PMID- 38405793 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20240430 DP - 2024 Feb 18 TI - Multiomic single-cell sequencing defines tissue-specific responses in Stevens-Johnson Syndrome and Toxic epidermal necrolysis. LID - 2023.11.26.568771 [pii] LID - 10.1101/2023.11.26.568771 [doi] AB - 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. To obtain an unbiased assessment of SJS/TEN cellular immunopathogenesis, we performed single-cell (sc) transcriptome, surface proteome, and TCR sequencing on unaffected skin, affected skin, and blister fluid from 17 SJS/TEN patients. From 119,784 total cells, we identified 16 scRNA-defined subsets, confirmed by subset-defining surface protein expression. Keratinocytes upregulated HLA and IFN-response genes in the affected skin. Cytotoxic CD8+ T-cell subpopulations of expanded and unexpanded TCRalphabeta clonotypes were shared in affected skin and blister fluid but absent or unexpanded in SJS/TEN unaffected skin. SJS/TEN blister fluid is a rich reservoir of oligoclonal CD8+ T-cells with an effector phenotype driving SJS/TEN pathogenesis. This multiomic database will act as the basis to define antigen-reactivity, HLA restriction, and signatures of drug-antigen-reactive T-cell clonotypes at a tissue level. FAU - Gibson, Andrew AU - Gibson A AD - Institute for Immunology and Infectious Diseases, Murdoch University, Western Australia, Australia. FAU - Ram, Ramesh AU - Ram R AD - Institute for Immunology and Infectious Diseases, Murdoch University, Western Australia, Australia. FAU - Gangula, Rama AU - Gangula R AD - Department of Medicine, Vanderbilt University Medical Centre, Nashville, Tennessee, USA. FAU - Li, Yueran AU - Li Y AD - Institute for Immunology and Infectious Diseases, Murdoch University, Western Australia, Australia. FAU - Mukherjee, Eric AU - Mukherjee E AD - Department of Medicine, Vanderbilt University Medical Centre, Nashville, Tennessee, USA. FAU - Palubinsky, Amy M AU - Palubinsky AM AD - Department of Medicine, Vanderbilt University Medical Centre, Nashville, Tennessee, USA. FAU - Campbell, Chelsea N AU - Campbell CN AD - Department of Medicine, Vanderbilt University Medical Centre, Nashville, Tennessee, USA. FAU - Thorne, Michael AU - Thorne M AD - Institute for Immunology and Infectious Diseases, Murdoch University, Western Australia, Australia. FAU - Konvinse, Katherine C AU - Konvinse KC AD - Department of Medicine, Vanderbilt University Medical Centre, Nashville, Tennessee, USA. FAU - Choshi, Phuti AU - Choshi P AD - Allergy and Immunology Unit, University of Cape Town Lung Institute, Cape Town, South Africa. FAU - Deshpande, Pooja AU - Deshpande P AD - Institute for Immunology and Infectious Diseases, Murdoch University, Western Australia, Australia. FAU - Pedretti, Sarah AU - Pedretti S AD - Allergy and Immunology Unit, University of Cape Town Lung Institute, Cape Town, South Africa. FAU - O'Neil, Richard T AU - O'Neil RT AD - Department of Veterans Affairs, Ralph H Johnson VA Medical Center and Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina, USA. FAU - Wanjalla, Celestine N AU - Wanjalla CN AD - Department of Medicine, Vanderbilt University Medical Centre, Nashville, Tennessee, USA. FAU - Kalams, Spyros A AU - Kalams SA AD - Department of Medicine, Vanderbilt University Medical Centre, Nashville, Tennessee, USA. FAU - Gaudieri, Silvana AU - Gaudieri S AD - Institute for Immunology and Infectious Diseases, Murdoch University, Western Australia, Australia. AD - Department of Medicine, Vanderbilt University Medical Centre, Nashville, Tennessee, USA. AD - School of Human Sciences, The University of Western Australia, Western Australia, Australia. FAU - Lehloenya, Rannakoe J AU - Lehloenya RJ AD - Allergy and Immunology Unit, University of Cape Town Lung Institute, Cape Town, South Africa. AD - Division of Dermatology, Groote Schuur Hospital, University of Cape Town, Cape Town, South Africa. FAU - Bailin, Samuel S AU - Bailin SS AD - Department of Medicine, Vanderbilt University Medical Centre, Nashville, Tennessee, USA. FAU - Chopra, Abha AU - Chopra A AD - Institute for Immunology and Infectious Diseases, Murdoch University, Western Australia, Australia. AD - Department of Medicine, Vanderbilt University Medical Centre, Nashville, Tennessee, USA. CN - Jason A Trubiano on behalf of the AUS-SCAR study group CN - Jonny G Peter on behalf of the AFRI-SCAR and IMARI-Africa study group FAU - Mallal, Simon A AU - Mallal SA AD - Institute for Immunology and Infectious Diseases, Murdoch University, Western Australia, Australia. AD - Department of Medicine, Vanderbilt University Medical Centre, Nashville, Tennessee, USA. FAU - Phillips, Elizabeth J AU - Phillips EJ AD - Institute for Immunology and Infectious Diseases, Murdoch University, Western Australia, Australia. AD - Department of Medicine, Vanderbilt University Medical Centre, Nashville, Tennessee, USA. LA - eng GR - R01 HG010863/HG/NHGRI NIH HHS/United States GR - D43 TW010559/TW/FIC NIH HHS/United States GR - R01 AI152183/AI/NIAID NIH HHS/United States GR - U01 AI154659/AI/NIAID NIH HHS/United States GR - P50 GM115305/GM/NIGMS NIH HHS/United States GR - P30 AI110527/AI/NIAID NIH HHS/United States GR - R21 AI139021/AI/NIAID NIH HHS/United States PT - Preprint DEP - 20240218 PL - United States TA - bioRxiv JT - bioRxiv : the preprint server for biology JID - 101680187 PMC - PMC10888802 EDAT- 2024/02/26 06:45 MHDA- 2024/02/26 06:46 PMCR- 2024/02/23 CRDT- 2024/02/26 04:50 PHST- 2024/02/26 06:45 [pubmed] PHST- 2024/02/26 06:46 [medline] PHST- 2024/02/26 04:50 [entrez] PHST- 2024/02/23 00:00 [pmc-release] AID - 2023.11.26.568771 [pii] AID - 10.1101/2023.11.26.568771 [doi] PST - epublish SO - bioRxiv [Preprint]. 2024 Feb 18:2023.11.26.568771. doi: 10.1101/2023.11.26.568771.