Abstract
Systemic sclerosis (SSc) is a chronic connective tissue disorder characterized by immune dysregulation, chronic inflammation, vascular endothelial cell dysfunction, and progressive tissue fibrosis of the skin and internal organs. Moreover, increased cancer incidence and accelerated aging are also found. The increased cancer incidence is believed to be a result of chromosome instability. Accelerated cellular senescence has been confirmed by the shortening of telomere length due to increased DNA breakage, abnormal DNA repair response, and telomerase deficiency mediated by enhanced oxidative/nitrative stresses. The immune dysfunctions of SSc patients are manifested by excessive production of proinflammatory cytokines IL-1, IL-6, IL-17, IFN-α, and TNF-α, which can elicit potent tissue inflammation followed by tissue fibrosis. Furthermore, a number of autoantibodies including anti-topoisomerase 1 (anti-TOPO-1), anti-centromere (ACA or anti-CENP-B), anti-RNA polymerase enzyme (anti-RNAP III), anti-ribonuclear proteins (anti-U1, U2, and U11/U12 RNP), anti-nucleolar antigens (anti-Th/T0, anti-NOR90, anti-Ku, anti-RuvBL1/2, and anti-PM/Scl), and anti-telomere-associated proteins were also found. Based on these data, inflamm-aging caused by immune dysfunction-mediated inflammation exists in patients with SSc. Hence, increased cellular senescence is elicited by the interactions among excessive oxidative stress, pro-inflammatory cytokines, and autoantibodies. In the present review, we will discuss in detail the molecular basis of chromosome instability, increased oxidative stress, and functional adaptation by deranged immunome, which are related to inflamm-aging in patients with SSc.
Highlights
Systemic sclerosis (SSc) is a complex multi-system autoimmune disease characterized by chronic inflammation and tissue fibrosis in the skin and internal organs [1–3]
The underlying molecular mechanism of SSc remains unclear until now. This heterogenous autoimmune disorder is featured by immune dysregulation, inflammation, and endothelial cell dysfunction followed by defective vascular repair, neovascularization, and tissue fibrosis [4,5]
Roberts-Thomson P.J. and Walker J.G. [59] speculated that these stochastic processes might result in acquired somatic mutations or epigenetic alterations that affect the genes coding for immune receptors, tolerogenic threshold, or proteins involved in immune regulation, inflammation, and/or repair
Summary
Systemic sclerosis (SSc) is a complex multi-system autoimmune disease characterized by chronic inflammation and tissue fibrosis in the skin and internal organs (especially the lung) [1–3]. The underlying molecular mechanism of SSc remains unclear until now This heterogenous autoimmune disorder is featured by immune dysregulation, inflammation, and endothelial cell dysfunction followed by defective vascular repair, neovascularization, and tissue fibrosis [4,5]. To the other systemic autoimmune diseases, the pathogenesis of SSc includes genetics/epigenetics, transcriptomics/proteomics/metabolomics, environmental/stochastic factors, immune dysfunction-mediated inflammation, and the factors mediating cell senescence or inflammaging [4,5,10–12] The latter factors include excessive oxidative stresses [13–16], chronic inflammation [17,18], vascular insufficiency [19,20], autoantibody formation [21], DNA damage/DNA damage responses [22], and telomere shortening [23]. Especially the MHC class II, may play important roles in the development of SSc, the concordant rate of SSc in monozygotic twins is only 4.27% [32] This rate is much lower than rheumatoid arthritis (12.3%) [33], multiple sclerosis (16.7%) [34], systemic lupus erythematosus (25%) [35], or primary biliary cirrhosis (77%) [36].
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