Single cell sequencing delineates T-cell clonality and pathogenesis of the parapsoriasis disease group

Background: Mycosis fungoides (MF), the most common cutaneous T-cell lymphoma, is often underdiagnosed in early stages due to similarities with benign dermatoses such as atopic dermatitis (AD). Furthermore, the delineation from so-called “parapsoriasis en plaque,” a disease that can appear either in a small- or large-plaque form, is still controversial. Here, we characterize the parapsoriasis disease spectrum. Methods: We performed single-cell RNA sequencing of skin biopsies from patients within the parapsoriasis-to-early-stage MF spectrum, stratified for small and large plaques, and compared them to AD, psoriasis and healthy control skin. Results: 6 out of 8 large-plaque lesions harbored either an expanded alpha/beta or gamma/delta T-cell clone with downregulation of CD7 expression, consistent with a diagnosis of early-stage MF. By contrast, 6 out of 7 small-plaque lesions were polyclonal in nature thereby lacking a lymphomatous phenotype, and also revealed a less inflammatory microenvironment than early-stage MF or AD. Of note, polyclonal small- and large-plaque lesions characteristically harbored a population of NPY+ innate lymphoid cells and displayed a stromal signature of complement upregulation and antimicrobial hyperresponsiveness in fibroblasts and sweat gland cells, respectively. These conditions were clearly distinct from AD or psoriasis, which uniquely harbored CD3+CRTH2+ IL13-expressing “Th2A” cells or strong type 17 inflammation, respectively. Conclusion: These data position polyclonal small- and large-plaque dermatitis lesions as a separate disease entity, that characteristically harbors a so far undescribed ILC population. We thus propose the new term “polyclonal parapsoriasis en plaque” to this kind of lesions, as they can be clearly differentiated from early and advanced-stage MF, psoriasis and AD on several cellular and molecular levels. Comparison of skin cells obtained from AD, PP and MF patients. Healthy Control samples from the trunk area 112 – HC1, 115 – HC2, 116 – HC3 and 121 – HC4 used in this manuscript, which are already publicly available via Gene Expression Omnibus GSE173205, were updated using the newer Cell Ranger version (v. 6.1.2; 10x Genomics) for consistency reasons: AD samples 74 – AD1, 75 – AD2, 77 – AD3, 81 – AD4 and 96 – AD5 used in this manuscript are also a part of publicly available dataset (Gene Expression Omnibus GSE222840, manuscript "Single-cell RNA sequencing defines disease-specific differences between chronic nodular prurigo and atopic dermatitis") *************************************************************** Submitter states that missing raw files are due to patient privacy concerns. ***************************************************************