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. 2025 Mar;155(3):892-908.
doi: 10.1016/j.jaci.2024.11.037. Epub 2024 Dec 16.

Single-cell RNA sequencing of chronic idiopathic erythroderma defines disease-specific markers

Sumanth Chennareddy  1 , Katharina Rindler  2 , Shannon Meledathu  1 , Malini P Naidu  1 , Natalia Alkon  2 , John R Ruggiero  1 , Lisa Szmolyan  1 , Wolfgang Weninger  2 , Wolfgang M Bauer  2 , Johannes Griss  2 , Constanze Jonak  3 , Patrick M Brunner  4
Affiliations
Free article

Single-cell RNA sequencing of chronic idiopathic erythroderma defines disease-specific markers

Sumanth Chennareddy et al. J Allergy Clin Immunol. 2025 Mar.
Free article

Abstract

Background: Chronic erythroderma is a potentially life-threatening condition that can be caused by various diseases, but approximately 30% of cases remain idiopathic, often with insufficient treatment options.

Objective: We sought to establish a molecular disease map of chronic idiopathic erythroderma (CIE).

Methods: We performed single-cell RNA sequencing combined with T-cell receptor sequencing of blood and skin from 5 patients with CIE and compared results with 8 cases of erythrodermic cutaneous T-cell lymphoma (eCTCL), 15 cases of moderate to severe atopic dermatitis, 10 cases of psoriasis, and 20 healthy control individuals.

Results: In eCTCL, we found strong expansion of CD4+ malignant clones with a CCR7+SELL+ central memory phenotype. In contrast, CIE exhibited a pattern of low-level, but consistent, expansion of CD8A+KLRK1+ T-cell clones, both in blood and in 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 patients with CIE and eCTCL lacked the strong type 2 or type 17 immune skewing typically found in atopic dermatitis or psoriasis, respectively, they were characterized by upregulation of MHC II genes (HLA-DRB1, HLA-DRA, and CD74) in keratinocytes and fibroblasts, most likely in an IFN-γ-dependent fashion. Overall, we found the strongest upregulation of type 1 immune mediators in CIE samples, both in the expanded CD8A+ clones and in the tissue microenvironment.

Conclusions: Despite the notion that CIE might be a mere bundle of various yet uncharacterized disease processes, we found specific pathogenic signatures in these patients, which 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.

Keywords: Erythroderma; atopic dermatitis; chronic idiopathic erythroderma; cutaneous T-cell lymphoma; erythrodermic cutaneous T-cell lymphoma; single-cell RNA sequencing.

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Conflict of interest statement

Disclosure statement This work was funded by a research grant to P.M.B. from the LEO Foundation (grant no. LF-OC-20-000621), the Austrian Science Fund (grant no. KLI 849-B), and the Medical Scientific Fund of the Mayor of the City of Vienna (grant no. 19067). S.C. was supported by the National Center for Advancing Translational Sciences National Research Service Award TL1 in the Clinical and Translational Science Award (award no. TL1TR004420). This work was supported in part through the computational and data resources and staff expertise provided by Scientific Computing and Data at the Icahn School of Medicine at Mount Sinai, New York, and supported by the Clinical and Translational Science Award (grant no. UL1TR004419) from the National Center for Advancing Translational Sciences. Disclosure of potential conflict of interest: C. Jonak has received personal fees from LEO Pharma, Pfizer, Recordati Rare Diseases, Eli Lilly, Novartis, Takeda, AbbVie, Janssen, UCB, STADA, Kyowa Kirin, Bristol Myers Squibb, Stemline, and Almirall; and is an investigator for Eli Lilly, Boehringer Ingelheim, Novartis, Innate Pharma, Incyte, AbbVie, and 4SC (grant paid to her institution). W. Weninger has received personal fees from LEO Pharma, Pfizer, Sanofi-Genzyme, Eli Lilly, Novartis, Boehringer Ingelheim, AbbVie, and Janssen. W. M. Bauer has received personal fees and travel grants from ViiV Healthcare, Gilead, AbbVie, Takeda, and MSD. J. Griss has received personal fees from AbbVie, Eli Lilly, Pfizer, Boehringer Ingelheim, and Novartis. P. M. Brunner has received personal fees from Almirall, Sanofi, Janssen, Amgen, LEO Pharma, AbbVie, Pfizer, Boehringer Ingelheim, GlaxoSmithKline, Regeneron, Eli Lilly, Celgene, Arena Pharma, Novartis, UCB Pharma, Biotest, and BMS; has received research support from Pfizer (grant paid to his institution), and is an investigator for Pfizer and AbbVie. The rest of the authors declare that they have no relevant conflicts of interest.