Multiomic single-cell sequencing defines tissue-specific responses in Stevens-Johnson syndrome and toxic epidermal necrolysis

Andrew Gibson; Ramesh Ram; Rama Gangula; Yueran Li; Eric Mukherjee; Amy M Palubinsky; Chelsea N Campbell; Michael Thorne; Katherine C Konvinse; Phuti Choshi; Pooja Deshpande; Sarah Pedretti; Mark W Fear; Fiona M Wood; Richard T O’Neil; Celestine N Wanjalla; Spyros A Kalams; Silvana Gaudieri; Rannakoe J Lehloenya; Samuel S Bailin; Abha Chopra; Jason Trubiano; Jonny G Peter; Simon A Mallal; Elizabeth J Phillips

doi:10.1038/s41467-024-52990-3

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Multiomic single-cell sequencing defines tissue-specific responses in Stevens-Johnson syndrome and toxic epidermal necrolysis

Journal article

Open access

Peer reviewed

Multiomic single-cell sequencing defines tissue-specific responses in Stevens-Johnson syndrome and toxic epidermal necrolysis

Andrew Gibson, Ramesh Ram, Rama Gangula, Yueran Li, Eric Mukherjee, Amy M Palubinsky, Chelsea N Campbell, Michael Thorne, Katherine C Konvinse, Phuti Choshi, …

Nature communications, Vol.15(1), 8722

2024

DOI: https://doi.org/10.1038/s41467-024-52990-3

PMCID: PMC11461852

PMID: 39379371

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Abstract

Antigen presentation

Antigens

Blistering

CD27 antigen

CD8 antigen

Cell proliferation

Cell surface

Cytotoxicity

Granzyme B

Histocompatibility antigen HLA

Immune response

Immune system

Immunopathogenesis

Keratinocytes

Lymphocytes

Lymphocytes T

Macrophages

Perforin

Populations

Proteomes

Skin

Stevens-Johnson syndrome

T cell receptors

Therapeutic targets

Toxic epidermal necrolysis

Transcriptomes

Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) is a rare but life-threatening cutaneous drug reaction mediated by human leukocyte antigen (HLA) class I-restricted CD8+ T cells. For unbiased assessment of cellular immunopathogenesis, here we perform single-cell (sc) transcriptome, surface proteome, and T cell receptor (TCR) sequencing on unaffected skin, affected skin, and blister fluid from 15 SJS/TEN patients. From 109,888 cells, we identify 15 scRNA-defined subsets. Keratinocytes express markers indicating HLA class I-restricted antigen presentation and appear to trigger the proliferation of and killing by cytotoxic CD8+ tissue-resident T cells that express granulysin, granzyme B, perforin, LAG3, CD27, and LINC01871, and signal through the PKM, MIF, TGFβ, and JAK-STAT pathways. In affected tissue, cytotoxic CD8+ T cells express private expanded and unexpanded TCRαβ that are absent or unexpanded in unaffected skin, and mixed populations of macrophages and fibroblasts express pro-inflammatory markers or those favoring repair. This data identifies putative cytotoxic TCRs and therapeutic targets.

Details

Title: Multiomic single-cell sequencing defines tissue-specific responses in Stevens-Johnson syndrome and toxic epidermal necrolysis
Authors/Creators: Andrew Gibson
Ramesh Ram
Rama Gangula
Yueran Li
Eric Mukherjee
Amy M Palubinsky
Chelsea N Campbell
Michael Thorne
Katherine C Konvinse
Phuti Choshi
Pooja Deshpande
Sarah Pedretti
Mark W Fear
Fiona M Wood
Richard T O’Neil
Celestine N Wanjalla
Spyros A Kalams
Silvana Gaudieri
Rannakoe J Lehloenya
Samuel S Bailin
Abha Chopra
Jason Trubiano
Jonny G Peter
Simon A Mallal
Elizabeth J Phillips
Publication Details: Nature communications, Vol.15(1), 8722
Publisher: Springer Nature
Identifiers: 991005707037307891
Murdoch Affiliation: Institute for Immunology and Infectious Diseases; Centre for Molecular Medicine and Innovative Therapeutics
Language: English
Resource Type: Journal article

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