Gene expression profiling offers insights into the role of innate immune signaling in SSc

Abstract

Systemic sclerosis (SSc) is characterized by inflammation, vascular dysfunction, and ultimately fibrosis. Progress in understanding disease pathogenesis and developing effective disease treatments has been hampered by an incomplete understanding of SSc heterogeneity. To clarify this, we have used genomic approaches to identify distinct patient subsets based on gene expression patterns in SSc skin and other end-target organs. Here, we review what is known about the gene expression-based subsets in SSc, currently defined as the inflammatory, fibroproliferative, limited, and normal-like subsets. The inflammatory subset of patients is characterized by infiltrating immune cells that include T cells, macrophages, and possibly dendritic cells, although little is known about the mediators these cells secrete and the pathways that govern cell activation. Prior studies have suggested a role for pathogens as a trigger of immune responses in SSc, and recent data have identified viral and mycobiome components as potential environmental triggers. We present a model based on analyses of gene expression data and a review of the literature, which suggests that the gene expression subsets observed in patients possibly represent distinct, interconnected molecular states of disease, to which an innate immune response is central that results in the generation of clinical disease.

Fig. 1

Pathway activation signatures show differential expression across the intrinsic gene expression subsets. a Normal and SSc dermal fibroblasts were treated with different pro-fibrotic and immune mediators that have been implicated in SSc. A subset of pathways and fibroblast time courses is shown. b Hierarchical clustering was performed on 329 microarray hybridizations from 287 unique biopsies representing 111 patients: 70 dSSc, 10 lSSc, 26 healthy controls, 4 morphea, and 1 eosinophilic fasciitis from three independent data sets [–3], as published in [24]. The array tree is color coded to indicate intrinsic subset designations (yellow = limited, green = normal-like, purple = inflammatory, red = fibroproliferative, and black = unassigned). Pearson correlation coefficients were calculated between each pathway and a sample and plotted. Adapted from Johnson et al. PLoS One (2015) with permission [24]

Fig. 2

Progressive model of SSc pathogenesis. 1 In this model, SSc pathogenesis is initiated by a disease trigger in a permissive genetic background, resulting in an innate immune response signaling through NF-κB. These early responses may be mediated in part through pDCs and macrophages, which induce the expression of T_H2-like cytokines, along with fibrotic mediators, such as TGF-β. 2 This early T_H2 bias results in persistent M2 macrophage activation, which further exacerbates the fibrotic phenotype. 3 Over time, the gradual decrease in pDC involvement results in a loss of IFN-α signaling, 4 resulting in transition to a more T_H17-like disease and the suppression of T_reg function. 5 This persistent inflammation further perpetuates the chronic fibrosis phenotype driven by TGF-β, which then stimulates production of pro-fibrotic PDGF. 6 Eventual resolution of inflammation allows for downregulation of innate immune responses. 7 Continued proliferation is supported through differentiation of resident adipocytes into fibroblasts, resulting in a persistent replicative phenotype, in combination with a decrease in lipid signaling. 8 Exhaustion of the adipocyte layer results in the loss of proliferating cells, ultimately resulting in transition to a more quiescent form of the disease