New insights into the pathogenesis of systemic sclerosis
Introduction
Systemic sclerosis (SSc) is characterized by skin and visceral fibrosis, and vascular abnormalities including Raynaud's phenomenon, pulmonary arterial hypertension (PAH) and renal crisis [1]. Extracellular matrix overproduction by fibroblasts is the hallmark of SSc. Collagen accumulation results from abnormal interactions among endothelial cells (EC), mononuclear cells (lymphocytes and monocytes) and fibroblasts leading to the production of fibrosis-inducing cytokines, in a setting of vascular hyperreactivity and tissue hypoxia (Fig. 1) [2]. Numerous autoantibodies have been identified in the serum of SSc patients, but their pathogenetic role(s) remains uncertain. Finally, alloreactivity, together with genetic and environmental factors could contribute to disease susceptibility.
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Cells and cytokines involved in the pathogenesis of SSc
SSc fibroblasts are activated and overproduce extracellular matrix proteins, such as collagens I, III, V, VI and VII, tenascin, proteoglycans, fibronectin, laminin and fibrillin-1 [3]. Myofibroblasts which can differentiate from fibroblasts in the presence of thrombin are mainly responsible for increased collagen production [4]. Collagen synthesis is dependent on transforming growth factor-beta (TGF-β) a cytokine produced by fibroblasts and EC, and on connective tissue growth factor (CTGF),
Autoantibodies
Autoantibodies to cellular components are detected in most SSc patients. Three of these autoantibodies are disease-specific and mutually exclusive; anti-centromere Ab (ACA), anti-topoisomerase 1 Ab (ATA) and anti-RNA polymerase (RNAP) III Ab. Other autoantibodies have been identified in SSc patients, directed against nucleolar, cytoplasm, membrane structures, extracellular matrix components, fibroblasts and/or EC.
Microchimerism
Several studies have shown an association between the development of SSc in women sometimes after pregnancy and the detection of fetal cells in peripheral blood [36], [37]. These results led to the hypothesis that SSc may be the consequence of an allogeneic fetomaternal reaction that might be a manifestation of an intergenerational HLA incompatibility [36], [37]. However, certain normal female controls also exhibit microchimerism, and its role in SSc remains unproven, but it probably
Genetic and environmental factors
With insufficient evidence supporting an environmental cause, recent attention has focused on the role of genetic factors in the occurrence of SSc. Thus, a positive family history is the strongest risk factor yet identified for SSc [38]. Human leukocyte antigen associations exist but more closely reflect the presence of particular autoantibodies than SSc and no single major histocompatibility complex allele predisposes to SSc in all ethnic groups. The fibrillin-1 gene, that is partially
Acknowledgements
This work was supported by the Association des Sclérodermiques de France and INSERM (CReS No. 4CR08F). Y. Chanseaud was funded by the Ministère de l'Enseignement Supérieur et de la Recherche, France.
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