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

Author

Listed:
  • Andrew Gibson

    (Murdoch University)

  • Ramesh Ram

    (Murdoch University)

  • Rama Gangula

    (Vanderbilt University Medical Centre)

  • Yueran Li

    (Murdoch University)

  • Eric Mukherjee

    (Vanderbilt University Medical Centre)

  • Amy M. Palubinsky

    (Vanderbilt University Medical Centre)

  • Chelsea N. Campbell

    (Vanderbilt University Medical Centre)

  • Michael Thorne

    (Murdoch University)

  • Katherine C. Konvinse

    (Vanderbilt University Medical Centre)

  • Phuti Choshi

    (Groote Schuur Hospital)

  • Pooja Deshpande

    (Murdoch University)

  • Sarah Pedretti

    (University of Cape Town Lung Institute)

  • Mark W. Fear

    (University of Western Australia)

  • Fiona M. Wood

    (University of Western Australia
    Fiona Stanley Hospital)

  • Richard T. O’Neil

    (Medical University of South Carolina)

  • Celestine N. Wanjalla

    (Vanderbilt University Medical Centre)

  • Spyros A. Kalams

    (Vanderbilt University Medical Centre)

  • Silvana Gaudieri

    (Murdoch University
    Vanderbilt University Medical Centre
    The University of Western Australia)

  • Rannakoe J. Lehloenya

    (University of Cape Town)

  • Samuel S. Bailin

    (Vanderbilt University Medical Centre)

  • Abha Chopra

    (Murdoch University
    Vanderbilt University Medical Centre)

  • Jason A. Trubiano

    (University of Melbourne
    Austin Health)

  • Jonny G. Peter

    (Groote Schuur Hospital
    University of Cape Town Lung Institute)

  • Simon A. Mallal

    (Murdoch University
    Vanderbilt University Medical Centre)

  • Elizabeth J. Phillips

    (Murdoch University
    Vanderbilt University Medical Centre)

Abstract

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.

Suggested Citation

  • 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 Pedre, 2024. "Multiomic single-cell sequencing defines tissue-specific responses in Stevens-Johnson syndrome and toxic epidermal necrolysis," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-52990-3
    DOI: 10.1038/s41467-024-52990-3
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    References listed on IDEAS

    as
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