Pathogenic Roles of Autoantibodies and Aberrant Epigenetic Regulation of Immune and Connective Tissue Cells in the Tissue Fibrosis of Patients with Systemic Sclerosis

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.

Spermine-Related DNA Hypermethylation and Elevated Expression of Genes for Collagen Formation are Susceptible Factors for Chemotherapy-Induced Hand-Foot Syndrome in Chinese Colorectal Cancer Patients

“…An acceleration of changes to the metabolome may lead to a profibrotic phenotype characterized by the suppressed immune function, elevated cellular proliferation, and tissue fibrosis. Once Capecitabine-based chemotherapy is administrated, it adds to the existing hazard factors and causes severe tissue damage ( Tsai et al, 2020 ). Finally, the accumulated molecular changes lead to severe cellular proliferation and fibrosis of tissues, and ultimately to HFS.…”

Non-Coding RNA in Systemic Sclerosis: A Valuable Tool for Translational and Personalized Medicine

“…Besides lncRNAs, miRNAs, circRNAs, and piRNAs have been tremendously studied and confirmed to modulate gene transcription through pivotal activities in a versatile regulation network [54,55]. miRNAs are epigenetic regulators~22 nucleotides in length and function as intracellular regulators of gene expression at the post-transcriptional level by inducing transcription degradation or retarding RNA transferase activity through binding to a 30-untranslated region (30-UTR) of target mRNA [12], modification of histone [12], or modulation of methylation in the DNA promoter regions [12,73]. A single miRNA can regulate and/or silence the expression of hundreds of genes, while multiple miRNAs can regulate the expression of a single gene [74,75].…”

“…The pathological mechanism starts with microvascular injury due to a critical imbalance between proangiogenic and antiangiogenic factors [ 10 ]. Therefore, endothelial cell injury promotes autoimmune reactivity and perivascular injury, inducing activation of fibroblasts, tissue fibrosis, and, therefore, scleroderma-like disease [ 11 , 12 ].…”

“…The process starts with transforming growth factor-β (TGF-β) release and other cytokines. Increased levels of Th2 cytokines, such as TGF-β and IL-13, have been found in the tissues of SSc patients [ 12 , 13 , 14 ]. Therefore, they induce the differentiation of fibroblast and infiltration fibroblast in the activated form [ 15 ].…”

“…The population of myofibroblasts cells is heterogeneous that derives from several different cellular precursors [ 16 ]. They are activated by various signaling pathways such as TGF-β, Wnt/β-catenin, which triggers canonical Smad 2/3 and non-canonical Smad 4 signaling pathways, as well as a platelet-derived growth factor, and hedgehog signaling [ 12 , 16 ]. Moreover, B lymphocytes are activated by Th2-derived cytokines, such as IL-4 and IL-5, and IL-6, derived from macrophages to produce several types of autoantibodies that result in vascular endothelial cell damage, tissue ischemia, chronic inflammation, and eventually tissue fibrosis [ 12 , 17 ].…”