Pathogenesis of Systemic Sclerosis

Abstract

Systemic scleroderma (SSc) is one of the most complex systemic autoimmune diseases. It targets the vasculature, connective tissue-producing cells (namely fibroblasts/myofibroblasts), and components of the innate and adaptive immune systems. Clinical and pathologic manifestations of SSc are the result of: (1) innate/adaptive immune system abnormalities leading to production of autoantibodies and cell-mediated autoimmunity, (2) microvascular endothelial cell/small vessel fibroproliferative vasculopathy, and (3) fibroblast dysfunction generating excessive accumulation of collagen and other matrix components in skin and internal organs. All three of these processes interact and affect each other. The disease is heterogeneous in its clinical presentation that likely reflects different genetic or triggering factor (i.e., infection or environmental toxin) influences on the immune system, vasculature, and connective tissue cells. The roles played by other ubiquitous molecular entities (such as lysophospholipids, endocannabinoids, and their diverse receptors and vitamin D) in influencing the immune system, vasculature, and connective tissue cells are just beginning to be realized and studied and may provide insights into new therapeutic approaches to treat SSc.

Niclosamide Prevents Systemic Sclerosis in a Reactive Oxygen Species–Induced Mouse Model

“…ystemic sclerosis (SSc) is a connective tissue disorder characterized by fibrosis of the skin and inner organs, vascular alterations, and dysimmunity including the presence of autoantibodies to nuclear proteins (1). The cause of this disease remains unknown, and its understanding is further complicated by its inherent heterogenous clinical manifestations (2).…”

Hearing loss in systemic sclerosis - clinically important, potentially treatable and often overlooked

“…Systemic sclerosis (SSc) is one of the most complex systemic autoimmune diseases [1] characterized by cutaneous and visceral fibrosis, immune dysregulation and vasculopathy [2]. The interplay of these three processes determines the clinical and pathologic manifestations of the disease [1].…”

“…The interplay of these three processes determines the clinical and pathologic manifestations of the disease [1]. The core signs and symptoms of SSc are Raynaud's phenomenon, skin thickening and serum autoantibody production, but patients have different patterns of internal organ involvement with variable presentations and outcomes [3].…”

Vitamin D and Myofibroblasts in Fibrosis and Cancer: At Cross-purposes with TGF-β/SMAD Signaling

“…Vitamin D has been extensively studied as an anti-fibrotic agent in non-neoplastic chronic diseases and a number of studies have shown that the myofibroblast is a main target cell of 1,25(OH) 2 D 3 inhibitory action (reviewed in 45,46). A main and recurring finding has been that 1,25(OH) 2 D 3 interferes with the pervasive pro-fibrotic action of TGF-β: this inhibitory effect is predictable since calcitriol, on its own, represses collagen synthesis in a variety of cells (47,48).…”