The Pathogenesis of Systemic Sclerosis: An Understanding Based on a Common Pathologic Cascade across Multiple Organs and Additional Organ-Specific Pathologies

Abstract

Systemic sclerosis (SSc) is a multisystem autoimmune and vascular disease resulting in fibrosis of various organs with unknown etiology. Accumulating evidence suggests that a common pathologic cascade across multiple organs and additional organ-specific pathologies underpin SSc development. The common pathologic cascade starts with vascular injury due to autoimmune attacks and unknown environmental factors. After that, dysregulated angiogenesis and defective vasculogenesis promote vascular structural abnormalities, such as capillary loss and arteriolar stenosis, while aberrantly activated endothelial cells facilitate the infiltration of circulating immune cells into perivascular areas of various organs. Arteriolar stenosis directly causes pulmonary arterial hypertension, scleroderma renal crisis and digital ulcers. Chronic inflammation persistently activates interstitial fibroblasts, leading to the irreversible fibrosis of multiple organs. The common pathologic cascade interacts with a variety of modifying factors in each organ, such as keratinocytes and adipocytes in the skin, esophageal stratified squamous epithelia and myenteric nerve system in gastrointestinal tract, vasospasm of arterioles in the heart and kidney, and microaspiration of gastric content in the lung. To better understand SSc pathogenesis and develop new disease-modifying therapies, it is quite important to understand the complex pathogenesis of SSc from the two distinct perspectives, namely the common pathologic cascade and additional organ-specific pathologies.

Keywords: a common pathologic cascade across multiple organs; additional organ-specific pathologies; systemic sclerosis.

Figure 1

The SSc-specific common pathologic cascade across multiple organs. The accumulation of predisposing factors through the interaction of genetic factors and environmental influences induces the phenotypical alterations of immune cells, vascular cells and interstitial fibroblasts. Vascular injury due to autoimmune attacks and unknown environmental influences triggers the SSc-specific common pathologic cascade across multiple organs, starting with vascular activation and vascular structural abnormalities, and subsequently resulting in chronic inflammation and the related activation of interstitial fibroblasts derived from various sources. pDCs, plasmacytoid dendritic cells; DCs, dendritic cells; TGF-β, transforming growth factor-β; Th, T helper; EndoMT, endothelial-to-mesenchymal transition; EMT, epithelial-to-mesenchymal transition; AMT, adipocyte-to-myofibroblast transdifferentiation.

Figure 2

The role of vasculopathy bridging between immune abnormalities and fibrosis. Initial vascular injury is caused by autoimmune attacks and unknown environmental influences. Vascular injury results in structural and functional abnormalities in the vasculature characteristic of SSc. Structural abnormalities are classified into arteriolar stenosis, capillary dilation and capillary loss, which are attributable to impaired angiogenesis and defective vasculogenesis. The functional abnormalities include endothelial dysfunction, primarily due to the low availability of nitric oxide (NO), the altered expression of cell adhesion molecules inducing the infiltration of Th2 and Th17 cells, mast cells and macrophages, the activated endothelial-to-mesenchymal transition (EndoMT) leading to fibro-proliferative vascular change and tissue fibrosis, the impairing of the coagulation/fibrinolysis system promoting the formation of intravascular fibrin deposits, and the excessive production of reactive oxygen species (ROS). These vascular changes eventually induce the constitutive activation of interstitial fibroblasts in multiple organs. ICAM-1; intercellular cell adhesion molecule-1, GlyCAM-1; glycosylation-dependent cell adhesion molecule-1, vWF; von Willebrand factor, TGF-β; transforming growth factor-β, CTGF; connective tissue growth factor, PDGF; platelet-derived growth factor, ECs; endothelial cells, vSMCs; vascular smooth muscle cells, PAH; pulmonary arterial hypertension, DUs; digital ulcers, SRC; scleroderma renal crisis.

Figure 3

The interaction of the common pathologic cascade with the skin-specific pathology of SSc. The SSc-specific common pathologic cascade is modified by keratinocytes and adipocytes. Keratinocytes produce various factors related to fibroblast activation. Adipocytes serve as a potential source of myofibroblasts by transdifferentiating into mesenchymal cells, and produce a variety of adipokines involved in SSc development.

Figure 4

The interaction of the common pathologic cascade with the esophagus-specific pathology in SSc. In addition to the SSc-specific common pathologic cascade, autoimmunity and vasculopathy affect the enteric nerve system through the anti-muscarinic acetylcholine receptor M3 antibody and tissue hypoxia, respectively, leading to dysmotility and hypomotility of the gastrointestinal tract. Persistent hypomotility promotes smooth muscle atrophy and the resultant fibrotic replacement, further contributing to the progression of gastrointestinal tract hypomotility. Esophageal squamous stratified epithelia may facilitate tissue fibrosis and functional heartburn by producing a variety of disease-associated molecules, such as cytokines and chemokines.