Global skin gene expression analysis of early diffuse cutaneous systemic sclerosis shows a prominent innate and adaptive inflammatory profile

Abstract

ObjectivesDetermine global skin transcriptome patterns of early diffuse systemic sclerosis (SSc) and how they differ from later disease.MethodsSkin biopsy RNA from 48 patients in the Prospective Registry for Early Systemic Sclerosis (PRESS) cohort (mean disease duration 1.3 years) and 33 matched healthy controls was examined by next-generation RNA sequencing. Data were analysed for cell type-specific signatures and compared with similarly obtained data from 55 previously biopsied patients in Genetics versus Environment in Scleroderma Outcomes Study cohort with longer disease duration (mean 7.4 years) and their matched controls. Correlations with histological features and clinical course were also evaluated.ResultsSSc patients in PRESS had a high prevalence of M2 (96%) and M1 (94%) macrophage and CD8 T cell (65%), CD4 T cell (60%) and B cell (69%) signatures. Immunohistochemical staining of immune cell markers correlated with the gene expression-based immune cell signatures. The prevalence of immune cell signatures in early diffuse SSc patients was higher than in patients with longer disease duration. In the multivariable model, adaptive immune cell signatures were significantly associated with shorter disease duration, while fibroblast and macrophage cell type signatures were associated with higher modified Rodnan Skin Score (mRSS). Immune cell signatures also correlated with skin thickness progression rate prior to biopsy, but did not predict subsequent mRSS progression.ConclusionsSkin in early diffuse SSc has prominent innate and adaptive immune cell signatures. As a prominently affected end organ, these signatures reflect the preceding rate of disease progression. These findings could have implications in understanding SSc pathogenesis and clinical trial design.

Chromatin accessibility landscapes of skin cells in systemic sclerosis nominate dendritic cells in disease pathogenesis

“…5a, b, P value = 0.0001, one-sided Mann-Whitney U test). Gene expression profiles from multiple published studies 26,33,34 have also shown that gene ZBTB46 were significantly higher expressed in SSc skin versus normal skin ( Fig. 5c, P value = 0.0002, 0.003, 0.00001, one-sided Mann-Whitney U test).…”

“…The time points Low and High can be different for different patients. In this analysis, 13 patients whose highest mRSS -lowest mRSS > 5 were included (patients' ID 03, 04, 05, 06, 10,16,17,21,30,33,37,42,45).…”

“…test P value = 0.003 U test P value = 0.00001Assassi S., et al, 2015 Hinchcliff M., et al, 2013Skaug B., et al (2020 c Conventional dendritic cells were more infiltrated in affected compare with normal skin. (a) Immunohistochemistry analysis of ZBTB46 expression in normal and affected skin from SSc patient.…”

“…Modified Rodnan skin score (mRSS) and bulk skin cell gene expression data of lesion skin biopsies of the SSc patients in treatment of mycophenolate mofetil (MMF), the accession number is GSE76886 26 ; (3). Bulk skin cell gene expression data of normal and lesion skin, the accession numbers are GSE130955 33 , GSE58095 34 . Other data used in our paper: (1).…”

Genomic Risk Score impact on susceptibility to systemic sclerosis

“…22 Functional defects or genetic susceptibility variants located in relevant genes for dendritic cells, macrophages and B cells have been described in patients with SSc. [39][40][41][42][43] T cell subtypes were relevant covariates in the model initially, but no T cell subset was selected for the multivariate model (online supplemental tables 2-4). Considering the central role of T cells in SSc, we hypothesise that since we could not include the Th1, Th2 or Th17 fractions in the model, this effect might have been overlooked.…”