Sumanth Chennareddy, Katharina Rindler, Shannon Meledathu, Malini P Naidu, Natalia Alkon, John R Ruggiero, Lisa Szmolyan, Wolfgang Weninger, Wolfgang M Bauer, Johannes Griss, Constanze Jonak, Patrick M Brunner
{"title":"Single-cell RNA sequencing of chronic idiopathic erythroderma defines disease-specific markers.","authors":"Sumanth Chennareddy, Katharina Rindler, Shannon Meledathu, Malini P Naidu, Natalia Alkon, John R Ruggiero, Lisa Szmolyan, Wolfgang Weninger, Wolfgang M Bauer, Johannes Griss, Constanze Jonak, Patrick M Brunner","doi":"10.1016/j.jaci.2024.11.037","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Chronic erythroderma is a potentially life-threatening condition that can be caused by a variety of diseases, but approximately 30% of cases remain idiopathic, often with insufficient treatment options.</p><p><strong>Objective: </strong>To establish a molecular disease map of chronic idiopathic erythroderma.</p><p><strong>Methods: </strong>We performed single-cell RNA sequencing combined with T-cell receptor sequencing of blood and skin from 5 chronic idiopathic erythroderma (CIE) patients and compared results with 8 cases of erythrodermic cutaneous T-cell lymphoma (eCTCL), 15 moderate-to-severe atopic dermatitis (AD), 10 psoriasis and 20 healthy control (HC) individuals.</p><p><strong>Results: </strong>In erythrodermic CTCL, we found strong expansion of CD4+ malignant clones with a CCR7+SELL+ central memory phenotype. By contrast, CIE exhibited a pattern of low-level, but consistent expansion of CD8A+KLRK1+ T-cell clones, both in blood and skin. KLRK1 was also expressed by CCR10+FUT7+ skin-homing CIE blood T-cells that had increased proliferation rates and were absent in all other conditions. While CIE and CTCL patients lacked the strong type 2 or type 17 immune skewing typically found in AD or psoriasis, respectively, they were characterized by upregulation of MHC II genes (HLA-DRB1, HLA-DRA, CD74) in keratinocytes and fibroblasts, most likely in an IFNG-dependent fashion. However, we found strongest upregulation of type 1 immune mediators in CIE samples, both in the expanded CD8A+ clones, as well as in the tissue microenvironment.</p><p><strong>Conclusion: </strong>Despite the notion that CIE might be a mere bundle of various yet uncharacterized disease processes, we found specific pathogenic signatures in these patients, that were different from other forms of erythroderma. These data might help to improve our pathogenic understanding of the blood and skin compartments of CIE, aiding in discovery of future treatment targets.</p>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":" ","pages":""},"PeriodicalIF":11.4000,"publicationDate":"2024-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Allergy and Clinical Immunology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.jaci.2024.11.037","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ALLERGY","Score":null,"Total":0}
引用次数: 0
Abstract
Background: Chronic erythroderma is a potentially life-threatening condition that can be caused by a variety of diseases, but approximately 30% of cases remain idiopathic, often with insufficient treatment options.
Objective: To establish a molecular disease map of chronic idiopathic erythroderma.
Methods: We performed single-cell RNA sequencing combined with T-cell receptor sequencing of blood and skin from 5 chronic idiopathic erythroderma (CIE) patients and compared results with 8 cases of erythrodermic cutaneous T-cell lymphoma (eCTCL), 15 moderate-to-severe atopic dermatitis (AD), 10 psoriasis and 20 healthy control (HC) individuals.
Results: In erythrodermic CTCL, we found strong expansion of CD4+ malignant clones with a CCR7+SELL+ central memory phenotype. By contrast, CIE exhibited a pattern of low-level, but consistent expansion of CD8A+KLRK1+ T-cell clones, both in blood and skin. KLRK1 was also expressed by CCR10+FUT7+ skin-homing CIE blood T-cells that had increased proliferation rates and were absent in all other conditions. While CIE and CTCL patients lacked the strong type 2 or type 17 immune skewing typically found in AD or psoriasis, respectively, they were characterized by upregulation of MHC II genes (HLA-DRB1, HLA-DRA, CD74) in keratinocytes and fibroblasts, most likely in an IFNG-dependent fashion. However, we found strongest upregulation of type 1 immune mediators in CIE samples, both in the expanded CD8A+ clones, as well as in the tissue microenvironment.
Conclusion: Despite the notion that CIE might be a mere bundle of various yet uncharacterized disease processes, we found specific pathogenic signatures in these patients, that were different from other forms of erythroderma. These data might help to improve our pathogenic understanding of the blood and skin compartments of CIE, aiding in discovery of future treatment targets.
期刊介绍:
The Journal of Allergy and Clinical Immunology is a prestigious publication that features groundbreaking research in the fields of Allergy, Asthma, and Immunology. This influential journal publishes high-impact research papers that explore various topics, including asthma, food allergy, allergic rhinitis, atopic dermatitis, primary immune deficiencies, occupational and environmental allergy, and other allergic and immunologic diseases. The articles not only report on clinical trials and mechanistic studies but also provide insights into novel therapies, underlying mechanisms, and important discoveries that contribute to our understanding of these diseases. By sharing this valuable information, the journal aims to enhance the diagnosis and management of patients in the future.