Single-cell sequencing delineates T-cell clonality and pathogenesis of the parapsoriasis disease group
Natalia Alkon, Sumanth Chennareddy, Emry R. Cohenour, J. Ruggiero, Georg Stingl, Christine Bangert, Katharina Rindler, Wolfgang Bauer, Wolfgang Weninger, Johannes Griss, Constanze Jonak, Patrick M. Brunner
Abstract
Background Mycosis fungoides (MF), the most common cutaneous T-cell lymphoma, is often underdiagnosed in early stages because of similarities with benign dermatoses such as atopic dermatitis (AD). Furthermore, the delineation from what is called "parapsoriasis en plaque", a disease that can appear either in a small- or large-plaque form, is still controversial. Objective We sought to 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 Six 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. In contrast, 6 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 + IL-13 expressing "T H 2A" cells, or strong type 17 inflammation, respectively. Conclusion These data position polyclonal small- and large-plaque parapsoriasis lesions as a separate disease entity that characteristically harbors a so far undescribed innate lymphoid cell population. We thus propose a new term, "polyclonal parapsoriasis en plaque", for this kind of lesion because they can be clearly differentiated from early- and advanced-stage MF, psoriasis, and AD on several cellular and molecular levels.