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bioRxiv · 10.1101/2021.01.10.426131

Distinct T cell chromatin landscapes in scleroderma subtypes

Dou, D. R.·Zhao, Y.·Abe, B.·Li, R.·Zaba, L. C.·Aren, K.·Carns, M.·Chung, L. S.·Hinchcliff, M.·Chang, H. Y.
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Abstract

ObjectivesSystemic sclerosis (SSc; scleroderma) disproportionately affects biological females, and results of multiple studies implicate lymphocyte derangements in disease pathogenesis supporting use of mycophenolate mofetil (MMF) treatment. Here, we surveyed chromatin accessibility of circulating CD4+ T lymphocytes from SSc patients commencing MMF to gain molecular insights into systemic immune activation. MethodsPeripheral blood samples were collected longitudinally. We used the Assay for Transposase-Accessible Chromatin by sequencing (ATAC-seq) to interrogate genome-wide chromatin accessibility profiles of peripheral CD4+ T cells compared with publicly available healthy control (HC) data. ResultsATAC-seq libraries were generated for 18 SSc patients [78% with diffuse cutaneous (dc), 78% female, and 17% + anticentromere autoantibodies (ACA)]. Disease status (SSc vs. HC), biological sex, and serum autoantibody type were significantly associated with CD4+ T cell epigenomic profile variability, while MMF treatment had no significant effect. Present serum ACAs associated with elevated T helper 2 (Th2) cell proportions. +ACA patients consistently displayed distinct epigenetic profiles of increased open chromatin at gene loci encoding fibrosis-driving Th2 cytokines IL-4, IL-13, and the IL-4 receptor. ConclusionsOur results demonstrate the utility of interrogating chromatin accessibility profiles of patient CD4+ cells to stratify and understand better clinical SSc heterogeneity. They highlight a potential mechanism underlying the female sex preponderance for SSc as females had more open chromatin. Our findings nominate Th2 cell activation as a novel mechanistic hallmark and therapeutic opportunity to address SSc, especially in those with +ACA.

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Dou, D. R., Zhao, Y., Abe, B., Li, R., Zaba, L. C., Aren, K., Carns, M., Chung, L. S., Hinchcliff, M., Chang, H. Y.. 2021-01-11. Distinct T cell chromatin landscapes in scleroderma subtypes. https://doi.org/10.1101/2021.01.10.426131

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