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

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.