some cases. Complications included preterm labor, vaginal stenosis, and vaginal adhesions.ConclusionGiven the predominance of studies focusing on the subset of pregnant patients who are infected with HIV, SJS and TEN is most commonly reported in young patients after antiretroviral therapy, primarily nevirapine. Overall mortality is lower than that of the general population, but similar to the expected mortality rates of younger adults. Early recognition and withdrawal of the offending agent is essential to mitigate the distinct consequences of these conditions in the pregnant population.

Dataset Information

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

Publications

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

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