Abstract
Systemic sclerosis (SSc) is a multi-system autoimmune disease with tissue fibrosis prominent in the skin and lung. In this review, we briefly describe the autoimmune features (mainly autoantibody production and cytokine profiles) and the potential pathogenic contributors including genetic/epigenetic predisposition, and environmental factors. We look in detail at the cellular and molecular bases underlying tissue-fibrosis which include trans-differentiation of fibroblasts (FBs) to myofibroblasts (MFBs). We also state comprehensively the pro-inflammatory and pro-fibrotic cytokines relevant to MFB trans-differentiation, vasculopathy-associated autoantibodies, and fibrosis-regulating microRNAs in SSc. It is conceivable that tissue fibrosis is mainly mediated by an excessive production of TGF-β, the master regulator, from the skewed Th2 cells, macrophages, fibroblasts, myofibroblasts, and keratinocytes. After binding with TGF-β receptors on MFB, the downstream Wnt/β-catenin triggers canonical Smad 2/3 and non-canonical Smad 4 signaling pathways to transcribe collagen genes. Subsequently, excessive collagen fiber synthesis and accumulation as well as tissue fibrosis ensue. In the later part of this review, we discuss limited data relevant to the role of long non-coding RNAs (lncRNAs) in tissue-fibrosis in SSc. It is expected that these lncRNAs may become the useful biomarkers and therapeutic targets for SSc in the future. The prospective investigations in the development of novel epigenetic modifiers are also suggested.
Highlights
Systemic sclerosis (SSc) is a systemic autoimmune disease characterized by the presence of a broad spectrum of autoantibodies, vascular endothelial damage, non-infective inflammation, and tissue fibrosis in the skin and internal organs, especially the lungs [1,2,3,4,5,6,7,8]
B lymphocytes are activated by Th2-derived cytokines, IL-4 and IL-5, as well as macrophage-derived IL-6 to produce diverse autoantibodies that result in vascular endothelial cell damage, tissue ischemia, and chronic inflammation, and eventually tissue fibrosis [8]
Benyamine et al [15] have found that SSc-derived natural killer (NK) cells with a particular phenotype of low expression of CXCR4, NKG2D, and CD69 are the potent inducer of endothelial microparticle release by the activated endothelial cells
Summary
Systemic sclerosis (SSc) is a systemic autoimmune disease characterized by the presence of a broad spectrum of autoantibodies, vascular endothelial damage, non-infective inflammation, and tissue fibrosis in the skin and internal organs, especially the lungs [1,2,3,4,5,6,7,8]. The autoantibody profiles relevant to respective clinical manifestations and pathological processes in SSc patients are listed in Table 1 [16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43] Among these autoantibodies, anti-scleroderma 70 (anti-Scl-70) or anti-double-stranded DNA topoisomerase 1 (anti-TOPO-1), and anti-centromere proteins (anti-CENPs) are the marker autoantibodies of the patients with SSc and its variant, CREST syndrome (acronymed from calcinosis, Raynaud’s phenomenon, esophageal dysmotility, sclerodactidy, and telangiectasis). Autoantibody Anti-topoisomerase 1 (anti-Scl-70) Anti-centromere proteins B and C
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