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.
Highlights
Systemic sclerosis (SSc, scleroderma) is a complex connective tissue disease of unknown etiology with multiorgan involvement and heterogeneous clinical manifestations
It is unclear whether the innate/adaptive immune system abnormalities, vasculopathy, and fibroblast dysfunctions are separate, unrelated processes or are mechanistically linked, which of the three processes is of utmost importance and how interaction among the three processes leads to the development of the disease
A Japanese case–control association study with 281 Systemic scleroderma (SSc) and 477 controls found that rs2004640, rs10954213, and rs2280714 were all significantly associated with SSc, with rs2280714 having the strongest association with SSc, and these single nucleotide polymorphisms (SNPs) were significantly enriched in diffuse cutaneous systemic scleroderma (dcSSc) and ATApositive patients [45]
Summary
Systemic sclerosis (SSc, scleroderma) is a complex connective tissue disease of unknown etiology with multiorgan involvement and heterogeneous clinical manifestations. There are many unresolved questions related to the etiopathogenesis of SSc. There are many unresolved questions related to the etiopathogenesis of SSc It is unclear whether the innate/adaptive immune system abnormalities, vasculopathy, and fibroblast dysfunctions are separate, unrelated processes or are mechanistically linked, which of the three processes is of utmost importance and how interaction among the three processes leads to the development of the disease. Subtypes DPB1*1301 and DPB1*0901 were most common in Korean patients with SSc, while DPB1*03:01, DPB1*13:01, DQB1*03:03, DQB1*05:01, and DQB1*06:11 were significantly increased in the Chinese SSc patient population [26] Those who carried the DPB1*03:01 had a higher chance of developing pulmonary fibrosis verses those who carried DPB1*04, and those SSc patients were more likely to be ACA positive [112]. No association PF, DU, sclerodactyly, myositis, SICCA dcSSc PF Renal crisis dcSSc
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